¹Schulich School of Medicine and Dentistry, Western University, Windsor, ON, Canada
²Department of Health Sciences, Brock University, St. Catharines, ON, Canada
³Windsor Clinical Research Inc, Windsor, ON, Canada

Conflict of interest: Karen Michael, Jaefer Mohaad and Nuha Nasir have no conflicts. Jerry Tan is an advisor, consultant, speaker and/or trialist for Bausch, Cipher, Cutera, Galderma and Sun Pharma.

Funding sources: None.

Abstract: Clindamycin phosphate 1.2%/benzoyl peroxide 3.1%/adapalene 0.15% (IDP-126) is a novel fixed-dose triad gel combination approved by the US FDA October 2023 and by Health Canada August 2024 for the treatment of acne vulgaris in patients aged 12 years and older. IDP-126 was efficacious in moderate to severe acne compared to vehicle and component topical dyads in phase 2 and to vehicle in phase 3 randomized controlled studies. Efficacy outcomes were inflammatory and noninflammatory lesion counts and Evaluator’s Global Severity Score. IDP-126 also had a favorable tolerability and safety profile.

Keywords: acne, topical, triple combination, fixed-dose, clindamycin, adapalene, benzoyl peroxide, treatment, Cabtreo™

Introduction

The pathogenesis of acne involves different mechanisms including follicular proliferation of Cutibacterium acnes (C. acnes), follicular hyperkeratinization, inflammation, and increased sebum production.¹ Current topical medications include retinoids, benzoyl peroxide, antibiotics, azelaic acid, and dapsone – either as monads or dyads. Recently, a novel topical fixed-dose triad, combining clindamycin phosphate 1.2%/benzoyl peroxide (BPO) 3.1%/adapalene 0.15% (IDP-126) has been developed. Herein, we summarize pivotal trials leading to regulatory approval in the US and Canada.

Phase 2 Studies

The phase 2 study, conducted in the US and Canada, was randomized, controlled and double-blinded involving participants 9 years or older with moderate [Evaluator’s Global Severity Score (EGSS) of 3] to severe (EGSS 4) facial acne.² Participants were randomized to one of five different treatment groups for 12 weeks: vehicle, IDP-126 (triple combination), and the following dyad formulations: benzoyl peroxide 3.1%/adapalene 0.15% gel (BPO/ ADAP), clindamycin phosphate 1.2%/benzoyl peroxide 3.1% (CLIN/BPO), or clindamycin phosphate 1.2%/adapalene 0.15% gel (CLIN/ADAP).

Treatment success, defined by achievement of ≥2-grade reduction in EGSS and clear/almost clear (EGSS 0 or 1), was achieved by 52.5% of participants at week 12 with IDP-126. This was significantly greater than the three dyad gels (range 27.8-30.5%; P ≤ 0.001, all) and vehicle (8.1%; P < 0.001). IDP-126 resulted in significant mean reductions in inflammatory (29.9) and noninflammatory lesions (35.5) from baseline to week 12 (P < 0.05, all) compared to all dyad treatments and vehicle (Figure 1). Overall, IDP-126 demonstrated over 70% reductions in both inflammatory and noninflammatory lesions.

Phase 3 Studies

Two identical randomized, double-blind, vehicle-controlled 12-week trials were conducted in subjects aged 9 years and older in moderate to severe acne.³ Participants were randomized to IDP-126 or vehicle gel, at a 2:1 ratio. Co-primary outcomes were ≥2-grade reduction from baseline and achievement of clear/almost clear on EGSS, and changes in inflammatory and noninflammatory lesion counts.

All coprimary efficacy endpoints were achieved in both trials with IDP-126 gel outperforming vehicle at week 12. Significantly greater percentages of participants achieved a 2-grade reduction in EGSS and clear/almost clear at week 12 with IDP-126 vs. vehicle (Study 1: 49.6% vs. 24.9%, P ≤ 0.01; Study 2: 50.5% vs. 20.5%; P ≤ 0.001).

When comparing IDP-126 vs. vehicle at week 12, greater reductions were also observed in inflammatory (Study 1: 27.7% vs. 21.7%, P ≤ 0.01; Study 2: 30.1% vs. 20.8%; P ≤ 0.001) and noninflammatory (Study 1: 35.4% vs. 23.5%, P ≤ 0.01; Study 2: 35.2% vs. 22.0%; P ≤ 0.001) lesion counts (Figure 2). Significant differences in inflammatory and noninflammatory lesion counts with IDP-126 vs. vehicle were noted by week 4 (P < 0.05).

Treatment-emergent adverse events (TEAEs) were observed with greater frequency in the IDP-126 group (Study 1: 24.6% vs. 8.2%; Study 2: 30.0% vs. 8.3%) and considered related in a smaller proportion (Study 1: 18.0% vs. 0%; Study 2: 21.7% vs. 3.3%). These were primarily mild-moderate in severity and attributed to application site pain (Study 1: 10%; Study 2: 15.0%), erythema (Study 1: 4.9%; Study 2: 2.5%), dryness (Study 1: 1.6%; Study 2: 4.2%), irritation (Study 1: 0.8%; Study 2: 3.3%), exfoliation (Study 1: 3.3%; Study 2: 0%) and xerosis (Study 1: 0%; Study 2: 2.5%). Three severe adverse events were reported, all in the IDP-126 cohorts (Study 1: application site burn, n = 1, led to study withdrawal; Study 2: application site pain and dryness, n =1; application site pain, n = 1; related). No serious adverse events were reported.

Network Meta-Analysis

A network meta-analysis compared the relative efficacy of commercially available acne treatments for moderate to severe acne.⁴ Inclusion criteria were randomized controlled trials (RCTs) with minimum duration of 4 weeks involving subjects aged 9 years and older. Notably, isotretinoin studies were excluded from this analysis due to either absence of global assessments in current use for regulatory approval, or non-randomized designs. Primary outcomes evaluated were percentage of patients achieving a ≥2-grade reduction in acne severity, almost clear/clear for global severity score, and changes in inflammatory lesion (IL) counts, and noninflammatory (NIL) counts. Treatments were ranked using surface under cumulative ranking (SUCRA) values. SUCRA scores rank treatments based on their effectiveness across studies, simplifying comparison by assigning higher scores to more consistently effective treatments. The top treatments across these outcomes were: (1) IDP-126, a combination of topical antibiotics/ BPO/retinoids (SUCRA 0.96 for Global Assessment, 0.90 for inflammatory lesions, and 0.91 for noninflammatory lesions), (2) fixed-dose dyad topical treatments with oral antibiotics (SUCRA 0.88, 0.98, and 0.99, respectively), and (3) topical retinoid/ BPO combinations (SUCRA 0.74, 0.79, and 0.79, respectively). These rankings highlight the strong overall performance of these treatment combinations across different acne efficacy outcome measures. In addition to efficacy, IDP-126 showed a favorable safety and tolerability profile with lower discontinuation rates (2.8%). It also had fewer patients with TEAEs than dyads.

Conclusion

The topical fixed-dose triad of clindamycin phosphate 1.2%/BPO 3.1%/adapalene 0.15% gel (IDP-126) represents an effective and well-tolerated novel topical treatment option for moderate to severe acne. In comparison to currently available topical and systemic treatments (except for oral isotretinoin), it ranks within the top three of the most effective treatments for moderate to severe acne.

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¹School of Medicine, Texas A&M University Health Science Center, Bryan, TX, USA
²Center for Clinical Studies, Webster, TX USA
³Dermatology Department, University of Texas Health and Sciences Center at Houston, Houston, TX, USA

Conflict of interest: The authors declare that there are no conflicts of interest.
Funding sources: This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Abstract:
A biofilm is a diverse community of microorganisms enclosed in an extracellular matrix. Although this organization of cells exists naturally in healthy skin, it is also involved in the pathogenesis of multiple skin disorders, such as acne and atopic dermatitis. Because biofilms provide microorganisms with a survival advantage and increased resistance to traditional antibiotics, they can be very difficult to treat, particularly when the goal is to also preserve the natural skin microbiota. This review aims to provide an overview of the role of biofilms in various dermatological diseases, as well as the conventional and newly developed therapies that can be used in their treatment.

Keywords: acne, atopic dermatitis, biofilms, dermal fillers, hidradenitis suppurativa, onychomycosis, chronic wounds

Introduction

Biofilms are a collection of microbial cells encased in a polymeric substance matrix.^1,2 Biofilms can range in population from tens of cells to hundreds of thousands, and can encompass multiple species of organisms.³ The first step in its formation involves the attachment of the microorganism to a living or abiotic surface.³ The cells can then begin secreting extracellular components of the matrix, including polysaccharides, DNA, proteins, and lipids.^3,4 This is followed by a maturation stage, with the formation of a stable, three-dimensional community that allows for the movement of nutrients and signaling particles within the biofilm.⁵

Biofilms provide cells with increased protection from desiccation, chemical perturbation, and invasion from other microorganisms.⁶ They can also reduce the susceptibility of bacteria to antibiotics by up to 1000 fold, due to reduced antibiotic penetration and the presence of metabolically dormant, antibiotic resistant persister cells, which can recolonize the biofilm following antibiotic administration.⁷ Biofilms can also alter the growth kinetics of bacteria, where cells deeper within the polymer are in a stationary phase of growth, which β‐lactam antibiotics are less effective against.⁷ These factors provide bacteria and certain species of fungi with a survival advantage compared to organisms in the planktonic state, which is the free floating state of microorganisms.³

Acne

The pathogenesis of acne is complex, involving inflammation of the pilosebaceous unit, as well as hyperkeratinization, androgen induced increase in sebum, and colonization of the follicle by Cutibacterium acnes (C. acnes).^8,9 The C. acnes genome was shown to encode genes for the synthesis of extracellular polysaccharides, an essential component of biofilms.³ In one study, over 50% of antibiotic treated patients were found to be colonized with erythromycin and clindamycin resistant strains, and over 20% of them had tetracycline resistant acne.⁸ Biofilms are one factor for this increased resistance to antibiotics observed in patients with severe acne.⁸ For example, in vitro studies showed that significantly higher concentrations of cefamandole, ciprofloxacin, and vancomycin were needed to inhibit C. acnes biofilms compared to free floating bacteria.⁸ In another study, C. acnes biofilms were less sensitive compared to planktonic bacteria to a range of antimicrobials, such as 0.5% minocycline, 1% clindamycin, 0.5% erythromycin, 0.3% doxycycline, 0.5% oxytetracycline and 2.5-5% benzoyl peroxide.⁸

