Conflict of interest: Monica K. Li is a consultant and speaker for Galderma Canada. Santina Conte has no relevant conflicts of interest.
Funding sources: None.

Abstract: Acne vulgaris is a common, often chronic inflammatory disease that can affect all ages and skin tones. Beyond acute lesions, the sequelae of acne – specifically scarring and dyspigmentation – can be long-lasting, challenging to treat and have substantial psychosocial impact on affected individuals. For acne scarring, treatment modalities include topical, physical, and laser and light therapies, with combination approaches typically yielding optimal outcomes. Trifarotene is a novel fourth generation retinoid with targeted action towards retinoid acid receptor gamma (RAR-γ), the most common isotype found in the epidermis, that has previously been approved for the management of moderate-to-severe facial and truncal acne in individuals over the age of 12 years. Recently, data on trifarotene supports its application in acne scarring. Herein, we provide a succinct review on various treatments for acne scarring and explore how trifarotene and its mechanism of action present an additional topical approach to target atrophic acne scarring.

Keywords: acne, atrophic scar, retinoid, scar, trifarotene

Introduction

Pathophysiological processes at the pilosebaceous unit, including increased sebum production, follicular hyperkeratinization, Cutibacterium acnes proliferation and augmented localized immune responses, contribute to the development of acne vulgaris (AV).¹ While its estimated global prevalence is almost 10%, AV most commonly affects adolescents, with 9 in 10 Canadian adolescents impacted by the disease.^2,3 However, AV commonly persists into adulthood, affecting 50% of women in their 20s and over 35% of women in their 30s.⁴

AV plays an important role on an individual’s self-perception, with patients expressing how acne-related concerns affect their social, personal and professional lives.⁴ Moreover, patient distress is not only linked to active AV lesions, but also to subsequent scarring, irritation and hyperpigmentation.⁵ Early, effective management of AV is therefore key to reduce the risk of irreversible scarring and long-term disfigurement, given that clinically relevant scars occur in roughly 50% of individuals.⁶ The majority of AV-induced scars are atrophic in nature, thought to be secondary to collagen loss, while approximately 10% are hypertrophic.⁷ Notably, acne scars, particularly atrophic ones, have proven to be surgically and cosmetically challenging to treat, reinforcing the importance of prevention.⁸

Current clinical treatments for atrophic acne scars include chemical peels, dermabrasion, punch techniques, laser and light-based devices, tissue-augmenting agents, needling, subcision, fat transplantation and combinations thereof – modalities typically requiring considerable out-of-pocket expenses and lengthy commitment for the patient.⁹ This underscores the importance of a proactive, preventative approach. Retinol products have long been established and recognized to promote skin resurfacing secondary to their capacity to increase cell turnover and re-epithelialize tissues.¹⁰ Recently, a phase 4 controlled study by Schleicher et al. demonstrated that trifarotene, a selective fourth generation retinoid, was effective and well-tolerated in reducing atrophic acne scarring.^11-13 The new data supports the utility of this topical retinoid as an evidence-based, adjunctive measure to manage a highly prevalent acne sequela.

Background

Trifarotene (Aklief®) is a fourth generation topical retinoid with activity selective for retinoid acid receptor gamma (RAR-γ), the most predominant RAR isotype in the epidermis.^9,10 Similar to other retinoids, trifarotene works by regulating epidermal keratinization, differentiation, maturation, and proliferation through the activation of specific genes, but its unique capacity to affect inflammation, cellular movement, immune cell trafficking and tissue remodelling, as well as to downregulate pro-fibrotic macrophages, lends to its efficacy and desirability as a molecule for acne treatment.^9,11 Moreover, an in vitro study that aimed to characterize trifarotene’s metabolism and pharmacology found that the product was an efficient comedolytic agent and demonstrated anti-inflammatory, depigmenting and anti-pigmenting properties, while having a favorable safety profile.¹²

