An update on the pharmacological management of acne vulgaris: the state of the art.

INTRODUCTION: Acne vulgaris is a chronic inflammatory disease of the pilosebaceous unit that affects approximately 9.4% of the global population. Current treatment strategies aim to target as many pathogenic factors involved in the appearance of acne lesions and are centered on a systematic treatment escalation based on disease severity, extension, and treatment response, starting with topical treatments for mild cases and progressing over to systemic therapies in more severe cases. A literature search, which included clinical guidelines, clinical studies, and review articles on acne treatment and maintenance, was conducted to review the pharmacological approaches currently available to treat this disease. AREAS COVERED: Topical therapies such as topical retinoids, benzoyl peroxide, azelaic acid, salicylic acid, topical antibiotics, and clascoterone, as well as systemic treatments such as oral antibiotics and isotretinoin are discussed in detail. Combined oral contraceptives and spironolactone will not be discussed in this article. EXPERT OPINION: There is a need for a blockbuster acne drug that simultaneously targets the four main pathogenic factors involved in the appearance of acne lesions while presenting with minimal side effects. Until such a drug exists, combination therapy will remain the standard of treatment for most acne patients.

Role of Trifarotene in the Management of Acne in Indian Patients: Insights From an Indian Dermatology Experts' Meeting.

Acne vulgaris, a prevalent inflammatory skin condition, significantly impacts individuals worldwide, particularly adolescents and adults. Its chronic nature, associated sequelae, and psychosocial impact underscore the substantial burden it poses. Current treatment guidelines primarily address facial acne, with limited guidance on managing truncal acne. Personalized approaches are increasingly recognized as essential for tailoring treatments to individual patient needs. This review integrates insights from an Indian Dermatology Experts' Meeting, featuring perspectives from nine leading dermatologists. Discussions centered on analyzing acne's burden, its effects on quality of life (QoL), unmet needs in management, trifarotene's role in Indian therapy, anticipated challenges, and the importance of ancillary care. The experts highlighted acne's profound impact on patients' QoL and identified gaps in current management guidelines, especially concerning truncal acne. Trifarotene, a fourth-generation topical retinoid approved by the FDA and Drug Controller General of India (DCGI) for facial and truncal acne, demonstrated safety and efficacy across age groups. This synthesis of expert perspectives underscores the need for personalized acne management. Trifarotene emerges as a promising therapeutic option but challenges remain, particularly in optimizing ancillary care to minimize treatment-related adverse effects. Addressing these issues will enhance treatment outcomes and patient satisfaction in acne management, emphasizing the importance of tailored approaches in clinical practice.

Trifarotene alleviates skin photoaging injury by inhibition of JNK/c-Jun/MMPs.

Long-term exposure to ultraviolet (UV) radiation induces skin photoaging, which manifests as oxidative stress, inflammation, and collagen degradation. Multiple approaches (topical or systemic retinoids, antioxidants, alpha-hydroxy acids, laser, surgery) are used in the treatment of photoaged skin, and the use of topical retinoids is currently a primary clinical treatment. Previous studies revealed that retinoic acid promotes keratinocyte proliferation and reduces melanin deposition and matrix metalloproteinase (MMP) secretion; it also causes potential allergic and inflammatory damage to the skin. This study aimed to investigate the therapeutic effects and mechanisms of trifarotene, a functional retinoic acid analog, on UV-irradiated photoaging ICR and BALB/c nude mice and UVB photodamaged human epidermal keratinocyte (HaCaT) cells by examining indicators such as collagen, oxidoreductase, and inflammatory factor presence through histochemical staining, Western blot, and ELISA. Results suggested that trifarotene significantly reduced UV-induced photoaging in mouse skin tissue, potentially by reducing oxidative stress damage and inflammatory factor release, and inhibiting melanin deposition and collagen degradation by downregulating MMP expression. Concentrations of malondialdehyde, tyrosinase, interleukin-6, interleukin- 12, and tumor necrosis factor-alpha in photoaged skin decreased, while SOD content in photodamaged HaCaT cells significantly increased. Trifarotene (3.3 µmol L-1) inhibited phosphorylated JNK and c-Jun expression both independently and collaboratively with the JNK activator anisomycin, demonstrating that trifarotene mitigates UV-induced collagen degradation and apoptosis through inhibition of the JNK/c-Jun/MMPs signaling pathway.