One hypothesis for the pathogenesis of acne is the formation of the comedone, which is a collection of keratin and sebum in the pilosebaceous unit caused by the hyperproliferation of keratinocytes in the follicular lining.⁹ Biofilms are thought to increase the cohesiveness between keratinocytes, which promotes the formation of the comedone and enables C. acnes to strongly attach itself to the follicular epithelium.⁹ Following the hyperproliferation of keratinocytes, the comedone grows with debris and releases its immunogenic contents into the surrounding dermis.⁹ As a result, proinflammatory cytokines can infiltrate the pilosebaceous unit and promote the development of inflamed pustules and papules seen in acne.⁹

In addition to certain antibiotics and antimicrobial peptides, agents that can specifically target biofilms in acne include surfactants such as rhamnolipids, which are produced by Pseudomonas aeruginosa (P. aeruginosa) and can dysregulate biofilms by creating central hollow cavities.^9,10 Surfactants can also be used to weaken the adhesion of biofilms to surfaces and promote their dispersal.¹¹ Quorum sensing (QS) plays an important role in the formation and maintenance of biofilms.¹¹ By altering microbial gene expression, they can promote the transformation from the planktonic state into a sessile form.¹¹ The use of QS inhibitors such as azithromycin, bergamottin, usnic acid, quercetin, and ellagic acid may help inhibit C. acnes virulence factors and biofilm formation.^9,10 Moreover, dispersin B and deoxyribonuclease (DNase) can be employed to degrade biofilm proteins, while metal chelators can be used to bind to magnesium and calcium in the outer cell wall, which disrupts the stability of the biofilm.¹⁰ Nitric oxide generating agents can also be used to decrease intracellular cyclic dimeric guanosine monophosphate levels, which leads to a favoring of the planktonic state over the formation of biofilm.¹⁰ Finally, bacteriophage therapy specifically directed against C. acnes, has proved to be successful in the animal model and is an exciting new therapy that has been studied more extensively in other diseases such as meningitis, but not in the treatment of skin conditions.¹⁰

Atopic Dermatitis

Atopic dermatitis (AD) is present in 10% of children and 7% of adults in the United States. Staphylococcus aureus (S. aureus) and Staphylococcus epidermidis (S. epidermidis) are the two most commonly found bacteria in AD lesions, and are also known to form biofilms^12-14 In a study of 40 patients with AD, 93% of biopsied lesions contained staphylococci, with 85% being strong producers of biofilms.¹⁵ Bacteria naturally colonize the epidermis, forming biofilms between squamous epithelial cells even in healthy skin.¹² In AD however, S. aureus and other pathogens enhance inflammation and weaken the skin barrier.^12,13,16 Although staphylococci natrally colonize the skin, those associated with biofilms have only been found in AD lesions.¹² Moreover, S. aureus can cause keratinocytes to undergo apoptosis when present as biofilms but not in the planktonic state.¹² This is significant to the pathogenesis of AD, as damaged keratinocytes release double-stranded RNA (dsRNA), which initiates the toll-like receptor (TLR)-3-mediated secretion of thymic stromal lymphopoietin (TSLP), a cytokine that causes a strong itch response.¹² TSLP also activates dermal dendritic cells and recruits T helper 2 cells, which subsequently produce interleukin (IL)-4 and IL-13, leading to the inhibition of adenosine monophosphate (AMP) and further weakening immunity against pathogens.¹² Bacterial biofilms can also result in the blockage of eccrine sweat glands and ducts, causing further inflammation or potentially inducing the inflammation and pruritus observed in AD.^12,17

Traditional treatment of AD does not typically involve the use of antibiotics due to their insufficient specificity and risk of promoting antibiotic resistant bacteria.¹⁸ In terms of reducing inflammation in AD, a major goal of treatment is the improvement of dysbiosis, which involves reducing the population of S. aureus.¹⁸ Sodium hypochlorite bleach baths are helpful for improving clinical AD symptoms by limiting bacterial colonization and restoring skin surface microbiome. In vitro and in vivo investigations have provided evidence of efficacy, with one study demonstrating significant anti-staphylococcal and anti-biofilm activity when used at a concentration of 0.02% compared to the standard recommendation of 0.005%.^18,19 There is also evidence supporting the topical use of farnesol and xylitol in supressing the formation of biofilms.^14,20 Additionally, use of emollients can improve skin hydration and decrease pH, which may play a role in preventing S. aureus proliferation, with some studies suggesting a decreased incidence of AD in susceptible individuals after consistent emollient use.¹⁹ One of the novel treatments currently being developed to specifically target S. aureus in AD lesions is Staphefekt™, an engineered bacteriophage endolysin with bactericidal activity towards S. aureus.¹⁸ Other potential new therapies include synthetic antimicrobial peptides that target staphylococci as well as their biofilms, and omiganan, an indolicidin analog was found to improve microbial dysbiosis as well as clinical scores in phase II trials in the treatment of AD lesions.¹⁸ Finally, dupilumab and ultraviolet-B (UVB) therapy also exhibited efficacy in decreasing S. aureus colonization, while increasing the bacterial diversity in AD patients.¹⁸

Wounds

Wounds are particularly susceptible to the formation of biofilms due to the absence of the protective covering of the skin.²¹ S. aureus, P. aeruginosa, and the Clostridiales family are among the most common biofilm-forming bacteria found in wound infections.^4,22 In chronic wounds, the healing process is impaired due to multiple factors that result in a constant state of inflammation.^23,24 These wounds are characterized by the presence of proinflammatory cytokines such as tumor necrosis factor alpha and IL-1 alpha.²³ One element that contributes to this state of chronic inflammation and recruits inflammatory cells is biofilm formation in the initial wound.^23,25 These inflammatory cells then secrete proteases and reactive oxygen species that delay the healing process.²³ In some cases, extensive use of antimicrobials, particularly in doses under the minimum inhibitory concentrations required for the infectious agent, promotes biofilm formation.⁴

Debridement is essential in the initial management of chronic wounds, including the removal of necrotic tissue and biofilms.^23,26 This should be followed by the administration of antimicrobials such as polyhexamethylene biguanide, acetic acid, and iodine.²³ Silver and hypochlorous acid have also shown therapeutic potential against biofilms when tested in vitro, exhibiting bactericidal activity against multiple microorganisms, including Pseudomonas and Staphylococcus.²⁷ Low-frequency ultrasound, lasers, and photodynamic therapy are also potential options for biofilm breakdown.²⁰

Hidradenitis Suppurativa

Hidradenitis suppurativa (HS) is a chronic, inflammatory skin disorder characterized by painful nodules, abscesses and pus-discharging sinus tracts or fistulas known as tunnels.^28,29 Microscopic analysis of HS lesions typically reveals inflammatory infiltrates that can partially be explained by the presence of biofilms in most cases of HS.²⁸ This is particularly evident in the late stages of HS pathogenesis.³⁰ Although HS is not an infectious disease itself, some studies have demonstrated the presence of slow-growing microbial agents.^28,31 One study of the microbiome of sinus tracts in patients with moderate to severe HS found that they were predominantly colonized by anaerobic species, such as Prevotella and Porphyromonas.³⁰ The deposition of intradermal corneocytes and hair fragments provides a suitable environment for the formation of biofilm by commensal bacteria.²⁸ This is supported by the consistent detection of anaerobic species in HS lesions, which can grow in the anoxic environment created by deep-seated HS nodules, dilated hair follicles, and sinus tracts.²⁸ In one study, 67% of sampled HS lesions contained biofilms.²⁸ Moreover, the difficulty in detecting these pathogens using traditional culturing techniques, which identify the planktonic state of bacteria, may be due to the presence of biofilms, especially in chronic lesions.²⁸

Conventional treatment of HS lesions continues to be tetracyclines, while second-line therapy involves a combination of clindamycin and rifampicin, which work synergistically and reduce risks of antibiotic resistance.³⁰ However, when administered as monotherapy, 65.7% and 69.3% of bacterial cultures from HS patients were found to be resistant to clindamycin and rifampicin, respectively.³⁰ Dapsone can also be used as a third-line treatment in mild to moderate HS, however, evidence supporting its use is weak.^30,32 Other therapeutic options include metronidazole or ertapenem in severe cases, with the latter exhibiting resistance rates of less than 1%.³⁰ Patients with HS often experience flare ups of the disease, which can also be partially attributed to biofilm formation.^28,33

Dermal Fillers

Injectable dermal fillers are the second most common nonsurgical cosmetic procedure performed in the United States.¹⁷ Adverse effects include erythema and nodules, which although heavily disputed, have recently been attributed to biofilm formation.^17,34 Conventional treatment of these side effects can involve the use of steroids, though when used at high doses can worsen the infection and symptoms.^17,34 In one study that investigated the role of dermal fillers in biofilm formation, the presence of as few as 40 bacteria was enough to cause infection.³⁵ Bacterial colonies in human skin contain up to 105 bacteria, which make them a potential source of needle contamination during skin penetration if proper precautions are not taken.³⁵

Treatment of dermal filler biofilms includes broad-spectrum antibiotics such as ciprofloxacin, amoxicillin or clarithromycin.³⁶ Dermal fillers composed of hyaluronic acid, one of the most common substances used in fillers, should also be treated with hyaluronidase.³⁶ This serves to lyse the gel and remove the mechanical support of the biofilm.³⁶ 5-fluorouracil, laser lyses, and surgical resection can also be employed in more severe, treatment-resistant cases.^17,36 Importantly, the conventional use of steroids, non-steroidal anti-inflammatory drugs, and antihistamines should be avoided.^17,36

Onychomycosis

Onychomycosis is a fungal infection of the nails that is associated with the formation of biofilms.^37-39 It is typically therapy resistant and relapses are common.³⁷ Trichophyton rubrum, Trichophyton mentagrophytes and the Candida family are all fungi that can cause onychomycosis, and are also potentially capable of producing biofilms.⁴ These biofilms are hypothesized to be responsible for the treatment resistance and infection recurrence observed in onychomycosis.³⁸ Multiple studies of patients with onychomycosis support the formation of fungal biofilms in vitro and ex vivo.³⁸ Amphotericin B and echinocandins are usually effective in clearing free existing fungi as well as biofilms, especially when combined with biofilm-targeted treatments such as cationic antimicrobial peptides and antibody-guided alpha radiation.³⁷ Antibody-mediated inhibition of matrix polysaccharides has been found to prevent biofilm formation in Cryptococcus neoformans.⁴⁰ Other biofilm-specific therapies being investigated aim to inhibit the extracellular matrix or matrix polysaccharides and increase antifungal penetration, including gentian violet, DNases, and quorum-sensing molecules.³⁷

Conclusion

The skin is colonized by a wide variety of microorganisms, which can aggregate and form biofilms.^3,41 In some conditions, these biofilms can play a significant role in the pathogenesis of multiple skin diseases such as acne, atopic dermatitis, and hidradenitis suppurativa.^8,12,28 With the growing concern of antibiotic resistance in dermatology, it is essential to consider the role of biofilms in the treatment of cutaneous disorders.^42,43 Recently developed treatments, such as bacteriophage therapy, that have been used extensively in other fields of medicine but not yet in dermatology, should also be investigated for their utility in the management of skin conditions.¹⁰

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¹Division of Dermatology, McGill University, Montréal, QC, Canada
²Department of Dermatology and Skin Science, University of British Columbia, Vancouver, BC, Canada

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, caused by pathophysiological processes at the pilosebaceous unit, is among the most common chronic dermatological disorders. Acne sequelae, including scarring and dyspigmentation, are common, and are often more distressing to patients than active acne lesions, reinforcing the importance of prevention and effective treatment. Trifarotene, a novel fourth generation retinoid selective for retinoid acid receptor gamma, is approved for the management of moderate-to-severe facial and truncal acne, with recent data supporting its efficacy in acne-induced hyperpigmentation. The purpose of this paper is to review treatment modalities for post-inflammatory hyperpigmentation and present trifarotene as a novel, evidence-based topical option.