The medication is sold as a 0.005% or 50 mcg/g cream in 75 g pumps, and 1 pump is directed for once daily application to affected skin.¹³ Other clinically relevant ingredients in the product include allantoin, copolymer of acrylamide and sodium acryloyldimethyltaurate with isohexadecane, polysorbate 80, sorbitan oleate, cyclomethicone 5, ethanol, phenoxyethanol, propylene glycol, purified water and medium-chain triglycerides.¹⁴ Some benefits of the aforementioned ingredients include increased proliferation of healthy tissue, wound healing, emulsification, improved moisturizing benefits and enhanced stratum corneum penetration.^15-18 Trifarotene has been approved by Health Canada and the United States Food and Drug Administration for the treatment of AV of the face and/or trunk in patients aged 12 years and older.¹⁴

Supporting Evidence from Clinical Trials

Results from a Phase 4 Study

In a phase 4, multi-centre, 24-week, double-blind, vehicle-controlled, split-face study, the efficacy and safety of trifarotene 50 mcg/g applied once daily along with skincare products (Cetaphil® cleanser and Cetaphil® moisturizer/SPF 30) in patients (n=121, aged 17-34 years) with moderate-to-severe facial acne and atrophic acne scarring was assessed.¹⁹ Moderate-to-severe facial acne was defined as an Investigator’s Global Assessment (IGA) score of 3 (moderate) or 4 (severe), with equal scores on both sides of the face, as well as at least 10 inflammatory lesions on each side, no more than 2 nodules, and a minimum of 10 total atrophic acne scars at least 2 mm in size on each side. Exclusion criteria included acne conglobata or fulminans, secondary acne, nodulocystic acne or acne requiring systemic treatment, and acne involving facial cysts or 3 or more excoriated lesions. In order to monitor the treatment’s efficacy, absolute and percentage change from baseline in atrophic acne scar counts, acne lesion counts, Scar Global Assessment (SGA) and IGA were followed at weeks 1, 2, 4, 8, 12, 16, 20 and 24, while patient-reported outcomes were evaluated through a self-assessment of clinical acne-related scars (SCARS) questionnaire.

With regards to trifarotene’s effect on AV clearance, the treated half of the face showed statistically significant improvement in comparison to the vehicle-treated side, with marked differences as early as week 1 and progressive improvement through week 24. Both inflammatory and non-inflammatory lesion counts decreased substantially in comparison to placebo from early in the treatment course (weeks 1 or 2), while hemifacial comparison of IGA success rates were significantly different between the two groups by 24 weeks (63.6% in trifarotene, 31.3% in vehicle, p < 0.05). Of note, each of the assessed acne lesion parameters, including mean total (-70.0% vs. -44.9%), inflammatory (-76.3% vs. -48.3%) or noninflammatory (-61.4% vs. -32.1%) lesion counts per half face, were statistically better in the trifarotene group than the control group at 24 weeks (all p < 0.05).

Trifarotene achieved similar success with regards to atrophic scarring. In addition to the treated portion of the face demonstrating a statistically significant superior reduction in atrophic scar counts (-5.9) compared to placebo (-2.7) by week 24, improvements were superior throughout the course of treatment and observed as early as week 2. The treated side also yielded significantly better outcomes with regards to reductions in total scar counts (55.2% vs. 29.9%) and mean SGA scores (53.5% vs. 32.3%).

With respect to evaluating patient preference and satisfaction, participants reported a numerically superior impact on atrophic acne scars with trifarotene in comparison to the vehicle (49% vs. 37% reporting that they saw “very few” indents/holes on their face), while the mean severity rating for scars also decreased more substantially on the retinoid-treated side (change of 3.0 for trifarotene vs. 2.3 for vehicle). There were also greater differences in the patients’ perception of their active acne for the trifarotene-treated side (change of 3.2 vs. 2.5 for vehicle).

Additionally, the safety and tolerability of trifarotene were assessed, which found that rates of mild treatment-related adverse events were higher on the treated side (5.8%) compared to the vehicle side (2.5%). The most reported adverse events included skin tightness, pruritus, erythema and rash. No severe adverse events occurred. Moreover, adverse events were found to be transient, with maximal discomfort noted at week 2.

