Recommendations to Improve Outcomes in Acne and Acne Sequelae: A Focus on Trifarotene and Other Retinoids

Abstract

Acne vulgaris affects nearly 50 million people in the USA, ranking as the eighth most prevalent disease globally. This chronic inflammatory skin condition often results in sequelae, including atrophic acne scars, acne-induced macular erythema and acne-induced hyperpigmentation, impacting patients’ quality of life. This commentary article reviews the use of topical retinoids, with a particular emphasis on trifarotene cream 0.005%, for managing both acne and acne sequelae. Topical retinoids are considered central to improving treatment outcomes because of their established efficacy, safety and tolerability. Adapalene, tretinoin and tazarotene have demonstrated efficacy in reducing acne and acne sequelae in several studies. Trifarotene has been extensively studied in Phase 3 trials, demonstrating notable success in treating mild-to-moderate acne. Recently, two large-scale, randomized, blinded, Phase 4 clinical trials investigated trifarotene cream 0.005% in patients with atrophic acne scarring and acne-induced hyperpigmentation across all Fitzpatrick phototypes. The START study found that there was a greater reduction in total atrophic acne scar count in the trifarotene group compared with the vehicle group at Week 24 (55.2% vs 29.9%) with statistical significance established as early as Week 2 (P = 0.001). Based on this evidence, we recommend that topical retinoids should be introduced as first-line therapy for the treatment of acne and acne sequelae. Retinoids should be implemented into a treatment routine as early as possible, especially for patients with darker Fitzpatrick phototypes or patients at risk of atrophic acne scarring. Furthermore, retinoids should be incorporated within a comprehensive skincare regimen that includes adequate photoprotection when treating patients with darker Fitzpatrick phototypes. Finally, management of acne and acne sequelae should include maintenance therapy with topical retinoids. This article supports the American Academy of Dermatology’s call for acne sequelae treatment guidance and emphasizes the need for continued research to optimize patient care.

Key Summary Points

Topical retinoids are effective, safe and tolerable treatments for acne and acne sequelae, with adapalene, tretinoin, tazarotene and trifarotene all demonstrating positive results in clinical studies.

Two recent, large-scale, randomized Phase 4 clinical trials of trifarotene cream 0.005% support its safety, efficacy and tolerability as a treatment option for acne sequelae, particularly atrophic acne scarring, across all Fitzpatrick phototypes.

Further analysis and education are crucial to bridge the gap between research and practice, optimize the use of topical retinoids and ultimately improve patient outcomes.

Introduction

The Burden of Acne and Acne Sequelae

Acne is a common, chronic and complex inflammatory skin condition that affects nearly 50 million people in the US alone [1]. Globally, acne ranks as the eighth most prevalent disease [2]. Acne is a polymorphic disease, with primary lesions and sequelae that often present concurrently. Sequelae form from primary active lesions and include atrophic acne scars, acne-induced macular erythema and acne-induced hyperpigmentation (AIH) [3].

Although acne is commonly associated with adolescents and young adults and is generally regarded as a hallmark of this stage of life, research indicates that the prevalence of adult acne is increasing [4]. A 2024 global study found an overall acne prevalence of 20.5%, peaking at 28.3% in the 16–24 age group and decreasing with age (25–39: 19.3%; 40–64: 9.3%; > 64: 4.7%) [5]. Acne is significantly correlated with depression and anxiety (P < 0.00001 for both) [6] and is associated with a sixfold increased risk of body dysmorphic disorder [7]. Therefore, dermatologists should consider screening patients with acne for depression, suicidal ideation and severe mood/anxiety disorders and refer patients to specialist capable of managing these aspects of psychodermatology [7]. Beyond these psychologic considerations, the physical presentation of adult acne is often categorized into persistent and late-onset presentations, with the former considered more common. However, both subtypes are characterized by inflammation, changes in AIH and atrophic acne scarring [4].

A meta-analysis of 37 studies (N = 24,649 patients with acne) from three databases revealed a 47% (95% confidence interval (CI): 38–56%) pooled prevalence of atrophic acne scarring [2]. Male gender [odds ratio (OR): 1.58, 95% CI 1.19–2.09], positive family history (OR: 2.73, 95% CI 1.26–5.91) and acne severity (moderate OR: 2.34, 95% CI 1.54–3.57; severe OR: 5.51, 95% CI 2.45–12.41) were associated with increased scarring risk [2]. Length of time to effective treatment has also been identified as a risk factor [8]. However, scar onset varies significantly and may even manifest in patients with mild acne [9]. AIH commonly affects patients with darker Fitzpatrick skin phototypes [10] and can be long-lasting and more bothersome than the initial lesions [10, 11]. In contrast, acne-induced macular erythema is considered more noticeable in patients with lighter Fitzpatrick skin phototypes [12]. Primary care physicians (PCPs) and dermatologists should monitor patients with macular erythema for atrophic acne scarring as some atrophic acne scars evolve from inflammatory and post-inflammatory lesions [3].