Keywords: acne, retinoid, trifarotene, hyperpigmentation

Introduction

Acne vulgaris (AV) is one of the most common dermatological disorders, triggered by chronic inflammation of the sebaceous gland in the hair follicle.¹ In addition to being notably common worldwide, with an estimated global prevalence of 9.38%, it occurs most frequently among adolescents, with 35-100% having acne at some point during their lives.² In Canada, it is estimated that 9 in 10 adolescents struggle with the disease, with AV commonly persisting into adulthood.^3,4 Acne-induced scarring and acne-induced dyspigmentation may persist long after the resolution of the primary lesions.⁵ The longer a patient with acne waits before starting an effective treatment, the greater the risk of sequelae development.⁵ Because acne is a common and chronic inflammatory condition that is frequently difficult to effectively manage, prevention of sequelae requires an assertive and sustainable treatment plan.⁶

AV and its sequelae play an important role on short-term and long-term self-perception and mental health, with psychosocial phenomena observed in affected individuals, including depression, suicidal ideation, anxiety, psychosomatic symptoms, pain, discomfort, embarrassment and social inhibition, which limit participation in daily and social activities and interpersonal relationships.^7,8 However, effective treatment of AV has been shown to reduce and prevent the development of acne sequelae as well as improve patients’ self-esteem, obsessive-compulsiveness, shame, embarrassment, body image, social assertiveness and self-confidence, reinforcing the importance of targeted management.^5,7

Acne-induced dyspigmentation is an impactful adverse sequela of AV in all skin phototypes, but is most frequent in skin of color. The chronic inflammation associated with AV may result in excess melanogenesis and abnormal melanin deposition, resulting in post-inflammatory hyperpigmentation (PIH) and post-inflammatory erythema (PIE) in all skin tones, with PIH more prevalent amongst patients with skin of color and PIE more common in lighter skin phototypes.^9,10 Acne-induced hyperpigmentation (AIH) is often long-lasting with negative impacts on patients’ quality of life, frequently causing more distress than active acne lesions,^9,11 and underlies their motivation to seek medical attention. In patients with active acne, the “post-inflammatory” in the term “PIH” may be misleading, as ongoing inflammation and new acne lesions present an additional challenge to treatment. Thus, in patients with active acne, it may be more accurate to refer to such pigmentary changes as AIH. For these patients, the most important goal in managing their AIH is ultimately optimal control and eventual resolution of their acne.

Currently, treatment options for acne-induced PIH can be grouped into four main classes: keratolytics, retinoids, corticosteroids, and depigmenting agents.¹² Topical therapy with hydroquinone is considered to be the gold standard treatment for hyperpigmentation, but usage may be limited due to adverse effects such as exogenous ochronosis.^13,14 The current therapeutic approach for PIH secondary to melasma specifically includes triple topical combination therapy with hydroquinone, a retinoid and a corticosteroid, but outcomes are often suboptimal due to adverse effects, limited efficacy and post-treatment relapses.¹⁵ Recently, a phase 4 doubleblind, placebo-controlled study by Alexis et al. demonstrated that trifarotene, a selective fourth generation retinoid, led to rapid improvement in overall disease severity, improvement in post-AV hyperpigmentation index, high patient satisfaction, and favorable treatment compliance, supporting the use of this topical retinoid in the management of AV-induced PIH.¹⁶

Background

Trifarotene is a new fourth generation topical retinoid approved by Health Canada and the United States Food and Drug Administration for the treatment of AV in patients over the ages of 12 years in Canada and 9 years in the United States.^17,18 In Canada, the indication is for topical treatment of AV of the face and/or trunk.¹⁷ It is sold as a 0.005% or 50 μg/g cream (Aklief® cream) in 75 g pumps, and is to be applied to affected areas once daily.¹⁹ Relevant ingredients 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, which have been noted to promote the proliferation of healthy tissue, wound healing, emulsification, improved moisturization and enhanced epithelial keratinocyte turnover, resulting in short-term thinning of the stratum corneum and resolution/prevention of comedones, as well as long-term thickening of the epithelium.^17,20-22

Retinoid acid receptor gamma (RAR-γ) is the principal receptor subtype found in the epidermis and is targeted by trifarotene.^23,24 Notably, acne-induced PIH occurs primarily in the epidermis.²⁵ Trifarotene, similar to retinoids from previous generations, normalizes follicular keratinization and has anti-inflammatory effects by modifying the expression of retinoic acid receptorregulated genes.²⁶ Moreover, a recent mouse study comparing the activity of several retinoids found that trifarotene demonstrated superior depigmenting and anti-pigmenting properties on mouse tail skin with and without ultraviolet (UV) exposure, reinforcing its favorability in the management of AV-induced PIH.²⁷

Supporting Evidence from Clinical Trials

Results from a Phase 4 Study

In a phase 4, double-blind, parallel-group study of patients (n=123) aged 13 to 35 years with moderate AV and AV-induced hyperpigmentation, the efficacy and safety of trifarotene 50 mcg/g applied once daily in conjunction with a skin care regimen (Cetaphil® Moisturizing Lotion, Cetaphil® Gentle Skin Cleanser and Cetaphil® PRO DermaControl Oil Control Moisturizer SPF30 sunscreen) over the course of 24 weeks was assessed.¹⁶ Notably, patients in the vehicle arm also used daily sun protection. Trifarotene’s efficacy in the management of AV-induced pigmentation was determined through overall disease severity scores (ODS) and post-AV hyperpigmentation indices (PAHPI). Moderate AV was defined as an Investigator Global Assessment (IGA) score of 3 on the face, ≥20 inflammatory lesions, and ≥25 non-inflammatory lesions (excluding the nose). Moderate to marked acne-induced hyperpigmentation (AIH) was qualified using an overall disease severity hyperpigmentation scale, with included patients having a score between 4-6. Patients with greater than one AV nodule or any number of cysts were excluded from the study, as well as female patients who were pregnant, lactating or using oral contraceptives approved for AV treatment. The primary endpoint was absolute change from baseline in ODS at 24 weeks of treatment. Additionally, percent change of AIH from baseline to week 24, absolute/percent change in AIH overall disease severity scores at weeks 12, 16 and 20, average AIH lesion size, post-AV hyperpigmentation index scores and intensity were assessed as secondary AIH variables. AV-related outcomes evaluated included absolute and percent change in total, inflammatory and non-inflammatory lesions, in addition to the proportion of patients achieving IGA success at 12 and 24 weeks. Subjective outcomes were assessed by means of qualitative exit interviews and a treatment satisfaction questionnaire.

The PAHPI score, a secondary endpoint measured in this trial, represents a real-world reflection and should be considered by all clinicians as a quantifiable, reproducible way to measure disease-related concerns such as symptom severity and the impact of skin disease on patients’ quality of life.²⁸ More specifically, it is a composite scale and includes quantification of the number, size and intensity of acne lesions.¹⁶ With regards to ODS, there was a statistically significant reduction in pigmentation with trifarotene as compared to the control at 12 weeks, however significance was not achieved at weeks 16 and 24. Overall, ODS decreased by -45.4% in the trifarotene group and -44.9% in the vehicle group, while the decrease in the percentage of patients with marked AIH at 12 weeks was much more impressive in the trifarotene group as compared to the vehicle (trifarotene -26.3%, vehicle -2%). Both the treatment and vehicle groups showing improvement at 6 months may be reflective of the natural rate of pigment clearance from the skin. For PAHPI scoring, statistically significant reductions in size, intensity and number of hyperpigmented lesions were observed in patients treated with trifarotene as compared to the control group at weeks 20 and 24, while sub-scores assessing size, intensity and number of lesions showed higher absolute and percent change in the trifarotene group as compared to the vehicle-treated group. Overall, there were greater reductions in PAHPI total facial scores in the trifarotene group (-8.4% at 12 weeks, -18.9% at 24 weeks) than the control group (-4.5% at 12 weeks, -11.3% at 24 weeks), with PAHPI sub-scores in the treatment group being nearly double those of patients treated with the vehicle. When determining improvement in AIH, over 60% of patients were noted to have lighter or much lighter skin when treated with trifarotene over 24 weeks, while the number of patients with over 45 AIH lesions decreased more significantly amongst treated patients than those who received the vehicle formulation (trifarotene -14.7%, vehicle -1.3%). Both subjects (trifarotene 91.2%, vehicle 83%) and investigators (trifarotene 91.2%, vehicle 81.1%) noted slightly better improvements in AIH with trifarotene as compared to the vehicle, which was also appreciated upon review of patients’ photographs.

In addition to assessing trifarotene’s efficacy in the management of AV-induced hyperpigmentation, changes in AV lesions were also evaluated. Trifarotene was found to result in significantly greater reductions in total acne lesion counts than the vehicle (12 weeks: trifarotene -64.1%, vehicle -46.7%; 24 weeks: trifarotene -72.0%, vehicle -62.8%). IGA success was also more notable among patients treated with trifarotene, whereby 38.0% achieved IGA success by week 12 as compared to 20.8% of vehicle-treated patients, with continued improvement through to 24 weeks (trifarotene 61.1%, vehicle 39.4%).

