madman
Super Moderator
Abstract
Since the US Food and Drug Administration (FDA) approved tretinoin in 1971, retinoids alone or combined with other agents have become the mainstay of acne treatment. Retinoids act through binding to retinoic acid receptors, altering the expression levels of hundreds of cellular proteins affecting multiple pathways involved in acne pathogenesis. Retinoids have evolved from first-generation agents, such as tretinoin, through chemical modifications resulting in a second-generation (etretinate and acitretin for psoriasis), a third-generation (adapalene and tazarotene), and, most recently, a fourth (trifarotene). For all topical retinoids, local irritation has been associated with poor tolerability and suboptimal adherence. Efforts to improve tolerability have utilized novel delivery systems and/or novel agents. This qualitative literature review summarizes the evolution of the four topical single-agent retinoids available for the treatment of acne in the US today and their various formulations, presenting the rationale behind their development and data from key studies.
1 Introduction
In 1971, the US Food and Drug Administration (FDA) granted approval of the first topical retinoid, tretinoin 0.05% solution (also: all-trans retinoic acid [ATRA]; vitamin A acid), for use in acne vulgaris [1]. In the years that followed, novel retinoids, formulations, and combinations were introduced to improve efficacy and tolerability. Today, topical retinoids, either alone or in combination with benzoyl peroxide or topical antibiotics, are the mainstay of acne therapy [2–6]. They are strongly recommended for acne management and treatment by the American Academy of Dermatology based on consistent, good-quality, patient-oriented evidence [5]. In addition, topical retinoids have provided treatment options in other dermatological conditions including atrophic scarring [7], postinflammatory hyperpigmentation [8], photodamaged skin [9], and melasma [10]. In this qualitative literature review, we focus on key aspects of the 50-year evolution of single-agent topical retinoids specifically for the treatment of acne vulgaris.
*Acne pathology and the mechanisms of action of retinoids are complex and multifactorial. Major factors in acne pathogenesis include epithelial hyperproliferation, increased sebum production with concurrent alterations in its composition increased Cutibacterium acnes population, and follicular and perifollicular inflammation [11]. These can impair normal functioning of the pilosebaceous unit, leading to the formation of microcomedones, comedones, infammatory lesions, or nodules.
Retinoids, analogs of vitamin A, have pleiotropic effects including comedolysis and reduction of microcomedonal formation. They have been shown to benefit both comedonal and inflammatory acne [12, 13]. The mechanisms through which these effects occur are believed to involve binding to retinoic acid receptors (RARs). Three subtypes, RAR-α, RAR-β, and RAR-γ, are known, of which RAR-γ expression is highest in human skin [14, 15]. Different retinoids vary in their receptor subtype affinity and may be more selective for one receptor versus another. The hypothesis that receptor subtype selectivity might improve topical retinoid efficacy and/or tolerability fueled the search for, and eventual discovery of, subtype-selective retinoids. However, no evidence exists to suggest that retinoid receptor subtypes influence efficacy or tolerability. Indeed, some retinoids have the same receptor binding yet differ in potency and tolerability.
Tretinoin, the principal active metabolite of vitamin A, binds with similar affinity to all three subtypes, but binding to RAR-γ is key to its effects. This binding activates the RAR-γ complex with the retinoid X receptor (RXR)-α [16, 17]. The activated complex in turn binds to specific DNA promoter sequences known as retinoic acid response elements (RAREs), stimulating gene transcription through transactivation and resulting in activation of more than 300 genes that alter expression levels of hundreds of proteins [16, 18].
*Tretinoin also exerts indirect effects on DNA lacking RAREs through downregulation of pro-inflammatory nuclear transcription factors such as AP-1, which normally upregulates the matrix metalloproteases responsible for acne scar formation [19]. The direct and indirect effects of retinoids result in inhibition of leukocyte migration, cytokine production, and arachidonic acid metabolism, as well as downregulation of toll-like receptor (TLR) activation. Collectively, these effects reduce inflammation, which is now increasingly recognized as a common feature of all acne lesions, whether clinically inflamed or not [11, 19].
2 Evolution of Topical Retinoids for Acne
2.1 First‑ and Second‑Generation Retinoids
2.2 Third‑Generation Retinoids
2.3 Fourth‑Generation Retinoids
3 Topical Retinoid Tolerability and Adherence
4 Improving Retinoid Tolerability
4.1 Short Contact Therapy
4.2 Non‑Daily Application
4.3 Role of Vehicle Formulation
4.4 Microsponge Delivery System
4.5 Polyolprepolymer‑2
4.6 Micronization and Polymeric Emulsion Technology
5 Conclusions
In the 50 years since the initial approval of tretinoin, topical retinoids—alone or in combination with other agents—have become the mainstay of acne treatment and have provided treatment options for other dermatological indications not addressed herein. Studies have shown, however, that adherence to these widely prescribed agents in acne vulgaris is remarkably low, with perhaps 30% of prescriptions never filled [55], and almost one-half of all patients poorly adherent with the prescribed regimen [50, 58]. The local irritation associated with topical retinoids, which is most prominent in the first few weeks of therapy, has been associated with poor adherence [53, 54]. Among the avenues explored to minimize irritation and maximize adherence, neither the theory that irritancy inherently paralleled efficacy for topical retinoids nor the idea that adverse events were due to insufficient retinoid receptor subtype selectivity have proven to be true. Half a century of research has resulted in new generations of retinoids with improved stability (primarily through structural modification) and greater tolerability (largely a result of improved formulation technologies).