The psychologic impact of atrophic acne scarring and AIH is high. Patients often report low self-esteem, embarrassment and general discomfort [13, 14]. Patients also report feeling worried about what others think of them and feeling stigmatized; nearly a third have been verbally or physically bullied [13, 14]. Patients suffering from atrophic acne scarring often pursue various treatments, including microneedling, chemical peels, subcision, resurfacing and fillers. However, these options can be expensive, have variable efficacy and may involve significant recovery periods [10, 15, 16].

In this article, we provide recommendations to support the use of topical retinoids to manage acne and acne sequelae, with a particular focus on trifarotene cream (0.005%). Trifarotene has recently been assessed for the treatment and prevention of acne sequelae in two large randomized Phase 4 clinical trials, with notable efficacy, safety and tolerability in patients with atrophic acne scarring and across all Fitzpatrick phototypes [17, 18].

Retinoids for the Treatment of Acne and Acne Sequelae

Retinoids are widely considered the foundation of acne therapy [19]. The scientific rationale includes evidence that this drug class targets multiple aspects of acne pathophysiology, having been shown to normalize desquamation, block several inflammatory pathways, reduce visible lesions and inhibit the development of microcomedones and new lesions [19]. For example, isotretinoin upregulates the expression of transcription factors p53, FoxO1 and FoxO3, which reduces sebum production by initiating sebocyte apoptosis [20]. This prevents pore blockage, which is a key factor in acne lesion development [21]. Additionally, isotretinoin therapy has been shown to significantly reduce both monocyte Toll-like receptor 2 expression and the subsequent inflammatory cytokine response to Cutibacterium acnes (C. acnes) within 1 week of treatment initiation [22]. Moreover, topical retinoids have been shown to improve sequelae such as atrophic acne scarring by stimulating fibroblasts to synthesize collagen [19, 23]. Topical retinoids are suitable for treating all levels of acne; when initiated early and/or in combination with other treatments, this medication can reduce the need for other therapies, including antibiotics and isotretinoin [24]. A retrospective cohort study demonstrated an inverse relationship between concomitant topical retinoid use and antibiotic therapy duration [25]. Regions with higher retinoid usage (~ 48%) exhibited shorter antibiotic treatment durations of 156–162 days compared with regions with the lowest concomitant retinoid usage (~ 33%) which had an antibiotic treatment period of 177–182 days [25]. However, a study of prescribing practices found that dermatologists and non-dermatologists prescribed retinoids for only 58.8% and 32.4% of cases, respectively [26]. Additionally, retinoids were less likely to be prescribed for patients aged ≥ 19 years compared with those aged 10–19 years [26]. Given the current sub-optimal utility of retinoids, PCPs should be encouraged to make appropriate referrals as they may not possess specialist knowledge of acne and are unlikely to consider important patient and treatment factors [27].

Current US-Based Guidelines and Publications

The American Academy of Dermatology (AAD) 2024 guidelines emphasize the importance of using retinoids to treat acne and describe them as the cornerstone of acne treatment as these drugs are “comedolytic and anti-inflammatory, improve dyspigmentation and enable maintenance of acne clearance.” The guidelines acknowledge that AIH, atrophic acne scarring and patient diversity remain as research gaps [28]. Acne sequelae remains an area that is vastly understudied, with a paucity of formal epidemiologic and clinical studies [29]. Additionally, there are several barriers to implementation of guidelines in clinical practice, including clinician-perceived lack of evidence, patient demand for antibiotics, practical challenges (e.g., discussions about contraception), cost, adherence issues, antibiotic resistance concerns and inconsistencies in severity classifications [30–32].

A Delphi consensus study and literature review based on treatment recommendations for AIH concluded that there is a need for more high-quality research on AIH as study designs are heterogeneous with small sample sizes and there is often a lack of follow-up [33]. To address gaps in clinical guidance, the 2020 Personalising Acne Consensus Project (PACE) provided expert recommendations to facilitate personalized, comprehensive and long-term management of acne sequelae [29]. However, these recommendations were general and did not consider stipulations from US governing bodies such as the Food and Drug Administration (Table 1).

Table 1.