To evaluate patients’ perspectives with regards to the efficacy of treatment, exit interviews were performed (n=30, mean age 24.8 years, 73.3% Fitzpatrick skin type IV-VI). Patients treated with trifarotene reported a greater reduction in AIH severity from baseline to week 24, with a higher proportion of individuals in the trifarotene group reporting an improvement in AIH (100%) compared to the vehicle group (83%). Moreover, the only patients to perceive a stagnation or worsening of their AIH were in the vehicle group. Furthermore, significantly more patients treated with trifarotene reported that their AIH was “much better” (83.3%) when compared to control patients (61.1%).

On safety, more adverse events were noted in vehicle-treated patients (n=19, 30.2%) than those treated with trifarotene (n=10, 16.7%), with differences thought to be secondary to infections, including COVID-19. Notably, the study was conducted during the height of the pandemic. Two vehicle-treated patients reported burning and dry skin at the application site, and all adverse events were mild or moderate in severity. Both treatments were shown to have good local tolerability, which could be due to the Cleanse, Treat, Moisturize, Protect (CTMP) regimen mandated on all patients in the clinical study.

This phase 4 study had multiple strengths. First, over two-thirds of all subjects included in the study were of Fitzpatrick phototypes IV to VI (67.5%), with 36.7% of patients treated with trifarotene of African American descent. Given that PIH is long-lasting, highly distressing and disproportionately affects individuals with skin phototypes III-VI, inclusion of patients with darker phototypes in clinical trials supports improved real-world translation.^29,30 Secondly, whereas traditional acne treatment clinical trials usually span 3 months, this trial assesses trifarotene’s efficacy over 6 months, providing greater insight into the drug’s ability to alleviate inflammatory changes in the skin and prevent and/or improve acne-induced pigmentary outcomes.

Short Summary of Results from Phase 4 Study

In essence, Alexis et al.’s clinical trial demonstrates that trifarotene is highly effective with good tolerability in the management of AV and AV-induced hyperpigmentation when used in conjunction with an appropriate skin care regimen that includes UV protection, yielding changes in overall disease severity and post-acne hyperpigmentation indices as early as 12 weeks. All parameters were noted to more significantly improve with trifarotene in comparison to vehicle therapy, including AIH lesion size, intensity and number, as well as total number of AV lesions, including both inflammatory and non-inflammatory lesions, utilizing assessments such as IGA, ODS score, post-AV hyperpigmentation index, exit interviews and photography.

Other Treatment Modalities for Post-Inflammatory Hyperpigmentation

There are currently several available treatment modalities for the management of AV-induced PIH. Regardless of the plethora of options, long-term strategies should include UV protection with sunscreen application of sun protection factor (SPF) 30 or above, a consistent skin care routine and where possible, the use of a topical retinoid proven to have depigmenting effects. Moreover, PIH has been shown to persist for greater than 1 year in nearly 50% of cases, and for over 5 years in 22.3% of patients affected by acne.³¹ Recognizing the need for prolonged treatment, consistent patient education is necessary to ensure long-term commitment and adherence to proposed treatment modalities, as well as to set patient expectations.³²

With management of PIH, treating the underlying, causative inflammatory process is the first step. In the case of AIH, trifarotene’s potent anti-inflammatory activity may contribute to its clinically demonstrated ability to limit the severity and duration of PIH.²⁴ Other safe and well-tolerated topicals with cutaneous anti-inflammatory properties include dapsone and clindamycin phosphate gels, which were also found to decrease acne severity and PIH.^33,34 Additionally, tyrosinase inhibitors, namely hydroquinone, are the mainstay of PIH therapy and work by suppressing melanin production.³² Cysteamine cream has also been proven to have comparable efficacy to topical hydroquinone. Should a less irritating agent be needed or desired, mequinol can be tried.¹³ Currently, PIH therapies have been best studied in melasma, with triple therapy preferred over unimodal therapy, such as combining hydroquinone 4%, tretinoin 0.05% and fluocinolone acetonide 0.01%.³² The hypothetical rationale of triple combination therapy is that the three molecules work synergistically to interfere with the production of melanin, slow the transfer of melanin to melanosomes, and accelerate the clearance of melanin from the epidermis by increasing keratinocyte turnover. Moreover, the retinoid counters the risk of steroid-induced skin atrophy, while the steroid component counters the irritation caused by the other two ingredients, which could lead to both patient discomfort and be counterproductive by inducing PIH. However, caution must be exercised, ensuring that patients understand the risks of exogenous ochronosis and steroid-induced cutaneous changes with prolonged and continuous hydroquinone and topical corticosteroid use, respectively. The usage of chemical peels, which work by removing the epidermal cells containing excess melanin, have been proven to be efficacious, with the most common peels using glycolic, salicylic and trichloroacetic acids.³² A comparative study previously demonstrated that serial glycolic acid peels with a modified Kligman formula (hydroquinone 2%, tretinoin 0.05% and hydrocortisone 1%) were efficacious and safe in the treatment of facial PIH in dark-skinned patients, while topical azelaic acid 15% gel was also found to successfully reduce acne and PIH in patients with skin of color.^35,36 Laser therapy has also proven to be successful in the management of PIH, including neodymium-doped yttrium aluminum garnet (Nd:YAG), picosecond (short, intense pulses) and ruby lasers.^12,32 However, as laser modalities deliver thermal energy, which may drive additional hyperpigmentation, usage should be reserved for experienced clinicians. Finally, regardless of the choice of therapy, any interventions must be well-tolerated and not add irritation or excess inflammation, given that the management of PIH is often lengthy and requires strict treatment adherence to optimize overall outcomes. Thus, user-friendly, well-tolerated and effective topical therapies, such as retinoids, are fundamental in the effective and sustainable management of acne-induced PIH.

Conclusion

Trifarotene 0.005% cream has been proven to be effective and welltolerated in the management of moderate AV and acne-induced PIH, likely due to its capacity to reduce inflammation throughout the epidermis via interactions with specific receptor isotypes. Not only has trifarotene proven to reduce the number and severity of active AV lesions, it has also shown to play a role in the prevention and reduction of PIH, which is especially important in preventing the long-term sequelae of acne in individuals of skin of color. Given its safety and tolerability profiles, as well as its relative cost-effectiveness, trifarotene should be considered when treating both acne and hyperpigmentation. Further studies evaluating the combination effect of trifarotene with other mainstay therapies, including a CTMP framework, beyond 6 months will be valuable in enhancing our understanding of optimal multimodal management of acne-induced hyperpigmentation.

Acknowledgement: We thank JP York, PhD and Rajeev Chavda, MBBS, MD, DBM for their editorial review and support.

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Schulich School of Medicine and Dentistry, Western University, Windsor, ON, Canada

Conflict of interest: Karen Michael has no conflicts. Jerry Tan is an advisor, consultant, speaker and/or trialist for Bausch, Cipher, Cutera, Galderma and Sun Pharma. Funding sources: None.

Abstract:
Oral isotretinoin continues to be unsurpassed in efficacy for acne. However, it is associated with potential adverse events including risk of fetal defects, necessitating appropriate mitigation strategies. Furthermore, the variance in bioavailability of the original formulation when ingested in fed versus fasted conditions can lead to differences in daily dosing and duration of exposure. Advances in formulation, with lidose encapsulation and subsequently with micronization, have led to iterative improvements in reducing bioavailability variation between fed and fasted conditions. Differences in bioavailability during fasting were 60% less for originator oral isotretinoin, 33% less for lidose-encapsulated form, and 20% less for micronized-isotretinoin formulation. The latter also demonstrated overall greater bioavailability such that a 20% dose reduction was required compared to the originator and lidose-encapsulated formulations. By reducing the effect of high-fat/high calorie food co-ingestion, this micronized formulation may facilitate clarity in determining appropriate oral isotretinoin dose requirements in achieving optimal patient outcomes.

Keywords: acne, isotretinoin, lidose, micronized, bioavailability

Oral isotretinoin was and continues to be the standard of treatment for severe or recalcitrant acne since regulatory approval was granted in the United States and Canada in 1982 and 1983, respectively ^1,2 While its efficacy remains unsurpassed, the past 4 decades have witnessed a barrage of reports regarding potential serious adverse events and attendant litigation. This began with the teratogenic potential of isotretinoin and consequential requirements for rigorous consenting and monitoring to mitigate pregnancy risks. Subsequent concerns including associations with depression, suicide, and inflammatory bowel disease led to studies to address these topics in a rigorous scientific manner and develop risk mitigation measures. It is thus a testament to the enduring value of this medication for people with acne and their caregivers that it remains an available therapy.

Mechanism of Action

Oral isotretinoin is a potent sebo-suppressive agent, likely due to its apoptotic effect on human sebocytes.³ Furthermore, it normalizes monocyte toll-like receptor 2 responses to Cutibacterium acnes (C. acnes).⁴ It has recently been found to induce expression of the transcription factor p53, which controls other pathways involved in the pathogenesis of acne vulgaris such as FoxO1, androgen receptor and genes involved in the induction of autophagy and apoptosis.⁵ These effects likely lead to downstream impacts including reduction in C. acnes proliferation, pro-inflammatory lipid mediators and direct and indirect anti-inflammatory effects in the pilosebaceous unit.⁵

Formulations (Table 1)

As isotretinoin is a lipophilic molecule, the originator product Accutane^® (Roche) was formulated with solubilization ingredients including hydrogenated vegetable oil and soybean oil.⁶ Nevertheless, it is only marginally soluble in the intestinal aqueous environment.⁶ Hence, co-administration with fatty meals was encouraged for greater absorption.⁶ Ingestion of a fatty meal can double drug bioavailability compared to the fasting state.⁶ Accordingly, important considerations include recognizing how varying dietary habits can influence drug absorption, which may in turn affect tolerability, safety, and efficacy.⁶

Subsequently, innovative formulations of isotretinoin have been developed to address the variability in absorption in fed and fasted states. The first iteration was lipid encapsulation, lidose-isotretinoin (Epuris^®, Cipher Pharma; Absorica^®, Sun Pharma), approved by the US FDA and Health Canada in 2012. Lipid encapsulation enhances bioavailability of isotretinoin with less dependency on high-fat, high-calorie meals. In this process, isotretinoin is presolubilized in a lipid matrix leading to greater and faster absorption with less food dependency.⁶ When compared with the conventional formulation of isotretinoin, lidose-isotretinoin was absorbed to a greater extent in the fasting state but equivalent in absorption when coadministered with a high-fat/calorie meal.⁷ It has been shown that lidose-isotretinoin delivered almost twice as much isotretinoin after an overnight fast.⁷ During fasting, isotretinoin bioavailability was 67% of that in the fed state with lidose-isotretinoin compared to 40% for conventional isotretinoin.^7,8 Moreover, lidose-isotretinoin was found to be noninferior to the conventional formulation in a blinded randomized controlled trial in efficacy and safety for severe recalcitrant nodular acne.⁹