There are two major strengths of this phase 4 study. First, over 30% of subjects were of skin phototypes IV and V, reflecting much greater diversity in recruitment efforts and improving generalizability of results to real-world practice, relative to other studies of prescription topical retinoids performed to date. Further importance of subject racial and ethnic representation is that scarring tends to be more prevalent and severe in skin of color populations.²⁰ Second, the study duration of 6 months provides greater insight into trifarotene’s impact on inflammation underlying active AV lesions, and its subsequent ability to prevent and/or improve secondary scarring. In contrast, pivotal clinical trials evaluating acne treatments typically last 3 months.

Post Hoc Analyses of Phase 4 Study

Additional analyses were performed following the publication of the above-mentioned evidence supporting trifarotene’s efficacy in the management of acne-induced atrophic scarring. First, improvement was assessed according to age quartiles (<18, 18-22, 22-27, and >27 years), which found a statistically significant difference in total atrophic acne scar counts in all age groups with trifarotene treatment as compared to placebo, with the most substantial improvement seen in patients over the age of 27. Comparisons with regards to Fitzpatrick phototypes were also performed, which is highly important given that scarring tends to be more extensive in darker skin tones. All phototypes were noted to have a greater improvement in scar counts with trifarotene, while statistical significance was achieved in Fitzpatrick types II, III and IV. With regards to Investigator and Subjective Global Assessments, trifarotene treatment resulted in statistically significant differences, with the greatest reduction observed in patients with acne severities of 3 (moderate) and 4 (severe), while patients who presented with more severe scarring at baseline tended to experience more substantial improvements in their scarring with trifarotene. Overall, all subgroups analyzed proved to be in favor of trifarotene treatment compared to vehicle for the management of atrophic scarring.

Summary of Results from Phase 4 Study

In essence, the above-mentioned phase 4 clinical trial suggests that trifarotene is highly effective and well-tolerated in the management of moderate-to-severe facial and truncal acne and facial acneinduced atrophic scarring, with treated inflamed areas responding as quickly as 2 weeks. Improved parameters included acne lesion and atrophic acne scar counts, Scar and Investigator Global Assessments, as well as patient-reported outcomes, which were all favorable with use of this RAR-γ selective topical retinoid.

Other Available Treatment Modalities for Atrophic Acne Scars

Many studies have assessed the effectiveness of a variety of treatments in the management of acne-induced scars. In real-world clinical practice, the optimal approach may be determined based on the skin phototype, treatment history, personal preferences and financial considerations of the patient, as well as the spectrum of therapeutic options available to the clinician. A 2023 review explored the efficacy of various topical modalities in the management of acne scars, including monotherapy with a range of retinoids (tretinoin, adalapene, adalapene/benzoyl peroxide gel, tazarotene), low strength glycolic acid, vitamin C derivatives and tacrolimus, as well as multimodal management with silicone gel, tranilast, plasma gel, lyophilized growth factors, amniotic fluidderived mesenchymal stem cell products, platelet-rich plasma (delivered via microneedling), insulin, polylactic acid and retinoic acid combined with glycolic acid.²¹ The authors concluded that despite such an array of available topical interventions, there remains an overall lack of evidence to support their efficacy.²¹ This contrasts trifarotene’s distinct and demonstrated capacity to improve acne scars.

Furthermore, non-laser and laser interventions have been widely used in acne scar management. For example, a single session of endo-radiofrequency subcision proved to be effective and safe, whereby scores associated with the number and quality of scars both significantly decreased, alongside patient (25-50%) and investigator (25-49%) improvement rates.²² With lasers, a comparison between erbium-doped yttrium-aluminum-garnet (Er:YAG) laser and 20% trichloroacetic acid (TCA), by which the laser was used for a total of 4 sessions and the TCA every 21 days for 3 months, found a statistically significant improvement in qualitative acne scar grading in both groups after 12 weeks (Er:YAG -21.7%, TCA -20.97%) with good tolerability.²³ Nd:YAG picosecond laser was also proven to have a similar clinical effect as ablative fractional Er:YAG laser (39.11% vs. 43.33%, p < 0.05), with patient satisfaction being slightly in favor of the Er:YAG laser.²⁴ Fractional carbon dioxide laser resurfacing, for a total of 4 sessions, yielded statistically significant decreases in qualitative scar scales with response seen in almost all patients (96%); results were observed as early as after the first laser session.²⁵ Moreover, varying laser settings have also been assessed, with one study finding that low-fluence neodymium-doped yttrium aluminum garnet (Nd:YAG) laser demonstrated comparable efficacy but superior safety than its high-fluence counterpart (-62.13% vs. -66.73%, p > 0.05) in the management of acne-related scarring.²⁶