An Overview on the Management of Atrophic Acne Scars: The Role of Trifarotene as an Adjunct.

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.

A review of the topical management of acne and its associated sequelae in the Asia-Pacific region with a spotlight on trifarotene.

Acne, a highly prevalent skin disease, can be particularly bothersome for patients of Asian background because of its impact on self-confidence and social interactions. In addition to active acne lesions, some patients may develop sequelae such as scarring, macular/postinflammatory hyperpigmentation, or erythema. The tendency of Asian skin to develop sequelae because of its increased susceptibility to irritation, cultural preferences for lighter skin phototypes, and differences in skincare regimens may all contribute to the increased burden of acne. Moreover, many Asia-Pacific countries do not have their own guidelines for acne management, and those that do often have no schedule in place for regular updates. In this article, we provide a critical review of the published guidance for the management of acne and its sequelae in the Asia-Pacific region, identifying gaps in current recommendations that could be addressed to enhance standards of acne care in Asia-Pacific countries. Along with highlighting the importance of a comprehensive skincare regimen to increase treatment efficacy and adherence, we discuss topical retinoids and retinoid combination options in the acne armamentarium that may be beneficial for sequelae prevention and management, such as adapalene 0.3% ± benzoyl peroxide 2.5%, tretinoin 0.05%, tazarotene 0.1%, and trifarotene 0.005%. In particular, trifarotene 0.005% has been observed to significantly reduce acne scar counts in a Phase 4 study. The recent data highlight the need to establish up-to-date guidance for acne and acne sequelae management in Asia-Pacific countries to provide optimal care to Asian patients.

Importance of treating acne sequelae in skin of color: 6-month phase IV study of trifarotene with an appropriate skincare routine including UV protection in acne-induced post-inflammatory hyperpigmentation.

BACKGROUND: Acne-induced hyperpigmentation (AIH) may accompany acne vulgaris (AV) inflammation in all skin phototypes. Trifarotene has shown depigmenting properties in vivo. This study evaluated trifarotene plus skincare because it is increasingly recognized that holistic AV management should include skincare and treatments. METHODS: This is a phase IV double-blind, parallel-group study of patients (13-35 years) with moderate AV and AIH treated with trifarotene (N = 60) or vehicle (N = 63) plus skincare regimen (moisturizer, cleanser, and sunscreen) for 24 weeks. Assessments included the AIH overall disease severity (ODS) score, post-AV hyperpigmentation index (PAHPI), exit interviews, photography, and acne assessments. Standard safety assessments were included. RESULTS: Trifarotene 50 µg/g cream improved significantly from baseline in ODS score versus vehicle (-1.6 vs. -1.1, P = 0.03) at Week 12, but scores were comparable between groups at Week 24 (primary endpoint). Trifarotene had a better reduction in PAHPI score at Week 24 (-18.9% vs. -11.3% vehicle, P < 0.01). Lesion count reductions were higher with trifarotene at Week 12 versus vehicle (P < 0.001) and at Week 24 (P < 0.05), as were IGA success rates versus vehicle at Weeks 12 (P < 0.05) and 24 (P < 0.05). Patients agreed that the skincare regimen contributed to less irritation, making treatment adherence easier. Photography showed improvements in pigmentation and erythema across all skin types. AEs were more common in the vehicle group versus trifarotene (30.2 vs. 16.7%, respectively). CONCLUSIONS: In all skin phototypes, there was more rapid improvement in the ODS and PAHPI scores with trifarotene by Weeks 12 and 24, respectively. The combination of trifarotene and skincare correlated with high patient satisfaction and adherence to the treatment protocol.

Guidelines of care for the management of acne vulgaris.

BACKGROUND: Acne vulgaris commonly affects adults, adolescents, and preadolescents aged 9 years or older. OBJECTIVE: The objective of this study was to provide evidence-based recommendations for the management of acne. METHODS: A work group conducted a systematic review and applied the Grading of Recommendations, Assessment, Development, and Evaluation approach for assessing the certainty of evidence and formulating and grading recommendations. RESULTS: This guideline presents 18 evidence-based recommendations and 5 good practice statements. Strong recommendations are made for benzoyl peroxide, topical retinoids, topical antibiotics, and oral doxycycline. Oral isotretinoin is strongly recommended for acne that is severe, causing psychosocial burden or scarring, or failing standard oral or topical therapy. Conditional recommendations are made for topical clascoterone, salicylic acid, and azelaic acid, as well as for oral minocycline, sarecycline, combined oral contraceptive pills, and spironolactone. Combining topical therapies with multiple mechanisms of action, limiting systemic antibiotic use, combining systemic antibiotics with topical therapies, and adding intralesional corticosteroid injections for larger acne lesions are recommended as good practice statements. LIMITATIONS: Analysis is based on the best available evidence at the time of the systematic review. CONCLUSIONS: These guidelines provide evidence-based recommendations for the management of acne vulgaris.