A more recent development was a formulation combining isotretinoin micronization with a lidose vehicle carrier system (micronized-isotretinoin; Absorica LD^®, Sun Pharma) that was approved by the FDA in 2019 and Health Canada in 2023. This advancement was based on recognition that drug solubility is also dependent on particle size, with smaller sizes resulting in higher penetration and distribution across a larger total surface area. In micronization, isotretinoin particles are reduced to micrometer or nanometer size. The newest formulation of isotretinoin combines both micronization and lipid encapsulation to enhance solubility, absorption, and bioavailability.⁶ For comparison, conventional formulations of isotretinoin have a mean particle size of about 100 μm while micronized isotretinoin can reach a particle size of 10 μm and the median size (D50) is less than 15 μm.^6,10

Bioequivalence

This micronized formulation was evaluated as an abbreviated new drug application as isotretinoin with lidose encapsulation had been previously approved by the FDA. The demonstration of bioequivalence required pharmacokinetic studies evaluating concentration maximum (Cmax; peak serum concentration after administration) and extent of absorption (AUC; area under the curve).¹¹

The pivotal trial for micronized-isotretinoin comprised 2 open-label, crossover pharmacokinetic studies comparing bioavailability of micronized-isotretinoin 32 mg against lidose-isotretinoin 40 mg in healthy adults. A prior internal study by the sponsor determined that micronized-isotretinoin 0.8 mg/kg would achieve similar plasma levels to lidose-isotretinoin 1 mg/kg, or a 20% dose reduction.¹² One study assessed bioequivalence in the fed state and assessed the effect of food (Figure 1A), and the second evaluated bioavailability in the fasted state (Figure 1B).¹² The fed state was based on administration of a standardized high-fat, high-calorie breakfast as defined by the FDA containing 150 protein calories, 250 carbohydrate calories, and 500 fat calories. In practice, this comprised 2 fried eggs, 2 bacon strips, 4 oz hash browns, 2 slices buttered toast, and 8 oz whole milk.¹²

In the first study, healthy adults of both genders aged 18 years or greater were enrolled in a 3 treatment, 3 period, crossover study. Subjects were sequentially exposed to a single dose of either micronized-isotretinoin 32 mg after an overnight fast (minimum 10 hours); micronized-isotretinoin 32 mg after a high-fat/caloric meal; or lidose-isotretinoin 40 mg after a high-fat/caloric meal. For each subject, crossover was undertaken with intervening durations of 21 days for exposure to each of the 3 treatments. Data were available for 65 subjects. In the fed state, Cmax and AUC parameters were similar for those receiving micronized-isotretinoin 32 mg and for lidose-isotretinoin 40 mg. The comparative results fell within the 80-125% range for bioequivalence, inferring that micronizedisotretinoin 32 mg was bioequivalent to lidose-isotretinoin 40 mg under fed conditions.¹²

The pharmacokinetic effect of food on micronized-isotretinoin 32 mg showed that the high-fat/calorie meal delayed maximum isotretinoin absorption (Tmax) by 1.5 hours. Furthermore, food increased AUC by just over 20%. By comparison, the food effect was 60% for originator isotretinoin and was 33% for lidoseisotretinoin.¹²

The second study evaluated relative bioavailability in the fasted state. Data from 18 subjects were available. Cmax and AUC results for micronized-isotretinoin 32 mg were almost double those for lidose-isotretinoin 40 mg. Under fasted conditions, micronizedisotretinoin 32 mg had almost 2 times greater bioavailability compared with lidose-isotretinoin 40 mg.¹²

Conclusion

Prior literature on oral isotretinoin regarding benefit/risk profiles of low versus conventional isotretinoin dosing and the utility of cumulative dosing in achieving remissions focused on originator and conventional formulations. The present micronized-isotretinoin formulation, due to greater bioavailability, requires transforming these metrics into doses 20% lower than those published for originator and conventional formulations. The pivotal trials for micronized-isotretinoin were comprised of fed bioequivalence, food effect and fasting studies compared to lidose-isotretinoin. As micronized-isotretinoin 32 mg was found to be bioequivalent to lidose-isotretinoin 40 mg under fed conditions, these formulations are not interchangeable. Furthermore, in fasted conditions, micronized-isotretinoin confers 2 times greater bioavailability compared with lidose-isotretinoin 40 mg. In comparing absorption during fed versus fasting conditions, a 20% increase was observed with micronized-isotretinoin compared to 33% with lidoseisotretinoin. Thus, micronized-isotretinoin bioavailability was less food dependent. Micronized-isotretinoin substantially reduced the food effect for oral isotretinoin bioavailability.

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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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¹Rush University Medical Center, Department of Dermatology, Chicago, IL, USA
²SkinCare Physicians, Chestnut Hill, MA, USA
³Yale University School of Medicine, Department of Dermatology, New Haven, CT, USA

Conflict of interest: Julie Bittar and Perry Hooper have no conflicts to disclose. Jeffrey Dover has received funding for research and consulting from Cutera Inc.

Abstract: The treatment of acne vulgaris traditionally consists of a combination of topical and oral medications. The use of lasers to treat this condition has been an area of increasing research, and several types have previously been used in the treatment of acne. New 1726 nm lasers specifically target the sebaceous gland, which is known to be pivotal in acne pathophysiology. This laser wavelength demonstrates substantial potential as a safe and effective therapeutic option for moderate to severe acne without the risks of systemic therapy. This paper reviews the 1726 nm lasers for acne vulgaris.

Keywords: 1726 nm laser, acne laser, laser acne treatment, laser treatment, contact cooling, forced-air cooling, acne vulgaris, acne scarring, acne severity, acne skin types, acne treatment, sebaceous glands, selective photothermolysis

Introduction

Acne vulgaris is a chronic inflammatory disease of the pilosebaceous unit. The pathophysiology of acne formation is multifactorial. Elevation of androgen levels, associated with puberty, lead to increased production of sebum in the pilosebaceous unit. This is accompanied by proliferation of Cutibacterium acnes (C. acnes) and resultant inflammation. While several factors have been associated with acne formation and progression, the sebaceous gland has long been known to play an essential role in the disease.

Various treatments are typically used in the management of acne vulgaris. Standard treatments for moderate to severe acne use a combination of topical and systemic medications, light-based therapy, lasers, photodynamic therapy, radiofrequency devices, and other physical modalities, but supporting studies of their effectiveness have been limited.¹ Use of lasers is an area of increasing research as several devices have shown promise in the reduction of acne lesions and improvement of the overall appearance of skin (Table 1).² Very recently, two new 1726 nm lasers which target sebaceous glands were approved by the US FDA for the treatment of acne.

The efficacy of these devices is based on the theory of selective photothermolysis.³ Selective photothermolysis is the precise and localized injury of microscopic tissue targets through a combination of selective light absorption and a pulse duration less than or equal to the thermal relaxation time (TRT) of a target chromophore. Simply stated, different structures preferentially absorb specific wavelengths of light. By using these “absorption peaks”, specific chromophores (e.g., sebaceous gland) can be targeted while sparing other structures. The result is an increased efficacy and safety profile. In 2012, Sakomoto et al. studied the absorption spectrum of sebum to determine feasibility of selective photothermolysis of sebaceous glands.² They found that at 1726 nm, in vivo sebum has 1.2x the optical absorption of water. Further, laser-induced heating was approximately 1.5x higher in sebaceous glands than water at 1710 nm and 1720 nm. Thermal imaging showed focal heating near sebaceous follicles. Histologic evaluation demonstrated selective thermal damage to sebaceous glands while the epidermis remained undamaged.⁴

Supporting Data

1726 nm lasers have been tested in all skin types and, because of low absorption in pigment, these systems have been found to be safe in all skin types. The two FDA approved 1726 nm devices are the AviClear Laser System (Cutera, Inc.) and Accure Laser System (Accure Acne Inc.) (Table 2).

The AviClear device is a 1726 nm laser that treats acne via selective photothermolysis of the sebaceous gland. It is FDA approved to treat mild to severe inflammatory acne in all skin types. AviClear uses a 3 mm spot size and contact cooling to prevent damage to other surrounding structures. As there is no visible clinical endpoint for the 1726 nm lasers, the AviClear laser treats to a target fluence, which correlates to sebaceous gland destruction. The Accure laser treats to a target epidermal temperature, which also correlates to sebaceous gland destruction. The duration of each treatment is approximately 30 minutes. In a study by Scopelliti et al., the authors tested the 1726 nm AviClear device at a fluence of 20.5 J/cm² on human facial skin around the ear and then biopsied the site 5 days post treatment. Histology showed total necrosis of the sebaceous gland with complete sparing of the epidermis and follicular epithelium.

Early evidence for this device is promising. Goldberg et al. studied the AviClear device in 17 patients and performed three treatments, spaced up to 7 weeks apart. All patients tolerated the treatment without anesthetic (discomfort score of 4.9± 1.5 out of 10). Patients had statistically significant reductions in acne with a 52% reduction in inflammatory lesion count within 1 month of treatment and a 97% reduction 24 months after the last treatment.⁵ A larger, non-randomized, open label study by Alexiades et al. enrolled 104 patients with moderate to severe acne, allowed for a 30-day washout of all acne products, and then performed 3 monthly treatments utilizing the 1726 nm AviClear laser. Three dermatologists assessed patients at baseline and post-treatment at 4-, 12-, and 26-week timepoints utilizing Investigator’s Global Assessment (IGA) scale. An IGA score of 0 correlates to clear skin, IGA 1 is almost clear, IGA 2 is mild, IGA 3 is moderate, and IGA 4 indicates severe acne. The authors found that at 3 months, 87% of patients achieved a score of IGA 1+, 47% achieved IGA 2+, and 36% were clear or almost clear. Additionally, at the 12 month follow-up, 93% of patients had achieved IGA 1+, 79% with IGA2+, and 68% were clear/almost clear.⁶ Furthermore, there is no available data on the differences in outcomes for facial versus truncal acne outcomes with this device, however, AviClear is currently developing a truncal handpiece.