Other modalities have also been used in conjunction with laser therapy, such as fractional microneedle radiofrequency (RF), whereby RF energy combined with ablative laser therapy demonstrated significantly superior efficacy in terms of inflammatory acne and acne scar grading, lesion counts, and subjective satisfaction.²⁷ Beyond laser interventions, microneedling with 35% glycolic acid or 15% TCA were found to be equally efficacious, with glycolic acid peels conferring better improvement in skin texture, while microdroplet injections with botulinum toxin type A (e.g., microbotox) and microneedling also showed similar significant results.^28,29

Conclusion

Trifarotene 0.005% cream has been shown to be an efficacious treatment modality for moderate-to-severe acne and acne-induced scarring, likely correlating to its novel specificity for RAR-γ, the most common isotype found in the epidermis. In comparison to conventional treatment approaches for acne-induced scars, trifarotene appears to be a relatively cost-effective, safe, well-tolerated and long-term option to improve atrophic acne scars on the face. Based on recent supporting studies, and given that acne scarring often requires multiple treatment modalities over many months, trifarotene can be considered an appropriate, useful and accessible topical adjunct for patients across the skin spectrum. Further studies, particularly with a longer observation period as well as in skin of color populations, evaluating the combined use of trifarotene with currently used interventions, will be valuable to explore its potential synergistic benefits in acne-induced atrophic scarring.

Acknowledgement: We thank Rajeev Chavda, MBBS, MD, DBM for his editorial review and support.

Conflict of interest: Dr. Lipson has been a speaker, or advisory board member for, or received a grant, or an honorarium from AbbVie, Amgen, Bausch Health, Beiersdorf, Boehringer Ingelheim, Bristol Myers Squibb, L’Oréal, Galderma, Janssen, Leo, Lilly, Novartis, Pfizer, Sanofi, Sun Pharma and UCB.
Funding sources: None.

Abstract: Acne is a common inflammatory condition of the skin worldwide. The skin is an endocrine organ and hormones are a key pathogenic factor in all types of acne with a particularly important role in adult female acne pathogenesis and management. In females, we have the unique opportunity to manipulate hormones systemically to successfully manage acne and, more recently with the approval of clascoterone 1% cream, we can target the hormones topically in both genders. The intent of this paper is to provide physicians with an up-to-date clinically relevant review of the role of hormones in acne, the impact of currently available contraceptives and therapies available to target hormones in acne.

Keywords: adult female acne, etiopathogenesis, hormones, oral contraceptives, prevalence, systemic therapy, topical therapy

Introduction

Acne is an incredibly common condition affecting almost 10% of the global population and recognized as the 8th most common condition worldwide.¹ There is a misconception among the public that acne is only a disease of adolescence. Acne is prevalent through adulthood, especially in women. The results from the ALL PROJECT research initiative presented at the European Academy of Dermatology and Venereology (EADV) Congress in October 2023 reported the prevalence of acne in 50,552 patients aged 16 years and older (69.5% older than 34 years of age) from 20 countries across 5 continents. This study found the frequency of acne in this broad population to be 18.99%, 16.3% in men and 21.95% in woman.² The prevalence of adult female acne (AFA) has been shown to peak in the 20s (50.9%) and decreases with each decade to 15.3% in patients aged 50 years and older.³ In keeping with adolescent acne, acne in adult woman has sequelae of scarring and dyspigmentation, as well as mental health impacts. A 2014 survey of American women with AFA elucidated that the majority feel less confident, more self-conscious, frustrated and embarrassed when they see or think about their acne. The isolating nature of this condition was also identified in this survey; the majority of women reported feeling like ‘no one understands what it’s like to have adult female acne’.⁴

