Topical Tretinoin: A Versatile Option for Adult Female Acne

Adult female acne can be challenging—from patients being frustrated at having to deal with acne for the first time or again at this stage of life, to being unsatisfied with treatments because they are irritating or ineffective. Achieving best outcomes and improving patient satisfaction requires physicians to understand patients’ treatment goals, to realistically set patient expectations regarding the effects of treatment, and to empower patients to be active and compliant in their care.

According to the Global Burden of Disease (GBD) study,¹ acne vulgaris affects ~85% of young adults aged 12–25 years. The disease has shown continuous progression, and according to the American Academy of Dermatology, 53.8 percent of patients with acne who present to a physician for treatment are in the 18- to 44-year-old age category.²

Recently, leading dermatologists gathered for a roundtable discussion to discuss strategies and tips for effective treatment, particularly in light of a recently approved FDA-approved topical treatment, ALTRENO™ (tretinoin) Lotion, 0.05%.

“Many of us know that about 4 in 5 people will experience acne at some point in their lives. And even many of our adult female patients who present for aesthetic treatments have acne,” says Sabrina Fabi, MD, a dermatologist in San Diego and roundtable moderator. Dr. Fabi says the first step in any treatment plan is starting the conversation and opening a dialogue with patients about their concerns and the fact that good, effective treatment options are available.

The first priority is to make sure that you don’t offend patients, says Jeanine Downie, MD, a dermatologist in Montclair, NJ. When patients present to her office for another concern such as removing a mole or to improve the appearance of wrinkles in their forehead with a neurotoxin injection, she says she makes sure to bring up acne if the patients show any signs of it. “If they’re worried about wrinkles in their forehead, etc., I’ll inject botulinum toxin and then I’ll say, ‘Oh, and by the way, you do realize what’s going to crop up in another week or whenever the botulinum toxin kicks in for you? Then you’re really going to be focused on those small little acne bumps you have up there because they’re going to become more noticeable as your wrinkles go away from use of the botulinum toxin.’ Typically, patients respond by saying they meant to ask me about their acne,” Dr. Downie says. “So I address their first concern first and then I’ll blend it into a conversation like that.”

She finds most patients are happy she addressed the concern and learn about treatment because for most patients with visible acne, it likely bothers and frustrates them.

Diane Berson, MD, who practices in New York City, agrees. Dr. Berson says she has a similar approach. She always asks patients about their skincare regimens and finds acne comes up with a majority of her patients. “Honestly, most everyone really gets acne to some degree. Invariably, it becomes a discussion mostly for my patients, but also about my patients’ kids—there’s often a conversation about acne,” says Dr. Berson. “Obviously when discussing acne therapy there are a few things that are relevant, especially for adult women. Retinoids are usually first-line therapy targeting acne. Women prefer skincare products that are cosmetically elegant. Vehicles and formulations are key for products used on aging skin, including moisturizers, sunscreens, and makeup. We can choose the best vehicle for each patient’s skin type.”

Doris Day, MD, who also has a practice in New York City, finds she never has to worry about starting the conversation. “In my practice, if a patient has one pimple they want to make sure it doesn’t leave a mark behind and they want to make sure more pimples don’t follow. They want their skin to be as clear as possible. It’s not like I have to worry about bringing it up, if they’re in for something else, they will say, ‘I’m here for my botulinum toxin but this pimple is driving me crazy and I’m worried it will get worse.’ They’re very sensitive about appearance and about a pimple leaving a scar,” Dr. Day says.

Erin Gilbert, MD says that no matter what a patient is coming to her office for, she starts the visit by discussing everything they are already using in their daily skincare routines, which can trigger a discussion about a concern like acne. “If they’re coming in and they’re getting injections with me I also sit down and say, ‘Okay, we’re going to break it up into morning and evening, what products do you use? Do you have any concerns about those products? Do you want to talk about changing those products?’ So that’s an opportunity for me to make suggestions. I ask them if they’re using a retinoid for their acne and if they are appropriate for a retinoid but not on one, I get them on a retinoid,” says Dr. Gilbert, who also practices in New York.