Current guideline publications and their level of evidence

US-based guideline publications	Level of evidence
AAD 2024 guidelines [28]	1/2/4
Treatment recommendations for AIH: Results of the Delphi consensus and literature review [33]	5
2020 PACE expert recommendations [29]	5

Grades for level of evidence – 1: individual and systematic review of randomized controlled trials; 2: individual and systematic review of cohort studies; 3: individual review of control studies; 4: individual and systematic review of case-control studies; 5: expert opinion based on non-systematic review of results

AAD American Academy of Dermatology, AIH acne-induced hyperpigmentation, PACE Personalising Acne: Consensus of Experts

Recommendations and Supporting Evidence

Topical Retinoids Should Be Introduced as First-Line Therapy for the Treatment of Acne and Acne Sequelae

Topical retinoids are recommended as first-line therapy unless contraindicated or not well tolerated [34]. Adapalene, tretinoin, tazarotene and trifarotene have shown efficacy for the treatment of acne. In a Phase 3 study with adapalene 0.3% gel for the treatment of facial acne, 23.3% of patients achieved IGA success defined as “clear” or “almost clear” after 12 weeks of once-daily application [35]. Use of tretinoin 0.025% gel resulted in a 44% reduction in open comedones and inflammatory lesion counts on the face after 12 weeks [36]. In the same study, tazarotene 0.1% gel reduced non-inflammatory lesions by 55% [36]. Trifarotene has been studied extensively in Phase 3 and Phase 4 clinical trials to evaluate its efficacy and long-term safety in patients with moderate and severe facial and truncal acne. High rates of IGA and PGA success were observed in addition to significant reductions in acne lesion counts [37–40] (Table 2). An open-label prospective study used gene expression analysis to investigate trifarotene’s efficacy in acne at the molecular level [41]. Gene expression was compared between acne-free skin, active acne lesions, spontaneously resolved acne lesions and trifarotene-treated resolved lesions [41]. Most (287/354) modulated genes overlapped between spontaneously resolving and trifarotene-treated acne papules [41, 42]. Sixty-seven genes were uniquely modulated by trifarotene, suggesting that trifarotene exerts its therapeutic effect in acne by downregulating several key genes upregulated in acne lesions such as CXCL13 [41, 42]. This B-cell chemoattractant interacts with CXCR5, contributing to humoral immunity; increased CXCL13 may exacerbate acne severity [41, 42]. Trifarotene also downregulates secreted phosphoprotein 1 (SPP1). This cytokine binds to integrins and CD44, mediating cell adhesion and migration. SPP1 influences Th1 immune responses stimulated by C. acnes and may affect sebum production [41, 42]. Also, trifarotene downregulates matrix metalloproteinases (MMP) 12 and 13. These matrix-remodeling enzymes are induced by C. acnes and regulated by activator protein 1 (AP-1), contributing to inflammation and tissue destruction [41, 42]. This study's results provide a good insight into how retinoids may alter cytokine production and influence the skin microbiome.

Table 2.

Trifarotene clinical trials investigating acne vulgaris

Trial title (NCT number)	Study design (N)	Primary endpoint(s)	Results
Efficacy and safety of trifarotene 50 μg/​g cream vs vehicle cream in acne vulgaris (PERFECT 1 NCT02566369 and PERFECT 2 NCT02556788) [37]	Two Phase 3, multicenter, randomized, double-blind, parallel-group, vehicle-controlled studies (PERFECT 1: 1208 and PERFECT 2: 1212)	Number of subjects who achieved an IGA score of 1 (almost clear) or 0 (clear) and at least a 2-grade improvement from baseline to Week 12	Higher rates of IGA success in facial acne were observed with trifarotene: – 29.4% in PERFECT 1 and 42.3% in PERFECT 2 vs 19.5% and 25.7% for vehicle, respectively (P < 0.001)
Long-term safety and efficacy study of trifarotene 50 µg/g cream in subjects with acne vulgaris (NCT02189629) [38]	A Phase 3, multicenter, open-label, non-comparative safety and efficacy study (453)	Number of subjects who achieved a PGA score of 1 (almost clear) or 0 (clear) from baseline to Week 52	At Week 12, IGA and PGA success rates were 26.6% and 38.6%, respectively; success rates increased to 65.1% and 66.9%, respectively, at Week 52
A multicenter study to evaluate subject-reported outcomes with use of trifarotene 50 μg/g cream in the treatment of moderate facial and truncal acne vulgaris (NCT03915860) [39, 60]	A Phase 3b, multicenter study (3)	Change from baseline at Weeks 12 and 24 in: • DLQI total score • DLQI (Children’s DLQI) score • Comprehensive QOL measure for facial and truncal acne (CompAQ) total score • EQ-5D-5L index score • EQ-5D-5L VAS Number of participants with satisfaction questionnaire at Weeks 12 and 24/end of treatment: • Treatment area face • Treatment area trunk	After the first 12 weeks of treatment with trifarotene 50 μg/g cream, reductions in lesions, especially inflammatory lesions, were observed for all three cases All subjects indicated being satisfied overall with the trifarotene 50 µg/g topical treatment for both the face and trunk, satisfied with how easy it was to use and satisfied with the time the treatment took to work
Efficacy and safety of trifarotene cream when used with an oral antibiotic for the treatment of severe acne vulgaris (DUAL) (NCT04451330) [40, 61]	A Phase 4, multicenter, randomized, double-blind, placebo-controlled study (202)	Absolute change from baseline in facial total lesion counts to Week 12	At Week 12, there was a significant reduction in mean absolute change in lesion count in the trifarotene and doxycycline group compared with the vehicle group:  − 69.1 vs − 48.1 (P < 0.0001)