The Accure device is another FDA approved 1726 nm laser that treats mild to severe inflammatory acne vulgaris via selective photothermolysis of the sebaceous gland. This device employs an infrared camera for real-time, continuous, epidermal temperature monitoring. This allows for a peak epidermal temperature (PET) of 40°C-46°C depending on body site to serve as the objective clinical endpoint. The PET correlates with selective sebaceous gland damage. The epidermis is protected via highly controlled, forced air cooling. These therapeutic and safety measures also allow use in all skin types. There are two “modes” on the device, “Standard Mode” and “Boost Mode”. The primary difference in these two modes lies in the anesthetic used. The Standard Mode utilizes injectable anesthesia (lidocaine/1% epinephrine/saline/sodium bicarbonate mixture) while the Boost Mode uses a topical anesthetic. The Boost Mode also utilizes a unique proprietary pulsing method. A single-use patient treatment kit contains a one-time-use device tip as well as template grids that guide the spacing of injection points. Using a marker, the markings are spaced 13 mm apart for the first treatment then 11.5 mm apart for the following treatments. The primary investigators found that this spacing interval provided safe and optimal results.⁷ The duration of each treatment is approximately 45 minutes.

To date, 10 institutional review board-approved clinical trials with more than 180 patients with mild to severe acne have been treated. It should be noted that all data described below is preliminary and unpublished.

In a previously presented study of 12 patients treated using the standard mode by Tanghetti et al., there was an 80% reduction in acne lesions noted 12 weeks after a fourth monthly treatment.⁸ An additional 30 patients treated in Standard Mode were enrolled in Accure’s facial acne trial. In this trial, there was a 100% responder rate, defined as a 50% reduction in active lesions, noted at 4, 8, 12, and 24 weeks after four monthly treatments post-treatment for patients with more than 5 acne lesions. There was an 82% average lesion reduction at 12 weeks following four monthly treatments and a 90% decrease at 12 months. The most commonly reported side effects with the Accure laser are post-treatment erythema, edema, and acne flares. Dryness and crusting are also possible, but rare.⁹

Initial data from Accure’s ongoing Boost Mode clinical trials showed a median reduction of inflammatory acne lesion counts of 79%, 68%, 75%, and 90% at 12, 26, 39, and 52 weeks, respectively, after four monthly treatments. However, only 17 of 35 patients were available for long-term data collection. The authors also showed a 100%, 83%, 80% and 88% responder rate, defined as a 50% reduction or greater in acne lesions, at 12, 26, 39, and 52 weeks.

Additionally, there is no available data for the difference in outcomes for facial versus truncal acne with the Accure device. This device currently uses the same single-use patient tip for all treatment areas and different target PET settings depending on body site.

Conclusion

1726 nm lasers appear to be effective and well tolerated therapeutic options for the treatment of mild to severe inflammatory acne vulgaris while eliminating the risks of systemic agents. The results from studies demonstrate significant reduction of inflammatory lesion count and do not report on comedonal lesions. The effects of both of these devices on comedonal acne still need to be investigated. As these devices are used in non-study settings, more will be learned about their effectiveness and how to best incorporate them into our acne therapeutic armamentarium. To date, no direct clinical comparisons have been made between the AviClear and Accure lasers.

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Introduction

Acne is a common chronic inflammatory disease of the pilosebaceous unit. It can cause physical disfigurement and scarring and is also associated with depression, anxiety and social isolation.¹ Although its prevalence is highest in adolescence, acne often persists into adulthood, especially in women. More than 50% of women in their 20s and 35% in their 30s experience acne.² Given that long-term treatment is frequently required, topical therapy plays a pivotal role in its management. Topical retinoids are recommended as first line therapy for most acne patients by evidence-based guidelines in the US, Europe and Canada.^3-5 Although utilization of retinoids has increased over time, a claims-based study of data obtained from a large US database indicated that of all patients seen by a dermatologist for acne, only 59% were prescribed either an oral or topical retinoid. Nondermatologist physicians prescribed a retinoid to 32% of acne patients.⁶ Retinoid use is limited in part due to their tendency to cause irritation of the skin.⁷ Novel retinoid formulations may improve tolerability and increase use.

Background

Topical retinoids target multiple pathophysiologic processes that contribute to acne. They decrease follicular occlusion and hence comedone and microcomedone formation. Retinoids also have anti-inflammatory effects.⁸ In addition, they may improve acne indirectly by enhancing penetration of other topicals, reducing postinflammatory hyperpigmentation, and improving acne scarring.⁷

Four topical retinoids have been approved by the United States Food and Drug Administration (FDA) for the treatment of acne: adapalene, tazarotene, and trifarotene. Studies comparing the efficacy and tolerability of tretinoin, adapalene and tazarotene have shown mixed results.^9-12 Whereas some of these studies have shown comparable efficacy and tolerability, others have shown greater efficacy but lower tolerability with tazarotene 0.1% cream, gel or foam. Studies comparing trifarotene to other topical retinoids have not yet been published.

Tazarotene 0.1% cream, gel and foam are FDA approved for the treatment of acne, initially in 1997. Although effective, cutaneous irritation has limited their clinical use.¹³ In an effort to improve tolerability and maintain efficacy, tazarotene has been reformulated at a lower concentration into a non-greasy lotion vehicle. Tazarotene 0.045% lotion was approved for the treatment of acne for patients 9 years and older by the FDA in 2019 and by Health Canada for those 10 years and older in 2021. Health Canada recommends use only on the face in those 10 to <12 due to increased systemic absorption in this age group. This new formulation utilizes polymeric emulsion technology, which encapsulates tazarotene within oil droplets along with moisturizing ingredients. These oil droplets are dispersed in an oil-in-water emulsion containing more hydrating ingredients that are trapped within a honeycomb matrix. This allows for a uniform distribution of tazarotene and moisturizing excipients on the skin, which should lead to more efficient drug delivery into the epidermis and reduced irritation.¹⁴

Phase 2 Data Comparing Different Formulations of Topical Tazarotene

A phase 2 multicenter, double-blind, randomized, vehicle-controlled study compared tazarotene 0.045% lotion and tazarotene 0.1% cream to their respective vehicles.15 A total of 210 patients 12 years and older were enrolled in the 12 week trial. Tazarotene 0.045% lotion showed statistically significant superiority in reducing both inflammatory and noninflammatory lesion counts compared to its vehicle. The mean percentage changes in inflammatory lesion counts from baseline to week 12 were 63.8% with tazarotene lotion versus 51.4% with vehicle, and in noninflammatory lesion counts 56.9% with tazarotene lotion versus 35.2% with vehicle. Tazarotene lotion showed a numerically greater reduction in both inflammatory and noninflammatory lesions than tazarotene cream but the differences were not statistically significant. Both formulations of tazarotene were well tolerated, although more treatment-related adverse effects were reported with tazarotene cream (5.6% versus 2.9%). The only treatment-related adverse effect with tazarotene lotion was application site pain, reported in 2 patients.

Phase 3 Data on the Efficacy and Safety of Tazarotene Lotion in the Treatment of Acne

Two phase 3 multicenter, double-blind, randomized, vehicle-controlled trials studied the efficacy, safety and tolerability of tazarotene 0.045% lotion in the treatment of acne.¹⁶ A total of 1614 subjects with moderate to severe facial acne who were 9 years or older were enrolled. Subjects were randomized 1:1 to receive tazarotene 0.045% lotion or vehicle once daily for 12 weeks. The co-primary efficacy endpoints were inflammatory and noninflammatory lesion counts and Evaluator Global Severity Score (EGSS). Treatment success was defined as a minimum 2-grade improvement in EGSS and achievement of either clear or almost clear.

Tazarotene 0.045% lotion showed statistically significant superiority to vehicle in reducing both inflammatory and noninflammatory lesions in both trials (P<0.001). The mean percent reductions in inflammatory and noninflammatory lesions from baseline were 55.5% and 51.4% with tazarotene lotion in Study 1 (versus 45.7% and 41.5% with vehicle) and 59.5% and 60.0% with tazarotene lotion in Study 2 (versus 49.0% and 41.6% with vehicle)(Figure 1 and 2). Tazarotene lotion was also significantly more likely than vehicle to achieve treatment success (P<0.001). Treatment success was achieved by 25.5% in Study 1 and 29.6% in Study 2 of subjects treated with tazarotene lotion, compared with 13.0% and 17.3% receiving vehicle in the respective studies.

Treatment-related adverse effects were reported in 11.3% (88/779) of subjects receiving tazarotene lotion. The most common were application site pain (5.3%), dryness (3.6%), exfoliation (2.1%) and erythema (1.8%). Most adverse effects were mild, peaked at week 2 and returned to baseline by week 12. The authors commented that application site reactions were less common than those reported previously with tazarotene 0.1% gel, cream and foam, which may be due to the formulation of the lotion and its lower concentration of tazarotene.

Sensitization and Tolerability Studies

In two phase 1 dermal safety studies of tazarotene lotion conducted in healthy adults, no participants developed dermal sensitization.¹⁷ Likewise, no cases of allergic contact dermatitis were reported in tazarotene-treated subjects in the phase 2 and 3 trials. In the phase 1 cumulative irritation patch test study which compared tazarotene 0.045% lotion to vehicle lotion, saline solution, and sodium lauryl sulfate (SLS), tazarotene lotion was deemed to be “slightly irritating”. Although the mean irritation score for tazarotene lotion was statistically greater than that of the SLS positive control, this was felt to be due to the exaggerated dosing conditions employed. The authors commented that the cumulative irritancy score for tazarotene 0.045% lotion was less than half of those reported previously in other studies with tazarotene 0.1% gel, cream and foam.

Clinical Use

Tazarotene is contraindicated in pregnancy. Although pharmacokinetic studies show low systemic exposure with use of topical tazarotene, exposure levels that could lead to teratogenicity in humans are unknown and there is currently very limited data regarding pregnancy outcomes after in utero exposure.¹⁸

As with all topical retinoids, topical tazarotene may increase sun sensitivity and sun protection is recommended with its use. Concomitant application of oxidizing agents such as benzoyl peroxide is not recommended to avoid potential degradation of the retinoid.¹⁹

When prescribing a topical retinoid, it is important to counsel patients on strategies to minimize irritation including:

• Use of mild cleansers
• Use of small amounts of retinoid
• Starting with every other day use and increasing to daily use if tolerated
• Applying a moisturizer before or after use

Conclusions

Topical retinoids are recommended as first line therapy for most patients with acne. Despite strong data supporting their pivotal role in acne management, topical retinods continue to be underutilized. An important reason for this underuse is irritation. Although comparative studies have shown similar or better efficacy of tazarotene compared to other retinoids, higher rates of irritation have limited the use of older formulations of topical tazarotene. Tazarotene 0.045% lotion is a novel formulation that utilizes polymeric emulsion technology to improve tolerability and epidermal penetration. Despite the lower concentration of tazarotene in the lotion formulation, which likely also contributes to improved tolerability, tazarotene 0.045% lotion is at least as effective as tazarotene 0.1% cream. Given its effectiveness and improved tolerability, tazarotene 0.045% lotion is a useful addition to our armamentarium of topical retinoids for the treatment of acne.