Ava Shamban, MD, who practices in Santa Monica, CA and Beverly Hills, CA, agrees with Dr. Gilbert’s approach to patient consultations, no matter what brings them to her office. “The quality of the skin to me is first and foremost, so I always start there. Virtually everyone, especially in California, could benefit from a tretinoin whose mechanism of action includes stimulating collagen and normalizing cell differentiation. I think it’s a key component of an optimal skincare regimen.” she explains.

“Tretinoin stimulates collagen production and it also interferes with the transfer of melanin,” says Dr. Berson.

Dr. Day agrees. “I think if you look at any magazine, any month of any year, retinoids still come up as a go-to key ingredient to treat acne and make your skin look healthy,” she says. “And it has not gotten old. The more that we learn about it, the more that we study it, the more we realize how important and relevant it is.”

First Steps in the Acne Treatment Regimen

The roundtable participants all agree that recommending a retinoid to patients is their first step in any acne treatment plan.

“Basically, when you have any bacteria over-proliferate, they stimulate an immune reaction. Part of that immune reaction is the release of cathelicidin and antimicrobial peptides, which start the whole inflammatory response that leads to acne, because you get inflammation and what’s involved with that inflammation are toll-like 2 receptors. And we now know that when you interact with a retinoid receptor, it inhibits that toll-like 2 receptor. Therefore, you are decreasing the inflammatory response,” Dr. Berson explains.

Topical tretinoin historically has had many uses. Although retinoids are recommended as a first-line treatment in acne consensus guidelines, barriers to treatment compliance with retinoids include tolerability and irritation factors, the physicians note. Their patients don’t want to have irritated, stinging skin, overly dry skin, they say, so the vehicle is an essential factor in choosing the right retinoid for their patients.

“If you remember the old days with the first tretinoin products, those were not very tolerable or cosmetically acceptable,” says Dr. Berson. While the doctors agree that tretinoin was an effective treatment, tolerability issues led to discontinuation. There are also effective and tolerable over-the-counter options that can be recommended to patients, but the physicians say there’s a lack of clinical trials studying the efficacy of these products, and they often prefer to prescribe a retinoid so they know exactly what the patients are getting and what they can expect. When prescribing a retinoid for acne, they prefer prescription products.

“Vitamin A, retinol, retinoid—they’re all derived from Vitamin A with antioxidant and anti-inflammatory properties. Tretinoin, the prescription retinoid, also gets into the sebaceous follicle and is keratolytic and comedolytic. It can prevent clogging, help prevent comedones, and prevent acne recurrences. Although retinol is an ingredient commonly found in OTC skincare products, no clinical studies have shown its efficacy in acne. Prescription tretinoin has been proven to prevent new outbreaks while also clearing the acne that is present,” says Dr. Berson, adding that some patients should expect to see results from topical retinoids in as little as six weeks.

The roundtable panelists said that tretinoin is their go-to retinoid prescription treatment, and yet all have encountered some barriers to prescribing retinoids to acne patients. Prescriptions for tretinoin often require prior authorization, which Drs. Day, Fabi, Gilbert, and Shamban find difficult to get from insurance companies. Dr. Downie uses a dermatology-specific specialty pharmacy to handle prior authorizations and they are rarely done through her office. And cost can also be a factor. “Some of my patients have been charged as much as $800 for their retinoid prescription,” Dr. Berson adds, saying this can often lead to patients not filling their prescriptions.

There are available generic formulations, but Dr. Day and Dr. Berson point out that some patients have found the formulations can be drying. And this can lead to non-compliance, according to Dr. Fabi.

Tretinoin in a Lotion

The FDA approved the New Drug Application for Ortho Dermatologics’ ALTRENO™ (tretinoin) Lotion, 0.05% for the topical treatment of acne vulgaris in patients aged 9 and up in August, 2018. ALTRENO Lotion is the first and only tretinoin available in a lotion for acne—it was developed leveraging a polymeric emulsion technology with the aim of improving efficacy and tolerability. In this micronized tretinoin formulation, 85 percent of ALTRENO tretinoin particles are less than 10 microns.

The product launched in late October 2018 and is available to patients by prescription for as little as $115 with no insurance copays, no coupon cards, and no reimbursement. Patients can receive their prescription via home delivery through Ortho Dermatologics’ distribution channel.