AIH, acne-induced hyperpigmentation, DLQI Dermatology Life Quality Index, EQ-5D-5L five-level EuroQol five-dimensional questionnaire, IGA Investigator’s Global Assessment, NCT National Clinical Trials, ODS overall disease severity, PGA Physician’s Global Assessment, QOL quality of life, VAS visual analog scale

Topical retinoids have also been investigated for treating acne sequelae. However, the trifarotene Phase 4 studies have the most participants. There have also been no head-to-head studies comparing these retinoids with trifarotene (Table 3). Adapalene 0.3%/benzoyl peroxide 2.5% gel resulted in a 21.7% and 26.9% decrease in scar count at Week 24 and Week 48, respectively [43]. Adapalene 0.1% gel also reduced hyperpigmentation in 65 African patients with dark skin after 12 weeks of treatment. Tretinoin 0.05% demonstrated a marked improvement in superficial acne scars in one patient after 4 months of daily application [44]. After 40 weeks of daily application, tretinoin 0.1% significantly lightened post-inflammatory hyperpigmentation in 92% of patients compared with 57% in the vehicle group [33]. In 34 patients, tazarotene 0.1% showed a significant improvement in facial acne scar severity from baseline [45]. Additionally, after 18 weeks of daily application, tazarotene 0.1% significantly reduced the intensity and area of hyperpigmentation compared with vehicle in 74 darker-skinned patients [33].

Table 3.

Clinical studies investigating topical retinoids for the management and treatment of atrophic acne scarring and AIH

	Trial title (NCT number)	Study design (N)	Primary endpoint(s)	Results
Atrophic acne scarring studies	Evaluation of the risk of atrophic acne scar formation during treatment of acne vulgaris subjects with trifarotene 50 μg/g cream vs vehicle cream (START) (NCT04856904) [17, 62]	A Phase 4, multicenter, randomized, double-blind, vehicle-controlled study (121)	Absolute change from baseline in total atrophic acne scar count per half face at Week 24	At Week 24, a statistically significantly greater reduction in the mean absolute change from baseline in the total atrophic scar count was noted in the trifarotene- vs vehicle-treated area: − 5.9 vs − 2.7 (P < 0.0001)
	Adapalene 0.3%—benzoyl peroxide 2.5% gel and risk of formation of atrophic acne scars (OSCAR) (NCT02735421) [43, 63]	A Phase 4, 2-part study: • Part 1: A0.3/BPO2.5 gel or vehicle was applied on each half-face for 24 weeks in a randomized, investigator-blinded, split-face design • Part 2: 24-week, open-label extension phase during which A0.3/BPO2.5 gel was applied on both sides of the face (Part 1: 54 and Part 2: 45)	Part 2: Total atrophic acne scar count per half-face at Week 24	Adapalene 0.3%/benzoyl peroxide 2.5% gel resulted in a 21.7% and 26.9% decrease in scar count at Week 24 and Week 48, respectively
	A case study on the treatment of fine atrophic acne scarring with tretinoin 0.05% [44, 64] (case study)	Tretinoin 0.05% cream applied to unwashed affected keloid scars, nightly for 4 months (1)	Improvement in scarring	Tretinoin 0.05% demonstrated a marked improvement in superficial acne scars in one patient after 4 months of daily application
	A comparison between microneedling daycare procedure and tazarotene 0.1% gel local application in acne scarring (NCT03170596) [45]	A prospective, randomized, active-controlled, observer-blinded pilot study (36)	Improvements in acne scar severity based on: • Goodman and Baron quantitative and qualitative scores • Subjective independent dermatologist score (range, 0–10)	In 34 patients tazarotene 0.1% showed a significant improvement in facial acne scar severity from baseline to final visit at 6 months
AIH studies	Evaluation of AIH during treatment of acne vulgaris subjects with trifarotene 50 μg/g cream (LEAP) (NCT05089708) [18, 65]	A Phase 4, multicenter, randomized, double-blind, vehicle-controlled study (123)	Absolute change from baseline in AIH ODS scores at Week 24	At Week 24, AIH ODS scores were comparable between trifarotene and vehicle groups: − 2.1 vs − 2.1 (P = 0.8879); however, at Week 12, there was a significant difference in the trifarotene group compared with the vehicle group: − 1.6 vs − 1.1 (P = 0.03)
	Adapalene gel 0.1% for topical treatment of acne vulgaris in African patients [33, 57]	An open-label, 12-week study (65)	Effect on hyperpigmented lesions in people with dark skin	AIH macules and AIH density decreased in 66% of patients
	Topical tretinoin (retinoic acid) therapy for hyperpigmented lesions caused by inflammation of the skin in black patients [33, 66]	A double-blind, vehicle controlled 40-week study (54)	Color change of lesions assessed by: • The clinical investigator • Colorimetry • Light microscopy • Photography	Reduction of AIH in 92% of tretinoin-treated patients vs 57% of control (P < 0.001)
	Tazarotene cream for post inflammatory hyperpigmentation and acne vulgaris in darker skin: a double-blind, randomized, vehicle-controlled study [33, 67]	A double-blind, randomized, vehicle controlled, 18-week study (74)	ODS of PIH: • Pigmentary intensity of hyperpigmented lesions • Area of hyperpigmented lesions • Degree of hypopigmentation	Mean reductions in tazarotene compared with vehicle respectively: • ODS, 1.2 vs. 0.2, P = 0.010 • Pigmentary intensity, 1.1 grades vs. 0.5 grades (P = 0.044) • Area of hyperpigmented lesions, 0.9 grades vs 0.4 grades (P = 0.026)