¹Harvard Medical School, Harvard University, Boston, MA, USA
²Department of Dermatology, Brigham and Women’s Hospital, Boston, MA, USA
³King Saud bin Abdulaziz University for Health Sciences, Jeddah, Saudi Arabia
⁴King Abdullah International Medical Research Center, Jeddah, Saudi Arabia
⁵Division of Dermatology, Department of Medicine, Ministry of the National Guard-Health Affairs, Jeddah, Saudi Arabia
⁶Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
⁷Farwaniya Hospital, Kuwait City, Kuwait
⁸Division of Dermatology, University of Toronto, Toronto, ON, Canada

Conflict of interest:
The authors have no conflicts to disclose.

Abstract:
Acne vulgaris is a troubling skin disease known to have both physiologic and psychological effects on patients. Acne scars, a frequent complication, can further impact patients’ quality of life. Scars result from an impairment in the healing process. Acne scars can be categorized as follows: atrophic scars (including ice pick, rolling, boxcar subtypes) and trophic (including hypertrophic and keloid scars), the latter being less common. Though various treatment approaches have been suggested, there is a lack of high‐quality evidence on effective, type-specific acne scar approaches. Herein, we aim to review the current evidence for treating various acne scars.

Key Words:
acne scars, atrophic, ice pick, rolling, boxcar, hypertrophic, keloid

Introduction

Acne vulgaris is the most common skin disease affecting adolescents and adults.¹ Studies have demonstrated that about 99% of the population has had acne at some point in their lives, varying in degree of severity, duration, and age of onset.¹

The psychological impact of acne is well known. Acne can have social and psychological consequences beyond the apparent visual deformity. This common condition has been linked to stress, anxiety, depression, and suicidal ideation.² Singam et al. reported that severe acne is associated with comorbid mental health disorders in 25% of acne patients, including anxiety, adjustment, personality, and substance use disorders.³ Acne has also been associated with reduced academic achievement and social difficulties.¹

Acne scars are a frequent complication that results from damage to the skin during the healing process of lesions, with studies indicating that 50% of those suffering from acne may develop scars.⁴ Increased risk of scarring is associated with severe disease, time between acne onset and first effective treatment, relapsing acne, and males.4 Herein, we discuss different types of acne scars and present an updated review on type-specific management approaches.

Discussion

Acne scars can be classified as atrophic, hypertrophic, or keloidal. The morphology of these scars is summarized in Figure 1. Atrophic acne scars are further subdivided into three subtypes: ice pick, rolling, and boxcar.

The management approach for treating acne scars should be type-specific given the differences in underlying pathophysiology. Treatment options for each type of scar are summarized in Table 1.

Table 1. Clinical presentation and treatment options of acne scars

Ice Pick Scars

Ice pick scars extend vertically into the deep dermis or subcutaneous tissue. They are narrow (<2 mm) at the surface and taper as they extend into the deep dermis. Conventional skin resurfacing treatment options may not be adequate due to their depth. Punch excision can be used to treat ice pick scars. Though this method forms a new scar, it is generally less visible than the original ice pick scar.⁵ The punch excision can be followed by a resurfacing procedure after 4 to 6 weeks, which can further improve the scar’s appearance. Notably, laser skin resurfacing can be safely and effectively performed on the same day that the punch scar is created.⁶

Another treatment option for ice pick scars is chemical reconstruction of skin scars (CROSS) using high concentrations of trichloroacetic acid (TCA) to induce skin regeneration. TCA is strictly applied to localized areas; the controlled application results in a shorter recovery time compared to medium or deep chemical peels. The degree of clinical improvement is dependent on the total number of treatments.⁷

TCA CROSS can also be used in darker skin types. In a study evaluating the efficacy and safety of CROSS technique, researchers used 100% TCA to treat ice pick scars in patients with Fitzpatrick phototypes IV and V. Nearly 75% of participants experienced excellent improvement in the appearance of their scars after 4 sessions at 2-week intervals.⁸

Radiofrequency (RF) is another option for treating ice pick scars. RF devices use electromagnetic radiation to produce an electric current that delivers heat to the dermis, which in turn causes neocollagenesis and skin contraction. This technique is considered both safe and efficacious, offering minimal downtime and adverse events.9 Additionally, RF is a safe procedure in skin of color (SOC) as it does not directly target pigment.

Several studies have demonstrated the effectiveness of RF in the management of ice pick scars. Ramesh et al. reported that fractional bipolar RF (FRF) achieved good results in 73% patients after 4 sessions. Patients with ice pick scars exhibited a better response than those with rolling and boxcar scars.¹⁰

Conversely, Peterson et al. found that 15 patients diagnosed with rolling and boxcar scars responded better to 5 sessions of a combination of RF and FRF than patients with ice pick scars.¹¹

Another mode of therapy for ice pick scars is resurfacing lasers. This treatment modality has yielded only mild-to-moderate efficacy for ice pick scars, compared to other subtypes. Sardana et al. reported that treatment with a 1,540 nm fractional nonablative laser improved scar appearance for only 25.9% of patients with ice pick scars, compared with 52.9% and 43.1% improvement in boxcar and rolling scars, respectively.¹²

Combining ablative fractional carbon dioxide (CO2) laser with platelet-rich plasma (PRP) injections represents an innovative approach. PRP involves preparing and administering the patient’s own concentrated platelets in plasma containing variable growth factors and cytokines that promote wound healing. A recent meta-analysis investigated the efficacy and safety of combining fractional CO2 laser with PRP for managing atrophic acne scars. It was concluded that the dual approach led to enhanced outcomes compared to using ablative fractional CO2 laser alone. Specifically, the combination resulted in clinical improvement, increased patient satisfaction, and accelerated recovery after laser damage. However, further research is needed to evaluate the efficacy of PRP for acne scars.¹³ PRP can also be combined with microneedling to treat any atrophic acne scars.

Rolling Scars

Rolling scars result from dermal tethering of abnormal fibrous bands that produce skin indentation. The scars are 4-5 mm wide and are sloped, with shallow borders.

Rolling scars can be best managed surgically with subcision, which involves the use of a tri-beveled hypodermic needle to free the tethering subdermal fibrous bands. Al-Dhalimi et. al showed
that subcision downgraded the severity of rolling acne scars from moderate-to-severe grade to mild grade in 53% of patients, with minimal side effects.¹⁴ The subcision was done once and repeated every 6 weeks, as required.

Subcision has been combined with the application of soft tissue fillers and non-ablative laser to improve the appearance of rolling scars. Hyaluronic acid fillers can expand the volume of tissue in these scars and encourage collagen production. Sapra et al. assessed the management of rolling scars with poly-L-lactic acid (PLLA) in 22 patients and demonstrated that after 3 to 4 treatments at 4-week intervals with PLLA, 54.4% of patients exhibited excellent results.¹⁵ A controlled and blinded study was performed on 147 patients with rolling acne scars to evaluate the effectiveness of 1 injection of polymethylmethacrylate (PMMA) filler. Neary 65% of patients demonstrated good improvement, compared to 33% of control subjects.¹⁶

Microdermabrasion and dermabrasion are physical ablating modalities used to manage rolling scars. Microdermabrasion is more superficial whereas dermabrasion reaches the deeper papillary dermis layer. The procedures promote a wound healing response and new collagen formation. Eventually, dermabrasion treatment results in smoother and uniform appearance of the scar.¹⁷ Microdermabrasion received at weekly intervals appears to be safe in SOC.¹⁸

Microneedling is another beneficial option for managing rolling scars. Microneedling involves creating small wounds in the dermis to activate a cascade of growth factors and eventually stimulate collagen production.¹⁹ Microneedling can be effective in managing rolling scars for darker-skinned patients due to the low risk of hyperpigmentation compared to fractional nonablative laser therapy.⁷

RF can also be used safely and effectively to manage rolling acne scars with minimum adverse effects and limited downtime.⁷

Non-ablative lasers can also be used to manage rolling scars. Their mechanism of action involves targeting tissues in the dermis for selective photothermolysis to encourage collagen and
dermal remodeling, thereby improving the appearance of scars.²⁰

Boxcar Scars

Boxcar scars are broad, round-to-oval or rectangular box-like depressions with sharply defined edges. Punch excision and punch elevation are two excellent techniques for the treatment of boxcar scars, but there is still a paucity in literature evaluating their effectiveness for improving acne scarring.⁷ For punch elevation, the punch biopsy tool is used to fragment the deeper aspect of the scar without removing any epidermis or dermis.

Dermabrasion can be an effective option for managing boxcar scars, but it is a painful procedure that requires local or general anesthesia and the healing time may extend to several weeks, with significant postoperative discomfort.²¹ Microneedling RF is another useful technique that can be employed to manage atrophic boxcar scars.¹¹ RF does not directly target melanin and can thus be safely used in SOC.

Subcision is moderately effective for managing boxcar scars, but it can be combined with other resurfacing procedures such as cosmetic fillers and non-ablative lasers to achieve better results.²⁰ Chemical peeling with TCA can be used to manage hard-to-treat boxcar scars.²² Finally, laser skin resurfacing can deliver excellent results for managing acne scars. One study demonstrated that use of a high-energy pulsed CO2 laser provided 75% improvement in atrophic facial scars, including boxcar scars.²³ Ablative lasers, such as CO2 and erbium-doped yttrium aluminum garnet (Er:YAG), should be used with caution when treating atrophic scars in SOC. The risk of postinflammatory hyperpigmentation (PIH) appears to be decreased with Er:YAG. Post ablative laser PIH may last for 5 weeks and can be treated with a topical depigmenting agent such as hydroquinone 4% or combination topicals (retinoid, hydroquinone and corticosteroid).^24,25

Hypertrophic Scars and Keloids

Hypertrophic scars and keloids are more severe types of acne scars. They are less common compared to atrophic acne scars, but can be difficult to treat. Typically, hypertrophic scars appear as pink, raised lesions that persist within the borders of the original site of injury.²⁶ Keloids present as reddish-purple scars that frequently extend beyond the borders of the original site of injury.²⁷ From a pathophysiological perspective, hypertrophic and keloidal scars demonstrate excessive expression of collagen with reduced collagenase activity.²⁸

Intralesional corticosteroid injections represent the mainstay of treatment for hypertrophic and keloid scars. However, multiple treatment approaches can be used simultaneously to maximize the potential for success and minimize adverse effects.²⁹ For example, intralesional corticosteroid injections can be accompanied by 5-fluorouracil (5-FU) to reduce the risk for hypopigmentation, skin atrophy, telangiectasias, rebound scars, ineffectiveness, and injection site pain.²⁸