ALTRENO Lotion has been shown to be effective and generally well-tolerated for the management of acne and is provided in a formulation with known moisturizers sodium hyaluronate, glycerin and soluble collagen.

The results of two identical Phase 3, multicenter, randomized, double-blind, vehicle-controlled, parallel group studies examining the efficacy and safety of ALTRENO³ showed that ALTRENO Lotion had significantly greater efficacy compared to vehicle.

Patients were randomized 1:1 to receive ALTRENO Lotion or vehicle once-daily for 12 weeks—they were assessed at four, eight, and 12 weeks of treatment. The co-primary efficacy endpoints were the absolute change from baseline to week 12 in mean inflammatory and noninflammatory lesion counts, and the proportion of patients who were clear to almost clear and achieved at least a two-grade reduction from baseline to week 12 in EGSS. Secondary efficacy endpoints included mean percent change from baseline to week 12 in inflammatory and noninflammatory lesion counts and the proportion of patients who achieved at least a two-grade reduction from baseline.³

Additional assessments included a patient satisfaction score (PSS) assessment, a validated acne-specific quality of life (Acne-QoL) questionnaire, and an assessment of degree of shininess/oiliness of facial skin and its range of bothersomeness. Adverse events, which were summarized by treatment group, severity, and relationship to study medication, were evaluated throughout.³ The most common adverse reactions were application site dryness (4%), pain (3%), erythema (2%), irritation (1%), and exfoliation (1%). Depending on the severity of these reactions patients may need to use a moisturizer and/or adjust or discontinue dosing.

By week 12, 17.7 percent of patients treated with ALTRENO Lotion achieved treatment success compared to 9.3 percent of patients receiving vehicle. ALTRENO Lotion also demonstrated statistically significant reductions in both inflammatory and noninflammatory lesion counts (both P<.001) at week 12 compared to vehicle (52.1 percent versus 41.0 percent for inflammatory lesion counts and 46.1 percent versus 29.9 percent in noninflammatory lesion counts). The most common adverse reactions were application site pain (3.1 percent), dryness (3.7 percent), and erythema (1.4 percent). The study found ALTRENO Lotion was generally well-tolerated across treatment groups.³

Results showed that mean scores for cutaneous safety and tolerability were <0.5 (where 1=mild). They did note slight increases over baseline in mean scores for scaling, burning, and stinging at week 4, which is consistent with tretinoin’s well established safety profile. These scores were reduced at subsequent visits. At week 12, the study found, mean scaling, erythema, itching, burning and stinging scores were 0.27, 0.33, 0.14, 0.13, and 0.07, compared with 0.15, 0.29, 0.14, 0.07, and 0.05 with vehicle, respectively.³

The study results also showed patient satisfaction was significantly greater with ALTRENO Lotion compared to vehicle, increasing from baseline to week 12 by 53 percent compared to 43 percent with vehicle (P<.001), and with 9 out of 10 patients reporting satisfaction with their treatment. Patient satisfaction was measured using the acne-specific quality of life (Acne-QoL) questionnaire.³

Dr. Shamban says the tolerability factor, particularly being able to reduce inflammation and irritation to the skin, is very important when treating acne in active adult skin, and even for adolescents. “We all know that adult acne tends to be on the jawline, neck, and maybe a little more on the chest and shoulders. The skin is more delicate there, so it’s really imperative to have a formulation that’s tolerable in that area,” she says. “To be able to treat acne with a formulation that’s not going to aggravate the inflammation that’s already there is key.”

The physicians concur that the ALTRENO lotion formulation with its hydrating vehicle should make it more tolerable for patients, which could improve compliance. “It spreads and absorbs easily. It has a hydrating vehicle including humectants. It gets into the pores easily, and has a cosmetically acceptable formulation,” Dr. Berson explains. “It includes glycerin and sodium hyaluronate, which are humectants that hydrate the skin. Looking at the studies, at 12 weeks the vehicle alone did well especially for inflammatory acne. If the hydrating base improves tolerability, patients may be more compliant with treatment.”