A 0.3/BPO2.5 adapalene 0.3%/benzoyl peroxide 2.5%, AIH acne-induced hyperpigmentation; ODS overall disease severity; NCT National Clinical Trials

The START and LEAP Phase 4 studies investigated the effect of trifarotene in patients with acne and a risk of atrophic acne scar formation or patients with acne and AIH, respectively [17, 18]. The LEAP study did not meet its primary endpoint of the absolute change from baseline in AIH overall disease severity (ODS) at Week 24 [18]. ODS is a 9-point scale that assesses the pigmentary intensity of hyperpigmented lesions with 0 = clear and 8 = severe [18]. A key secondary endpoint was a significant reduction in total post-acne hyperpigmentation index (PAHPI) score in the trifarotene group compared with the vehicle group at Week 24 (− 18.9% vs − 11.3%) [18]. PAHPI is a composite score assessment of the full face, with weighted values assigned to lesion size, intensity and quantity [18]. The reduction in PAHPI was observed as early as Week 12 in the trifarotene group compared with the vehicle group (– 8.4 vs – 4.5%). All adverse events were mild or moderate in severity, and local tolerability was good in both trifarotene and vehicle groups [18]. Additionally, results from the START study show a greater reduction in atrophic acne scar counts as early as Week 2 in the trifarotene group compared with the vehicle group [17]. The incidence of treatment-emergent adverse events was 5.8% (trifarotene) and 2.5% (vehicle); the most common (> 1%) was skin tightness (1.7% vs 0.8%), and all events were mild to moderate in severity [17].

A post hoc analysis of the START study found that from baseline to Week 24, there was a statistically significant difference in total atrophic acne scar counts in all age groups with trifarotene treatment compared with vehicle treatment. The greatest improvement was observed in patients aged > 27 years [46].

Similarly, in the LEAP post hoc analysis, for total PAHPI score categorized by age, the greatest improvement was observed in patients aged 21–28 years [46]. These results support using trifarotene to combat adult acne, concomitant AIH and atrophic acne scarring concurrently and effectively.

Retinoids Should Be Implemented into a Treatment Routine as Early as Possible for Patients with Darker Fitzpatrick Phototypes or Patients at Risk of Atrophic Acne Scarring

Data shows that inflammation drives the development of acne lesions, atrophic acne scars and AIH [34, 47]. Early inhibition of inflammatory pathways with topical retinoids can reduce the onset of atrophic acne scars and AIH [34, 47]. Compared with atrophic acne scars, which are usually permanent [48], AIH fades naturally over time. However, the process of spontaneous resolution may take ≥ 3–24 months [49]. The rate of clearance may depend on the contrast between the pigmented area and the surrounding skin tone, which may correlate with the severity of the inflammatory process and the risk of AIH, based on skin type [49]. The most frequent occurrence of AIH is observed in individuals with darker skin tones (Fitzpatrick skin phototypes IV–VI), with a reported prevalence ranging from 45.5 to 87.2% [49, 50]. AIH in individuals with darker skin tones often takes longer to resolve because of the higher epidermal melanin content [51].