Acne Pathophysiology

Management of acne focuses on targeting the four main pathogenic factors: sebum, Cutibacterium acnes (C. acnes), inflammation and abnormal follicular keratinization. The relationship between these factors is complex. Acne begins with adrenarche, when sex hormone production begins. Sebocytes have androgen receptors and are exquisitely androgen responsive. Sebocytes begin to produce increased sebum upon androgen stimulation and sebum production rates have been shown to correlate with acne severity.^5,6 The sebum in patients with acne has altered composition contributing to development of acne.^6,7 Androgens also directly stimulate sebocytes to produce inflammatory cytokines in the skin, another important pathophysiologic factor in acne.^6,8 Studies have shown that in the sebocytes of patients with acne there are increased number and/or activity of enzymes converting weak androgens to potent androgens, such as 5-alpha reductase, which converts testosterone to dihydrotestosterone (DHT). Patients with acne may also have increased numbers of androgen receptors and/or polymorphisms of androgen receptors making them more sensitive.⁶ Other hormones can stimulate the sebaceous gland, but to a lesser extent, such as insulin-like growth factor-1 (IGF-1), growth hormone and pro-opiomelanocortin. Within the pilosebaceous unit, the sebum rich environment creates a microenvironment ideal for C. acnes proliferation and activity.⁵ Loss of diversity of C. acnes with increased proportion of acnegenic phylotypes, such as phylotype IA1, stimulate inflammation and the break down of triglycerides in sebum to free fatty acids. Pro-inflammatory free fatty acids from the sebum and C. acnes biofilm stimulate keratinocytes and result in hyperkeratinization and comedogenesis.^5,6

The Skin is an Endocrine Organ

AFA is notoriously challenging to treat with standard acne therapies that do not address the hormones. It frequently does not respond to monotherapy with topicals and is recurrent after courses of antibiotics and isotretinoin.⁹ Women experience acne lesions on the lower face and jawline often flaring prior to menses. As lesions resolve, post-acne dyspigmentation, erythema and even scarring are common. AFA responds well to systemic anti-androgen treatment. This is possibly a contributing factor to the common misconception that women with AFA have abnormal hormone levels and the condition being referred to as ‘hormonal acne’. Hormones play an integral role in all acne. While it is known that women with polycystic ovarian syndrome (PCOS) and several other hormonal conditions have greater incidence of acne, the majority of women with AFA have normal systemic hormone levels.⁶ The skin is an endocrine organ and, as reviewed in the pathophysiology, the increased androgen and androgen effect implicated in acne is at the level of the skin. Women with adult female acne do not require assessment of systemic hormone levels unless there are other signs or symptoms indicating hormonal abnormalities.¹⁰

Managing the Hormones

Targeting the hormones in the treatment of patients with AFA is highly effective. In female patients we have the unique opportunity to manipulate the hormones systemically to manage acne. Traditionally this has been achieved with combined oral contraceptives and/or spironolactone. The combined oral contraceptives (COCs), which contain both estrogen and a progestin, have varying degrees of anti-androgenic effects. Estrogen is anti-androgenic through the increase of sex hormone globulin, which results in lower levels of circulating free testosterone.⁹ The progestins vary in their androgenic and anti-androgenic effect, resulting in distinct differences in efficacy of the various COCs.^11,12 First generation progestins, such as norethindrone, have a marked intrinsic androgenic effect. COCs containing first generation progestin can cause or exacerbate acne and should be avoided in acne prone women or stopped in women who develop acne (Table 1).^2,11 Second generation progestins have variable androgenic effect. COCs containing second generation progestins such as levonorgestrel and norgestrel are commonly prescribed and may improve acne in some patients and exacerbate in others. While there are levonorgestrel-containing COCs approved for both contraception and treatment of acne, they are not as effective at treating acne as COCs containing more anti-androgenic progestins.¹³ Third generation progestins, such as desogestrel, norgestimate and etonogestrel, are the least androgenic. COCs containing third generation progestin are effective for treating acne.^11,14 The fourth generation synthetic progesterone analogues, drospirenone and cyproterone acetate, are anti-androgenic and highly effective in the treatment of acne.¹⁴ In Canada, there are only five COCs approved for the treatment of acne (Table 2).^15-19 Based on pathophysiology of the hormones, all COCs containing third or fourth generation synthetic progesterone should work effectively to treat acne. COCs can take at least 4-6 months to show effect when treating acne.