Dr. Day adds: “The vehicle feels really good on the skin. For my acne patients who are on many products—they may also be using a benzoyl peroxide, clindamycin combination or they may be exfoliating and possibly over-treating their skin—to have an ingredient that I believe is a core ingredient of treating acne and supporting healthy skin, and to have it in a formulation that is aesthetically elegant really may improve compliance. And the fact that the company is bypassing the insurance reimbursement model where prices are very unpredictable for adult female patients—I feel like this actually goes right to the source. It’s, ‘Here’s the product. Here’s the doctor who’s going to write it for you. Here’s what it’s going to cost you and this is how you get it. Period.’ A great vehicle and a prescription strength ingredient in a way that a consumer knows exactly what they’re going to get and the doctor knows what the patient is going to get and the time in which they’re going to get it. I’m hoping and expecting that this will be a success.”

ALTRENO is actually less expensive than many over the counter doctor dispensed retinols. In addition, ALTRENO was clinically tested in large multicenter trials and received FDA approval for the treatment of acne to support that it actually decreases inflammatory acne, Dr. Fabi adds.

Real-World Approaches to Treatment

Of course, not all adult female acne is the same. Some patients have comedonal acne that may be largely mediated by hormones. Some have cystic acne that may be mediated by hormones. Sometimes adult acne is a combination of genetics and hormones, Dr. Downie says.

“There are the people who come in my office who are 35, 40, and 45. They have never had acne before and everything was riding along beautifully until all of a sudden their hormones flipped around in their 40s usually, and all of a sudden they start getting acne,” says Dr. Downie. “Those who have never had acne before and get acne in their 40s, they’re angry—they’re angry at you, they’re angry at their regimen, they’re angry at everything. Meanwhile it’s their hormones 9 times out of 10. I tell them it’s stress, it’s genetics, and it’s your hormones.”

Many frustrated patients come into the office with a laundry list of products they’ve tried and report that nothing worked, Dr. Fabi says, or that they were unable to tolerate them she adds.

“Most of the over-the-counter products that you find at the drugstore level are targeted for teen acne. They can be drying and irritating” explains Dr. Berson.

Dr. Downie says frustration can lead to patients resisting a new acne regimen.

“I tell my patients that people in their 80s have acne—they may have missed it for the first 40 years, but now they may have to deal with it for the next 40 years, which bothers them. I tell them it’s important to treat it, especially if I notice any pitting in their face at all and that’s true scarring,” Dr. Downie says. “Again, the first thing I do is put them on a retinoid and then turmeric. And I build from there—oral antibiotics, spironolactone, chemical peels, etc. And I recommend a good skincare regimen and tell them they always need to wear sunscreen.”

Dr. Gilbert notes that based on what she was taught by Alan Shalita, MD, if a female patient’s acne is bad enough, she will start them on a topical tretinoin and will add oral therapies, such as hormonal treatment, spironolactone, and/or a low-dose oral doxycycline, minocycline, or tetracycline antibiotic. She says she crosses them over, starting orals and topicals at the same time, with the goal of getting patients off of oral treatments as soon as possible.

Dr. Day’s treatment approach includes telling her female patients she can offer a short-term fix and a long-term fix. “Spironolactone takes three to four months to really kick in. I believe a low-dose works as well as a high dose—I usually start with 25-50mg and don’t find for most people that I have to go above that. If I start them at 50, once they’re clear I go down to 25. But I say that is going to take some time to be effective, so if the female patient is really bothered by their acne or we’re seeing signs of scarring, I add an antibiotic,” Dr. Day explains. “I start with the antibiotic by mouth and with a retinoid and a benzoyl peroxide (BP) wash. I also add in a dietary supplement that has niacinamide, copper, zinc, etc.” She advises patients to start with the topical and antibiotic one week, then if no side effects, add the niacinamide, and a week later if they have no side effects, add the spironolactone for female patients. And then after three months, they should be able to stop the oral antibiotic. They can continue on the spironolactone, the topical retinoid and BP wash, and a clindamycin phosphate and benzoyl peroxide, she adds.

Dr. Berson says for some women, hormonal fluctuations play a bigger role than for others, but agrees that for most women, whether they are pre- or peri-menopausal, there is a hormonal contribution. Spironolactone and oral contraceptives can be helpful for these patients; oil reduction can be noted after only a few weeks of treatment with spironolactone, Dr. Berson explains.