Results from a prospective split-face study of 32 subjects with moderate facial acne over 6 months demonstrated that 66.2% of scars did not resolve within 6 months and 81.7% of the scars remaining at 6 months were still present at the 2-year follow-up [3]. Atrophic acne scars and photoaged skin are both characterized by net collagen degradation in the dermis [52]; photoaged skin is caused by chronic exposure to ultraviolet light [52] and atrophic scars by an altered wound healing response to cutaneous inflammation [53]. A study investigating the photoaged skin of mice found that treatment with tretinoin resulted in the appearance of new collagen in the repair zone of the papillary dermis [52]. This observation, coupled with the known effects of retinoids on cell turnover and collagen production, suggests a potential therapeutic role for retinoids in the treatment or prevention of atrophic acne scars.

Retinoids Should Be Incorporated Within a Comprehensive Skincare Regimen that Includes Adequate Photoprotection when Treating Patients with Darker Fitzpatrick Phototypes

African Americans are less likely to use sunscreen compared with other races despite their increased risk of developing pigment-related disorders [54]. A study investigating sunscreen composition in African American and Hispanic individuals with pigmentary discoloration found that patients who received sun protection factor (SPF) 60 sunscreen showed a greater improvement in overall skin lightening and number of hyperpigmented macules compared with patients who received SPF 30 sunscreen [55]. The outcomes of the LEAP study investigating the effect of trifarotene on AIH confirms the importance of including sunscreen in the overall skincare regimen [18]. The ODS scores showed a rapid reduction in AIH with trifarotene treatment, with nominal significance between trifarotene and vehicle achieved at Week 12 (P = 0.03) [18]. Some investigators attributed this to a comprehensive skincare routine with an active (vehicle was perceived to be active) ingredient that also included SPF 30, instructed to be reapplied to the face before sun exposure.

Management of Acne and Acne Sequelae Should Include Maintenance Therapy with Topical Retinoids

The START Phase 4 controlled study found that there was a greater reduction in total atrophic acne scar count in the trifarotene group compared with the vehicle group at Week 24 (55.2% vs 29.9%) with statistical significance established as early as Week 2 (P = 0.001) [17]. The early and continued improvement observed with trifarotene treatment supports using trifarotene as a first-line and maintenance treatment option for acne and acne sequelae. At Week 24, 81.8% (n = 99/121) of patients successfully completed the study and adhered to the treatment regimen [17]. Patient education by PCPs was found to improve compliance significantly as patients were four times more likely to follow directions when the role of products was explained compared with when no explanation was given [56]. Thus, patient education on retinoid use along with notable improvement of atrophic acne scars may contribute to adherence.

Suggested Analyses to Further Investigate the Effect of Retinoids on Acne Sequelae

The current AAD guidelines do not provide guidance on how to approach the treatment of acne sequelae, as the guidelines themselves acknowledge [28]. Data from clinical studies with adapalene, tretinoin and tazarotene provide evidence to support the effectiveness of retinoids to treat acne sequelae as reductions in atrophic acne scar count, scar severity and AIH were observed [43–45, 57]. The START Phase 4 study demonstrated a reduction in atrophic acne scarring with trifarotene across all Fitzpatrick skin phototypes and acne severities [17]. Trifarotene was well tolerated, and any adverse events were mild or moderate in severity, consistent with outcomes from previous studies [17, 18, 38–40].

Further analyses would be helpful to provide more information on effective and evidence-based treatments for acne sequelae. Skin examination analyses could verify the importance of applying photoprotection and maintaining barrier protection to improve atrophic acne scarring. In addition, several key research questions could be addressed through biomarker and transcriptomic analyses.

Biomarker analyses: How do biomarker responses to retinoids vary with patient characteristics (age, atrophic scar type, acne severity and ethnicity) in patients with atrophic acne scars? What biomarkers can predict the onset of atrophic acne scarring? What biomarkers can be used to assess scar remodeling in atrophic acne scars? Furthermore, how can the genes involved in acne scarring severity (e.g., variations in NEDD4, WNT10A, MMP2 and SPP1⁺ macrophage subset [41, 42, 58]) be targeted therapeutically?

Transcriptomic analyses: How do retinoids affect RAR-γ, melanogenesis and scar improvement at the transcriptomic level, including associated mechanisms of action? Also, how does knocking out RAR-γ alter the effect of retinoids on acne sequelae in human cell or skin explant culture?

Additionally, studies in patients with skin of color (SOC) to determine patients at risk of AIH may help guide decisions in clinical practice. The Fitzpatrick phototype system, originally designed to assess sunburn risk during phototherapy, is now commonly used in routine clinical practice to categorize skin color. However, this practice can lead to subjective and potentially erroneous assessments as clinicians may conflate the classification system with race/ethnicity [59]. Although alternative skin type classification systems have been developed, the Fitzpatrick phototype remains the most common. Therefore, an improved method of categorizing and describing skin color needs to be considered [59] in both clinical practice and acne/acne sequelae clinical studies. Improving the classification of skin type will likely improve the quality of data from clinical trials. Consequently, decision-making recommendations, in clinical practice, should then be more reliable and accurate for patients with SOC.