Laser resurfacing can be considered for managing hypertrophic and keloid acne scars. Specifically, pulsed dye laser is an excellent option to consider.³⁰ Thick keloid or hypertrophic scars can benefit from using a combination of pulsed dye laser and intralesional corticosteroid injections along with 5-FU.³¹ In fact, this combination seems to be the most promising, currently available therapy for keloids.³²

Another effective non-surgical method for managing small hypertrophic acne scars is cryotherapy, which can also be combined with intralesional triamcinolone to maximize effectiveness.³³

Surgical excision can be used in combination with other approaches including radiotherapy, interferon, bleomycin, cryotherapy, or corticoids to optimize the efficacy of the management protocol.³⁴ Surgical excision may be needed when acne scars are disabling, but in some cases laser and light-based therapies may be preferential.³⁵

Large keloid scars have been effectively managed with surgical excision followed by radiation using brachytherapy. This is better tolerated and enables delivery of high radiation doses to a focused area, with decreased side effects, in comparison to traditional external beam radiation.³⁶ Intralesional injection of interferon and bleomycin are additional options for managing keloid and hypertrophic scars. These treatments work to increase collagen breakdown and inhibit collagen synthesis, respectively. Both therapies can enhance the scar’s appearance.^37,38

The post-excision recurrence of keloids has shown to decrease with daily application of topical imiquimod 5% cream for 8 weeks.^39,40

Conclusion

The management of acne scars often requires a combination of different treatment options. An understanding of each scar type and formulating a case-specific approach are required to achieve optimal outcomes.

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Conflict of interest:
Catherine Zip has served as a speaker and consultant for Bausch Health and Galderma.

Abstract:
Topical retinoids are recommended as first line therapy for the treatment of acne. Despite this recommendation, topical retinoids are underutilized, in part because of their tendency to cause cutaneous irritation. Tazarotene 0.045% lotion was developed using polymeric emulsion technology to provide an effective, well tolerated topical retinoid for the treatment of acne.

Key Words:
tazarotene, retinoid, acne, topical, facial

Introduction

Acne is a common chronic inflammatory disease of the pilosebaceous unit. Although its prevalence is highest in adolescence, acne often persists into adulthood, especially in women. In fact, more than 50% of women in their 20s and more than 35% in their 30s experience acne.¹ As long-term treatment is frequently required, topical therapy plays a pivotal role in its management. Topical retinoids are recommended as first line therapy for most acne patients by evidence-based guidelines in the US, Europe and Canada.^2-4 Although utilization of retinoids has increased over time, a claims-based study of data obtained from a large US database indicated that of all patients seen by a dermatologist for acne, only 59% were prescribed either an oral or topical retinoid. Nondermatologist physicians prescribed a retinoid to 32% of acne patients.⁵ Novel retinoid formulations may improve tolerability and increase use.

Background

Topical retinoids improve acne by normalizing follicular keratinization and reducing keratinocyte cohesiveness, thereby decreasing follicular occlusion and comedone and microcomedone formation. As well, retinoids have antiinflammatory effects.⁶ In addition, they may improve acne indirectly by enhancing penetration of other topicals, reducing postinflammatory hyperpigmentation, and improving acne scarring.⁷

Four topical retinoids have been approved by the United States Food and Drug Administration (FDA) for the treatment of acne: adapalene, tazarotene, tretinoin and trifarotene. Although retinoid effects are likely mediated by multiple pathways, retinoids bind with varying affinity to retinoic acid receptor (RAR) isotypes alpha, beta and gamma. Binding of the retinoid receptor to its agonist leads to modulation of gene transcription. RAR-gamma is the dominant subtype of RAR in the epidermis and hence believed to be a key mediator of retinoid effects in keratinocytes.⁸

Tazarotene, a third generation synthetic retinoid, is a prodrug which is rapidly converted in the skin to its active form, tazarotenic acid. Tazarotenic acid binds to all 3 RAR isotypes but shows relative selectivity for RAR-beta and RAR-gamma.

Studies comparing the efficacy and tolerability of tretinoin, adapalene and tazarotene have shown mixed results.^9-12 Whereas some of these studies have shown comparable efficacy and tolerability, others have demonstrated greater efficacy but lower tolerability with tazarotene 0.1% cream, gel or foam. Studies comparing trifarotene to other topical retinoids have not yet been published.

Tazarotene 0.1% gel, cream and foam are FDA approved for the treatment of acne, initially in 1997. Although effective, cutaneous irritation has limited their clinical use.¹³ In an effort to improve tolerability and maintain efficacy, tazarotene has been reformulated at a lower concentration into a non-greasy lotion vehicle. Tazarotene 0.045% lotion was approved for the treatment of acne for patients 9 years and older by the FDA in 2019 and by Health Canada for those 10 years and older in 2021. This new formulation utilizes polymeric emulsion technology, which solubilizes tazarotene in an oil-in-water emulsion containing hydrating ingredients that are trapped within a honeycomb matrix. This allows for a uniform distribution of tazarotene and moisturizing excipients on the skin, which should lead to more efficient drug delivery into the epidermis and reduced irritation.¹⁴

Phase 2 Data Comparing Different Formulations of Tazarotene

A phase 2 multicenter, double-blind, randomized, vehicle-controlled study compared tazarotene 0.045% lotion and tazarotene 0.1% cream to their respective vehicles.¹⁴ A total of 210 patients 12 years and older were enrolled in the 12 week trial. Tazarotene 0.045% lotion showed statistically significant superiority in reducing both inflammatory and noninflammatory lesion counts compared to its vehicle. The mean percentage changes in inflammatory lesion counts from baseline to week 12 were 63.8% with tazarotene lotion versus 51.4% with vehicle, and in noninflammatory lesion counts 56.9% versus 35.2% with vehicle. Tazarotene lotion showed a numerically greater reduction in both inflammatory and noninflammatory lesions than tazarotene cream but the differences were not statistically significant. Both formulations of tazarotene were well tolerated, although more treatmentrelated adverse effects were reported with tazarotene cream (5.6% versus 2.9%). The only treatment-related adverse effect with tazarotene lotion was application site pain, reported in 2 patients.

Phase 3 Data on the Efficacy and Safety of Tazarotene Lotion in Acne Treatment

Two phase 3 multicenter, double-blind, randomized, vehicle-controlled trials studied the efficacy, safety and tolerability of tazarotene 0.045% lotion in the treatment of acne.¹⁵ A total of 1614 subjects with moderate to severe facial acne aged 9 years or older were enrolled. Subjects were randomized 1:1 to receive tazarotene 0.045% lotion or vehicle once daily for 12 weeks. The co-primary efficacy endpoints were inflammatory and noninflammatory lesion counts and facial Evaluator Global Severity Score (EGSS). Treatment success was defined as a minimum 2-grade improvement in EGSS and achievement of either clear or almost clear. Demographic data were comparable across the two studies, with a mean age of 20 in both studies. Overall, 66% of subjects were female and 74% were Caucasian.

Tazarotene 0.045% lotion showed statistically significant superiority to vehicle in reducing both inflammatory and noninflammatory lesions in both trials (P<0.001). The mean percent reductions in inflammatory and noninflammatory lesions from baseline were 55.5% and 51.4% with tazarotene lotion in Study 1 (versus 45.7% and 41.5% with vehicle) and 59.5% and 60.0% with tazarotene lotion in Study 2 (versus 49.0% and 41.6% with vehicle). Tazarotene lotion was also significantly more likely than vehicle to achieve treatment success (P<0.001). Treatment success was achieved by 25.5% in Study 1 and 29.6% in Study 2 of subjects treated with tazarotene lotion, compared with 13.0% and 17.3% receiving vehicle in the respective studies.

Treatment-related adverse effects were reported in 11.3% (88/779) of subjects receiving tazarotene lotion. The most common were application site pain (5.3%), dryness (3.6%), exfoliation (2.1%) and erythema (1.8%). Most adverse effects were mild, peaked at week 2 and returned to baseline by week 12. The authors commented that application site reactions were less common than those reported previously with tazarotene 0.1% gel, cream and foam, which may be due to the formulation of the lotion and its lower concentration of tazarotene.

Sensitization and Tolerability Studies

In two phase 1 dermal safety studies of tazarotene lotion conducted in healthy adults, no participants developed dermal sensitization.¹⁶ Likewise, no cases of allergic contact dermatitis were reported in tazarotene-treated subjects in the phase 2 and 3 trials. In the phase 1 cumulative irritation patch test study which compared tazarotene 0.045% lotion to vehicle lotion, saline solution, and sodium lauryl sulfate (SLS), tazarotene lotion was deemed to be “slightly irritating”. Although the mean irritation score for tazarotene lotion was statistically greater than that of the SLS positive control, this was felt to be due to the exaggerated dosing conditions employed. The authors commented that the cumulative irritancy score for tazarotene 0.045% lotion was less than half of those reported in previous studies with tazarotene 0.1% cream, gel and foam.

Clinical Use

Topical tazarotene is contraindicated in pregnancy. Although pharmacokinetic studies show low systemic exposure with use of topical tazarotene, exposure levels that could lead to teratogenicity in humans are unknown and there is currently very limited data regarding pregnancy outcomes after in utero exposure.¹⁷

Based on a small study done with tazarotene 0.1% foam, topical tazarotene has a low potential to cause phototoxicity and has not been reported to cause photoallergic reactions.¹⁸ However, as with all retinoids, sun protective measures are recommended with its use. Concomitant application of oxidizing agents such at benzyl peroxide is not recommended to avoid potential degradation of the retinoid.¹⁹

When prescribing a topical retinoid, patients should be counselled regarding the use of mild cleansers and emollients, as the large variation in patient usage of topical retinoids may be an important determinant of tolerability.²⁰

Conclusion

Topical retinoids are recommended as first line therapy for most patients with acne. Despite strong data supporting their pivotal role in acne management, they continue to be underutilized. Although comparative studies have shown similar or better efficacy of tazarotene compared to other retinoids, higher rates of irritation have limited use of older formulations of topical tazarotene. Tazarotene 0.045% lotion is a novel formulation which utilizes polymeric emulsion technology to improve tolerability and epidermal penetration. Despite the lower concentration of tazarotene in the lotion formulation, which likely also contributes to improved tolerability, tazarotene 0.045% lotion is at least as effective as tazarotene 0.1% cream. Given its effectiveness and improved tolerability, tazarotene 0.045% lotion is a useful addition to our armamentarium of topical retinoids for the treatment of acne.

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