Trifarotene Reduces Risk for Atrophic Acne Scars: Results from A Phase 4 Controlled Study.

BACKGROUND: Atrophic acne scarring often accompanies acne vulgaris. The efficacy of topical retinoids for treatment of acne is well documented; however, evidence for use in atrophic acne scars is limited. METHODS: In this randomized, split-face, double-blind study, subjects (age: 17-34 years, N = 121) with moderate-to-severe facial acne, with acne scars present, were treated with either trifarotene 50 µg/g or vehicle once daily for 24 weeks. Efficacy was assessed by absolute and percent change from baseline in atrophic acne scar counts, Scar Global assessment (SGA), and IGA success rates as well as acne lesion counts. RESULTS: 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) with differences between sides noted as early as week 2 (- 1.5 vs - 0.7; p = 0.0072). The SGA success rate was higher in the trifarotene side at week 12 (14.9% vs 5.0%, P < 0.05) and improved through week 24 (31.3% vs 8.1%, P < 0.001). Similarly, at week 24, the IGA success rate was higher with trifarotene (63.6% vs 31.3%, P < 0.0001) along with reductions in total (70% vs 45%) and inflammatory (76% vs 48%) lesion counts. The incidence of treatment-emergent adverse events was 5.8% (trifarotene) and 2.5% (vehicle); most common (> 1%) was skin tightness (1.7% vs 0.8%), and all events were mild to moderate in severity. CONCLUSIONS: Trifarotene was effective and well tolerated in treating moderate-to-severe facial acne and reducing atrophic acne scars, with reduction of total atrophic scar count as early as week 2. TRIAL REGISTRATION: Clinicaltrials.gov NCT04856904.

Management of Acne Vulgaris With Trifarotene.

Topical retinoids have an essential role in treatment of acne. Trifarotene, a topical retinoid selective for retinoic acid receptor (RAR) γ, is the most recent retinoid approved for treatment of acne. RAR-γ is the most common isoform of RARs in skin, and the strong selectivity of trifarotene for RAR-γ translates to efficacy in low concentration. Trifarotene, like other topical retinoids, acts by increasing keratinocyte differentiation and decreasing proliferation, which reduces hyperkeratinization. Retinoids have also been shown to inhibit inflammatory pathways via effects on leukocyte migration, toll-like receptors, and Activator Protein (AP)-1. Large-scale randomized, controlled clinical trials have demonstrated trifarotene to be safe, well tolerated, and efficacious in reducing both comedones and papules/pustules of acne. However, unlike all other retinoids, trifarotene is the first topical retinoid with rigorous clinical data on safety and efficacy in truncal acne. Data supporting use of trifarotene to manage acne are reviewed in this publication.

Low irritation potential of tazarotene 0.045% lotion: Head-to-head comparison to adapalene 0.3% gel and trifarotene 0.005% cream in two studies.

BACKGROUND: Irritation with topical retinoids presents a significant impediment to acne treatment adherence. Two studies assessed the irritation potential of tazarotene 0.045% lotion versus adapalene 0.3% gel and trifarotene 0.005% cream. METHODS: In two double-blind, 12-day modified cumulative irritation patch studies, healthy adults (N = 20 each) had two active patches, containing 0.1 cc of tazarotene 0.045% lotion and either adapalene 0.3% gel (Study 1) or trifarotene 0.005% cream (Study 2), and one control patch (no product) placed on their upper back. Skin irritation was assessed and patches were replaced every 2-3 days. RESULTS: In Study 1, tazarotene 0.045% lotion and adapalene 0.3% gel were both mildly irritating, though irritation was lower overall with tazarotene 0.045% lotion. In Study 2, significantly greater irritation was observed with trifarotene 0.005% cream than tazarotene 0.045% lotion, beginning two days after the first patch application and at each subsequent visit. In sub-analyses of data from both studies, irritation among participants with acne was similar to the overall study populations. CONCLUSIONS: In two head-to-head studies comparing the irritation potential of third- and fourth-generation retinoids, tazarotene 0.045% lotion was significantly less irritating than trifarotene 0.005% cream and numerically less irritating than adapalene 0.3% gel.

