INTRODUCTION
Acne vulgaris is a common chronic inflammatory disease with a complex pathogenesis affecting sebaceous follicles in the skin. Four key pathogenic factors have been identified: (1) an alteration in the pattern of keratinization within the follicle, (2) increased sebum production, (3) colonization with Cutibacterium acnes, and (4) inflammation. Notably, inflammatory processes may precede the development of a visible lesion; thus, targeting inflammation is an essential part of acne therapy.1 Current guidelines recommend that topical retinoids should be part of first-line therapy for acne because they have comedolytic, anti-comedogenic, and anti-inflammatory actions in the skin, as discussed below.2-6 Retinoids are small natural or synthetic molecules that exert their effects through binding to retinoic acid receptors (RARs) in the cell nucleus.7-9 There are 3 RAR subtypes (α, β, and γ), and different retinoid molecules have differing binding affinities to each of the RAR subtypes. Through RAR binding, retinoids affect the expression of suites of genes involved in physiological pathways critical to acne pathogenesis, such as normalization of epithelial turnover and activation or suppression of inflammatory pathways.
With some international variations, topical retinoids approved for acne include tretinoin, tazarotene, topical isotretinoin in some countries, adapalene, and, recently, trifarotene. As synthetic retinoids have been developed, there has been a trend toward increasing receptor specificity. Notably, RAR-γ comprises nearly 90% of the RARs present in the epithelium, making it a logical and promising target for topical therapies.10 One of the most recent developments in retinoid research is the approval of trifarotene for the management of acne; trifarotene is the first selective RAR-γ agonist, with 65-fold affinity for RAR-γ compared with RAR-α, and 16-fold compared with RAR- β.11 As the first topical retinoid rigorously studied in truncal acne as well as facial acne, trifarotene represents a medical advance in the field of acne therapeutics. Pivotal randomized, placebo-controlled studies of trifarotene showed significant efficacy compared to vehicle in resolving both inflammatory and comedonal lesions in facial and truncal acne in patients aged 9 years and older, with favorable tolerability and safety.12 This review discusses what is known about the mechanisms of action of retinoids at the molecular level and how variations in receptor binding may translate to differences in the clinic.
With some international variations, topical retinoids approved for acne include tretinoin, tazarotene, topical isotretinoin in some countries, adapalene, and, recently, trifarotene. As synthetic retinoids have been developed, there has been a trend toward increasing receptor specificity. Notably, RAR-γ comprises nearly 90% of the RARs present in the epithelium, making it a logical and promising target for topical therapies.10 One of the most recent developments in retinoid research is the approval of trifarotene for the management of acne; trifarotene is the first selective RAR-γ agonist, with 65-fold affinity for RAR-γ compared with RAR-α, and 16-fold compared with RAR- β.11 As the first topical retinoid rigorously studied in truncal acne as well as facial acne, trifarotene represents a medical advance in the field of acne therapeutics. Pivotal randomized, placebo-controlled studies of trifarotene showed significant efficacy compared to vehicle in resolving both inflammatory and comedonal lesions in facial and truncal acne in patients aged 9 years and older, with favorable tolerability and safety.12 This review discusses what is known about the mechanisms of action of retinoids at the molecular level and how variations in receptor binding may translate to differences in the clinic.