“I often prescribe an antibiotic, spironolactone, and tretinoin. And again, from the Dr. Shalita camp, start the retinoid on day one.” You don’t need to wait, she explains, no matter the type of acne or patient skin type. However for nursing women, the developmental benefits of breastfeeding should be considered along with the mother’s clinical need for ALTRENO.

“And now we’re understanding that retinoids actually have anti-inflammatory properties, too,” she adds. “So even for patients with red, sensitive skin, I’ll start them on a retinoid, but just have them apply it over a moisturizer. If you’re a fair person, you may have signs of photodamage with redness and concomitant acne. I don’t consider this to be a contraindication. It’s how you use it with the right vehicle and the moisturizers. And the retinoid can indirectly help the inflammation.”

Dr. Shamban agrees that oral antibiotics—and she prefers subantimicrobial-dose doxycycline—can be an effective part of the acne treatment plan but says she is seeing a trend away from oral antibiotic use in her practice, and with patients in general.

“By the time they show up to our practice they’re looking for us to come up with a solution that’s not going to be oral,” says Dr. Fabi, agreeing with Dr. Shamban’s assessment that patients would like to avoid oral antibiotics for a variety of reasons, from concerns about antibiotic resistance to not wanting to disrupt their gut microbiome.

Dr. Shamban’s first-line treatment is a laser treatment along with a tretinoin and then a topical.

“We start with a combination of a treatment with lasers—we do a series of treatments and we do some longer wavelength treatments,” she says. “I would start with that and then add on all the usual and customary—especially the spironolactone.”

Dr. Fabi agrees that devices can play a role as first-line treatments for her adult female patients with acne. “Patients find our practice because we do so much photodynamic therapy (PDT) for acne using multiple sequential lasers and lights we use to activate the photosensitizer on the same day, which we have found is superior than using a single light source alone. We start with a pulsed dye laser, followed by an intense pulsed light and finish with blue and red light. It’s probably only five percent who are not interested in that, so that’s my typical regimen. I don’t start the tretinoin at that time because it’s too much,” she says. “I’ll do PDT, but I do start my adult female acne patients on spironolactone at the same time because that spironolactone helps maintain that result, and by the time the PDT effect kicks in within 4 weeks, the spironolactone is starting to take effect. And then within a month, I’ll start them on tretinoin. I won’t prescribe oral antibiotics very commonly and I prefer topicals or lasers and the combination ideally. I do prefer spironolactone to oral antibiotics because I am concerned about affecting the microbiome and affecting their GI.”

Although Dr. Fabi does not start every patient on tretinoin from day one, she does agree it’s a gold standard for any treatment plan.

Improving Adherence

The key to success with any treatment plan is patient compliance. If they aren’t following their treatment regimen, it will not work.

Dr. Day says it’s important to make sure patients understand the plan and have clear instructions. “Sometimes it’s overwhelming. It’s too many things. So we write things down for them. We have AM and PM regimens. If they’re using products at home or drugstore products, I’ll go over the drugstore items and explain which are their ‘must haves,’ versus ‘nice to haves.’ I will help guide them and understand what their obstacles are,” Dr. Day says. “The other problem is confusion. Patients sometimes don’t get that they have to apply to a whole area or the whole face. I take nothing for granted in the instructions. I always say wash your whole face. Apply this to the whole area. There are no spot treatments unless I say it’s a spot treatment.”

She always asks patients if they have any questions before they leave her office and recommends patients come back for a follow-up visit in six weeks to review. Dr. Day and Downie note that it’s important to tell patients to call if they have problems filling any prescription or if it’s too expensive, so that they can help the patient find an alternative pharmacy or prescription.

Dr. Shamban says that adult female patients do tend to be the most motivated and stick to it because they want their acne to go away. “The only thing that I would add is something to mitigate the irritation and inflammation,” she adds, explaining that irritation and dryness are significant factors in noncompliance (See sidebar on page 4).

And patients need to understand that there is no magic bullet that clears acne for life and that acne can be an ongoing inflammatory process. “I think it’s important for patients to understand that the breakouts and inflammation can be a chronic process with the potential to clear and flare. Retinoid maintenance helps prevent recurrences and can also improve post-inflammatory pigmentation. I think maintenance is as much of an important issue as treatment,” says Dr. Berson. “I also carefully write out the daily regimen for each patient on an instruction sheet to ensure compliance.