Trifarotene 0.005% Cream in the Treatment of Facial and Truncal Acne Vulgaris in Patients with Skin of Color: a Case Series.

The clinical appearance of acne vulgaris (AV) and the response to therapeutic agents may vary in people with skin of color (SoC) compared with those with lighter skin types. Given the heightened potential for postinflammatory hyperpigmentation and keloid development, effective and timely AV treatment in patients with SoC is especially important. However, these patients are frequently underrepresented in clinical trials, and SoC photographs are generally underrepresented in dermatology. Trifarotene 0.005% cream is a retinoid approved for the once-daily topical treatment of AV, and was studied in large-scale clinical trials that assessed the treatment of AV on both the face and trunk. For severe AV, a topical retinoid may be used in combination with an oral antibiotic, such as doxycycline. Five subjects covering Fitzpatrick skin phototypes III, IV, V, and VI were selected from two larger studies to visually demonstrate treatment of clinically diagnosed AV with trifarotene 0.005% cream. Two subjects received 24 weeks of treatment with trifarotene 0.005% cream for moderate AV on the face and trunk, while three subjects received 12 weeks of treatment with trifarotene 0.005% cream in association with 120 mg oral doxycycline with modified polymer coating for severe facial AV. This case series supports the favorable efficacy and safety of facial and truncal AV treatment with trifarotene 0.005% cream, with or without oral doxycycline, in subjects with SoC (phototypes III-VI).

A Randomized, Controlled Trial of Trifarotene Plus Doxycycline for Severe Acne Vulgaris.

Objective: We evaluated the efficacy and safety of trifarotene plus oral doxycycline in acne. Methods: This was a randomized (2:1 ratio) 12-week, double-blind study of once-daily trifarotene cream 50µg/g plus enteric-coated doxycycline 120mg (T+D) versus trifarotene vehicle and doxycycline placebo (V+P). Patients were aged 12 years or older with severe facial acne (≥20 inflammatory lesions, 30 to 120 non-inflammatory lesions, and ≤4 nodules). Efficacy outcomes included change from baseline in lesion counts and success (score of 0/1 with ≥2 grade improvement) on investigator global assessment (IGA). Safety was assessed by adverse events and local tolerability. Results: The study enrolled 133 subjects in the T+D group and 69 subjects in the V+P group. The population was balanced, with an approximately even ratio of adolescent (12-17 years) and adult (≥18 years) subjects. The absolute change in lesion counts from baseline were: -69.1 T+D versus -48.1 V+P for total lesions, -29.4 T+D versus -19.5 V+P for inflammatory lesions, and -39.5 T+D versus -28.2 for non-inflammatory lesions (P<0.0001 for all). Success was achieved by 31.7 percent of subjects in the T+D group versus 15.8 percent in the V+P group (P=0.0107). The safety and tolerability profiles were comparable between the T+D and V+P arms. Conclusion: T+D was demonstrated to be safe and efficacious as a treatment option for patients with severe acne.

Transcriptomics Analysis Indicates Trifarotene Reverses Acne-Related Gene Expression Changes.

Background and Objectives: Trifarotene is a topical retinoid selective for retinoic acid receptor gamma that was recently approved for treatment of acne vulgaris. We performed a gene expression analysis to identify the molecular and cellular impact of trifarotene treatment on acne papules. Methods: In this open-label prospective study, subjects with moderate inflammatory acne of the back were treated with trifarotene 0.005% or vehicle cream on dedicated areas for 27 days, and 4 biopsies were collected from each subject (1 from skin without a visible acne lesion and three at the site of an acne papule: one baseline, one after vehicle treatment, and one after trifarotene treatment). Large scale gene expression profiling of the biopsies was performed using Affymetrix technology, treatment-specific gene expression profiles were generated using statistical modeling, and pathway analysis was performed. Using single-cell RNAseq data, in silico deconvolution of transcriptomics data was performed to identify cellular signatures. Results: We discovered a unique set of 67 genes modulated by trifarotene that are primarily involved in cellular migration, inflammation, and extracellular matrix reorganization. Changes in cellular expression were similar in both trifarotene-treated and spontaneously-resolving lesions. However, only trifarotene treatment impacted SPP1+ macrophages, a subset of highly proliferative macrophages recently identified in fibrotic tissue. Conclusions: These results show that trifarotene has a novel action in acne treatment by affecting epidermal and immune components of acne pathogenesis.