Conclusions

Topical retinoids are central to improving treatment outcomes for patients with acne and acne sequelae because of their notable efficacy, safety and tolerability. Adapalene, tretinoin and tazarotene have been observed to reduce acne and acne sequelae in several studies. Trifarotene has been extensively studied in Phase 3 studies, with notable success for the treatment of mild-to-moderate acne and, recently, in a Phase 4 study, for the treatment of atrophic acne scarring across Fitzpatrick phototypes. To gain a better understanding of the specific needs of US patients and regions with similar populations, it is beneficial to establish a cohesive perspective from US-based dermatologists when treating acne and its sequelae. The AAD guidelines recognize the need for acne sequelae treatment guidance. Further analyses on the effects of retinoids, as suggested here, could help bridge the gap between evidence and practical use of topical retinoids. Ultimately, improving outcomes for patients with acne and acne sequelae requires consideration of effective therapies based on available data and effective patient education to optimize treatment adherence.

Author Contributions

Naiem Issa, Andrew Alexis, Hilary Baldwin, Iltefat Hamzavi, Adelaide Hebert, Pearl Kwong, Edward Lain, Angela Moore, Omar Noor, Todd Schlesinger, Jonathan Weiss, Heather Woolery-Lloyd, JP York, Kate Zibilich Holcomb, Leon Kircik and Rajeev Chavda participated in drafting, critical revision and approval of the final version of the manuscript. Galderma provided a formal review of the publication (reviewed for accuracy), but the authors had final authority.

Funding

Authors were invited by Galderma who funded the planning and delivery of this project including and the journal’s rapid service and open access fees.

Data Availability

Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.