Forms of contraception other than COCs also impact acne (Table 3). Depo-Provera® and the older progesterone-only pills Micronor® and Movisse™ contain first generation progestins, medroxyprogesterone acetate and norethindrone, respectively. These can cause or exacerbate acne. The new and highly effective progesterone-only birth control pill Slynd® is a fourth generation synthetic progesterone, drospirenone, at a dose equivalent to 25 mg of spironolactone.²⁰ While there are no studies investigating the effect of Slynd® on acne, based on the pathophysiology of drospirenone, this contraceptive option has promise as a treatment option for acne-prone women, in particular for those who require contraception without estrogen or are breastfeeding. Hormonal intrauterine devices (IUDs) contain the second generation progestin levonorgestrel without estrogen, and may cause or exacerbate acne.^21,22 The contraceptive vaginal ring and patch containing third generation progestins may reduce acne. The newer contraceptive device, Nexplanon®, contains a third generation progestin etonogestrel without estrogen. The effect of Nexplanon® implant on acne has yet to be determined. There is a promising retrospective claims-based analysis that looked at new incident acne encounters among women starting COC compared with various other forms of contraception. This showed increased risk of clinical encounters for acne with both copper and levonorgestrel IUDs and decreased risk of incident clinical encounters for acne with the etonogestrel implant.²³ More data is required on this topic. Interestingly, there are hormonal treatments prescribed for menopausal symptoms which contain first generation progestin and may cause acne; this should be considered in post-menopausal women presenting with acne (Table 1).

Spironolactone, an antagonist of the androgen receptor and aldosterone, is effectively used off-label for treatment of acne in females at doses typically between 50-200 mg daily.²⁴ Like COCs, spironolactone is very slow to show effect. Spironolactone is contraindicated in pregnancy but safe during lactation.

Another off-label therapy that has been used to target hormones in the treatment of acne is metformin. Metformin enhances peripheral tissue sensitivity to insulin, thereby reducing IGF-1. IGF-1 stimulates androgen production from the gonads and adrenals and decreases sex hormone binding globulin leading to increased free testosterone.^25,26 Metformin has long been considered a treatment option for patients with PCOS associated acne, with mixed efficacy results in the literature.²⁵ There are now studies showing promising results for treatment of acne with metformin in males and females as monotherapy (500 mg BID) or adjunct therapy (875 mg OD).^25,26

Most recently, clascoterone 1% cream (Winlevi®) has entered the acne treatment landscape; this first-in-class topical anti-androgen is approved for the treatment of mild to severe acne in males and females aged 12 years and older.²⁷ Clascoterone is believed to work by competitive inhibition of the androgen receptor resulting in decreased sebum and inflammatory cytokine production locally in treated skin.⁸ This will be a great addition to the repertoire of treatment options for all acne, including AFA. Clascoterone 1% cream is currently the only treatment available to target the hormonal factor in males with acne.

Conclusion

AFA is a common and devastating condition. It is frequently recurrent after standard acne treatments (topicals, antibiotics and isotretinoin) and responds very well to anti-androgen treatment. The majority of females with AFA have normal circulating hormone levels; the increased androgen level and effect is locally at the level of the skin. Understanding the androgenic effect of the various progestins in currently available hormonal treatments is helpful in managing AFA. Third and fourth generation COCs and spironolactone play important roles in treating this common condition. The drospirenone containing progesterone only birth control pill is a new option for females with acne who cannot take COC. Often simply an adjustment of contraceptive can result in acne resolution. Clascoterone cream is a topical anti-androgen with local effect in the skin and has a promising future in treatment of acne, including AFA.

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