Assessing the Safety and Efficacy of Trifarotene in the Treatment of Acne Vulgaris.

Acne vulgaris is a common skin condition of the face and trunk that negatively impacts quality of life. Trifarotene is a new first-in-class fourth-generation topical retinoid that has been uniquely studied in the treatment of both facial and truncal acne. Through selective agonism of retinoic acid receptor (RAR)-gamma, the most predominant RAR isotype in the epidermis, trifarotene exerts more targeted, skin-specific effects than earlier generation retinoids. This narrative review summarizes all currently available literature regarding the use of trifarotene in acne vulgaris. We focus on efficacy, safety, and tolerability data and highlight quality of life outcomes and patient-reported satisfaction. Future clinical trials and the clinical applicability of this novel medication in the treatment of acne are also discussed.

Updated Treatment for Acne: Targeted Therapy Based on Pathogenesis.

Previous approaches to acne management have focused on the four main factors implicated in acne, namely, androgen-mediated sebogenesis (considered integral to acne), hyperkeratinization, colonization with Cutibacterium acnes, and inflammation related to both innate and adaptive mechanisms. Recent advances have facilitated potential novel approaches to acne management, as the pathophysiology and the immunological aspects related to acne and wound healing have evolved. Particular targets that have been shown to be closely involved in acne pathophysiology and wound healing include interleukin (IL)-1ß, IL-17, IL-23, and tumor necrosis factor alpha (TNFα). Biological antibodies targeting IL-1ß, IL-17, IL-23, and TNFα could provide novel approaches for treating severe acne and related disorders. Acne is primarily a disease associated with sebogenesis. Monosaturated free acids are important components. Insulin growth factor 1 (IGF-1) promotes the proliferation and differentiation of sebocytes and IL-1ß. Research into the microbiome may also provide insights into potential future therapeutic options for acne. Scars, both atrophic and hypertrophic, are common sequelae to acne. Risk factors associated with the development of acne scars include genetic, systemic, local, and lifestyle factors. Pro-inflammatory cytokines have been shown to play a crucial role in the development of acne-induced hypertrophic scars. Treatment for extensive inflammatory keloid scarring is limited. Surgery and postoperative radiotherapy are two possible options. Transforming growth factor-ß (TGFß), IL-6, matrix metalloproteinase (MMP), IGF-1, and B cells are found in keloid or hypertrophic scar tissues. Biological antibodies targeting these cytokines may be a potential strategy for the prevention and treatment of this type of scar in the future. Future treatment for acne should embrace approaches that target the main etiological factors of acne. In particular, specific emphasis on aggressive treatment in the acute inflammatory phase to reduce the likelihood of scarring and other clinical sequelae, such as pigmentary changes would be highly desirable. Treatment for established acne-induced sequelae should also be considered.

Trifarotene: A Current Review and Perspectives in Dermatology.

Retinoids have numerous applications in inflammatory, dyskeratotic, and oncohematology diseases. Retinoids have now reached the fourth generation, progressively reducing toxicity whilst increasing their efficacy. Trifarotene is a new fourth-generation retinoid with a selective action on RAR-γ. In this review, we reported the trials-both concluded and in progress-including the use of trifarotene in dermatological diseases. Studies were identified by searching electronic databases (MEDLINE, EMBASE, PubMed, Cochrane, Trials.gov) from 2012 to today and reference lists of respective articles. Only articles published in English language were included. Randomized trials evaluating trifarotene tolerability, safety, and efficacy in congenital ichthyosis and acne have demonstrated great results and mild side effects, leading to the approval by the FDA of trifarotene for the treatment of lamellar ichthyosis in 2014, and of acne vulgaris in October 2019. No high-quality randomized clinical trials have evaluated the treatment of primary cutaneous lymphomas with trifarotene. Finally, we are hypothesizing future perspectives in the treatment of non-melanoma skin cancers, fungal infections, photoaging, and hand-foot skin reactions with trifarotene.