Declarations

Conflict of Interest

Dr. Naiem Issa has acted as a speaker, consultant and/or advisor for AbbVie, Almirall, Bristol-Myers Squibb, Castle Biosciences, Dermavant Sciences, DermTech, Galderma, Incyte, Journey, LEO Pharma, Lilly, National Eczema Association, Ortho Dermatologics, Pfizer, Regeneron, Sanofi, SUN Pharma, UCB, Verrica Pharmaceuticals and WebMD. Prof. Andrew Alexis has received grants (funds to institution) from LEO Pharma, Amgen, Galderma, Arcutis, Dermavant, AbbVie and Castle; participated on advisory boards or as a consultant for LEO Pharma, Galderma, Pfizer, Sanofi-Regeneron, Dermavant, Beiersdorf, Ortho, L’Oréal, Bristol-Myers Squibb, Bausch Health, UCB Pharma, Arcutis, Janssen Pharmaceuticals, Allergan, Almirall, AbbVie, Amgen, VisualDx, Eli Lilly, Swiss American, Cutera, Cara Therapeutics, EPI Health, Incyte Corporation, Castle, Apogee, Alphyn, Canfield, Avita Medical and Genentech; acted as a speaker for Regeneron, Sanofi, Bristol-Myers Squibb, L’Oréal, Janssen Pharmaceuticals and Johnson & Johnson; received royalties from Springer, Wiley-Blackwell and Wolters Kluwer Health; received equipment from Aerolase. Dr. Hilary Baldwin has acted as an investigator, consultant and/or speaker for Almirall, Bausch Health, Cassiopeia, EPI Health, Galderma, La Roche-Posay, L’Oréal, Mayne Pharma, Sol–Gel, Sun Pharma and Vyne. Dr. Iltefat Hamzavi has acted as a consultant and investigator AbbVie, Pfizer, Incyte, UCB, Boehringer Ingelheim, Sonoma, Union therapeutics, Novartis, Jansen, ITN, Avita, Galderma, Vimela, Almirall, Sonoma, Boehringer Ingelheim and Merck. Dr. Adelaide Hebert has received research grants paid to UTHealth McGovern Medical School from Galderma, Ortho Dermatologics, Pfizer, Arcutis, Dermavant, Amgen, Lilly, Leo Pharma; honoraria for consultation/speaker/advisor: Pfizer, Arcutis, Dermavant, Leo Pharma, Incyte, Almirall, Lilly, Beiersdorf and LaRoche-Posay. Dr. Pearl Kwong has acted as investigator, or consultant or speaker for Almirall, Bausch Health/Ortho, Galderma, Cerave, Apogee, AbbVie, Arcutis, Dermavant, Incyte, Sanofi/Regeneron, Pfizer, Eli Lilly, EPI Health UCB, Amgen, Bristol-Myers Squibb, Leo, Sun Pharma, Verrica Pharmaceuticals, Novan, Journey Pharmaceuticals and Novartis. Dr. Edward Lain has served as an investigator, speaker, advisor and/or consultant for AbbVie, Almirall, Amgen, Arcutis, Bausch, Beiersdorf, Bristol-Myers Squibb, Cassiopeia, Cellceutix, Dermavant, Eli Lilly, Galderma, GSK, Incyte, Kenvue, LEO, L’Oreal, Novartis, Pfizer, Pierre Fabre, Regeneron, Sanofi, Sun Pharma, Takeda, UCB Pharma and Vyne. Dr. Angela Moore has received honoraria or research funds from Almirall, Galderma, Mayne, Ortho Dermatologics, Parexel and Vyne. Dr. Omar Noor is a speaker, consultant and/or advisor for AbbVie, Almirall, Amgen Inc, Arcutis, Bristol-Myers Squibb, Castle Biosciences, Dermavant Sciences, DermTech, Galderma, Incyte Corporation, Journey Medical, LEO Pharma, Lilly, Novartis Pharmaceuticals Corporation, Ortho Dermatologics, Pfizer, Procter & Gamble Ventures, Regeneron Pharmaceuticals Inc, Sanofi Genzyme, Sun Pharmaceutical Industries Ltd and UCB. Dr. Todd Schlesinger serves as a consultant, investigator, speaker and/or advisor for AbbVie, Almirall, Allergan (An AbbVie company), ASLAN Pharma, Arcutis, Biofrontera, Beiersdorf, Benev, Bristol-Myers Squibb, Castle Biosciences, Galderma, Eli Lilly, ExoCoBio, Incyte, Janssen, LEO, L’Oreal, Novartis, Pfizer, Regeneron, Sanofi, Sun Pharma, Takeda, UCB Pharma and Verrica Pharmaceuticals. Dr. Jonathan Weiss serves as an advisory board member for Bristol-Myers Squibb, Dermavant Sciences, Foamix, Galderma Laboratories, L.P., Incyte Corporation, Novartis and UCB receiving honoraria; as a consultant for Arcutis, Inc., Biofrontera, Cutera, Inc., Leo Pharma Inc, Ortho Dermatologics and UCB receiving fees or honoraria; as an investigator for AbbVie, Bausch Health, Biofrontera, Bristol-Myers Squibb, Cutera, Inc., Dermavant Sciences, Foamix, Galderma, L.P., LEO Pharma, Mindera, Moberg Pharma North, America LLC, Novartis, Palvella Therapeutics and Verrica Pharmaceuticals Inc receiving grants and research funding; as a speaker for AbbVie, Arcutis, Inc., Galderma, L.P., Ortho Dermatologics, Regeneron and Sanofi Genzyme receiving honoraria. Dr. Heather Woolery-Lloyd has served as a research/investigator for AbbVie, Allergan, Eirion Therapeutics, Galderma, Pfizer and Arcutis. An advisor/consultant for Ortho Dermatologics, AbbVie, Incyte, Johnson & Johnson Consumer, Inc., L’Oréal, Arcutis, Beiersdorf, Unilever, Procter & Gamble, SC Johnson, Kenvue and Galderma. Acted on the speakers' bureau for Incyte, L’Oréal, Ortho Dermatologics, Pfizer and Galderma. Dr. JP York is an employee of Galderma. Dr. Katherine (Kate) Zibilich Holcomb has served as an investigator, speaker, advisor and/or consultant for AbbVie, Almirall, Bristol Myers Squibb, Galderma, Incyte and Sun Pharma. Prof. Leon Kircik has received research grants from AbbVie, Allergan, Almirall, Amgen, Arcutis, Boehringer Ingelheim, Breckenridge Pharma, Bristol-Myers Squibb, Celgene, Cellceutix, Centocor, Combinatrix, Connetics, Coria, Dermavant, Dermira, Dow Pharma, Dr Reddy’s Laboratories, Eli Lilly, Galderma, Genentech, GlaxoSmithKline, Idera, Johnson & Johnson, LEO Pharma, Maruho, Merck, Medicis, Novartis AG, Pfizer, PharmaDerm, Promius, Stiefel, Sun Pharma, UCB Pharma, Valeant and XenoPort; has received honoraria from AbbVie, Allergan, Almirall, Amgen, Arcutis, Biogen Idec, Bristol-Myers Squibb, Celgene, Cipher, Connetics, Dermavant, Dermira, Dr Reddy’s Laboratories, Eli Lilly, Galderma, Genentech, GlaxoSmithKline, Johnson & Johnson, LEO Pharma, Merck, Novartis AG, PharmaDerm, Promius, Serono (Merck Serono International SA), Stiefel, Sun Pharma, Taro, UCB Pharma and Valeant. Dr. Rajeev Chavda is an employee of Galderma.

Ethical Approval

Information presented in this article is based on previously conducted studies and does not contain any data from new studies with human participants or animals performed by any of the authors.