Since the US Food and Drug Administration (FDA) approved tretinoin in 1971, retinoids alone or combined with other agents have become the mainstay of acne treatment. Retinoids act through binding to retinoic acid receptors, altering the expression levels of hundreds of cellular proteins affecting multiple pathways involved in acne pathogenesis. Retinoids have evolved from first-generation agents, such as tretinoin, through chemical modifications resulting in a second-generation (etretinate and acitretin for psoriasis), a third-generation (adapalene and tazarotene), and, most recently, a fourth (trifarotene). For all topical retinoids, local irritation has been associated with poor tolerability and suboptimal adherence. Efforts to improve tolerability have utilized novel delivery systems and/or novel agents. This qualitative literature review summarizes the evolution of the four topical single-agent retinoids available for the treatment of acne in the US today and their various formulations, presenting the rationale behind their development and data from key studies.
1 Introduction
In 1971, the US Food and Drug Administration (FDA) granted approval of the first topical retinoid, tretinoin 0.05% solution (also: all-trans retinoic acid [ATRA]; vitamin A acid), for use in acne vulgaris [1]. In the years that followed, novel retinoids, formulations, and combinations were introduced to improve efficacy and tolerability. Today, topical retinoids, either alone or in combination with benzoyl peroxide or topical antibiotics, are the mainstay of acne therapy [2–6]. They are strongly recommended for acne management and treatment by the American Academy of Dermatology based on consistent, good-quality, patient-oriented evidence [5]. In addition, topical retinoids have provided treatment options in other dermatological conditions including atrophic scarring [7], postinflammatory hyperpigmentation [8], photodamaged skin [9], and melasma [10]. In this qualitative literature review, we focus on key aspects of the 50-year evolution of single-agent topical retinoids specifically for the treatment of acne vulgaris.
*Acne pathology and the mechanisms of action of retinoids are complex and multifactorial. Major factors in acne pathogenesis include epithelial hyperproliferation, increased sebum production with concurrent alterations in its composition increased Cutibacterium acnes population, and follicular and perifollicular inflammation [11]. These can impair normal functioning of the pilosebaceous unit, leading to the formation of microcomedones, comedones, infammatory lesions, or nodules.
Retinoids, analogs of vitamin A, have pleiotropic effects including comedolysis and reduction of microcomedonal formation. They have been shown to benefit both comedonal and inflammatory acne [12, 13]. The mechanisms through which these effects occur are believed to involve binding to retinoic acid receptors (RARs). Three subtypes, RAR-α, RAR-β, and RAR-γ, are known, of which RAR-γ expression is highest in human skin [14, 15]. Different retinoids vary in their receptor subtype affinity and may be more selective for one receptor versus another. The hypothesis that receptor subtype selectivity might improve topical retinoid efficacy and/or tolerability fueled the search for, and eventual discovery of, subtype-selective retinoids. However, no evidence exists to suggest that retinoid receptor subtypes influence efficacy or tolerability. Indeed, some retinoids have the same receptor binding yet differ in potency and tolerability.
Tretinoin, the principal active metabolite of vitamin A, binds with similar affinity to all three subtypes, but binding to RAR-γ is key to its effects. This binding activates the RAR-γ complex with the retinoid X receptor (RXR)-α [16, 17]. The activated complex in turn binds to specific DNA promoter sequences known as retinoic acid response elements (RAREs), stimulating gene transcription through transactivation and resulting in activation of more than 300 genes that alter expression levels of hundreds of proteins [16, 18].
*Tretinoin also exerts indirect effects on DNA lacking RAREs through downregulation of pro-inflammatory nuclear transcription factors such as AP-1, which normally upregulates the matrix metalloproteases responsible for acne scar formation [19]. The direct and indirect effects of retinoids result in inhibition of leukocyte migration, cytokine production, and arachidonic acid metabolism, as well as downregulation of toll-like receptor (TLR) activation. Collectively, these effects reduce inflammation, which is now increasingly recognized as a common feature of all acne lesions, whether clinically inflamed or not [11, 19].
2 Evolution of Topical Retinoids for Acne
2.1 First‑ and Second‑Generation Retinoids
2.2 Third‑Generation Retinoids
2.3 Fourth‑Generation Retinoids
3 Topical Retinoid Tolerability and Adherence
4 Improving Retinoid Tolerability
4.1 Short Contact Therapy
4.2 Non‑Daily Application
4.3 Role of Vehicle Formulation
4.4 Microsponge Delivery System
4.5 Polyolprepolymer‑2
4.6 Micronization and Polymeric Emulsion Technology
5 Conclusions
In the 50 years since the initial approval of tretinoin, topical retinoids—alone or in combination with other agents—have become the mainstay of acne treatment and have provided treatment options for other dermatological indications not addressed herein. Studies have shown, however, that adherence to these widely prescribed agents in acne vulgaris is remarkably low, with perhaps 30% of prescriptions never filled [55], and almost one-half of all patients poorly adherent with the prescribed regimen [50, 58]. The local irritation associated with topical retinoids, which is most prominent in the first few weeks of therapy, has been associated with poor adherence [53, 54]. Among the avenues explored to minimize irritation and maximize adherence, neither the theory that irritancy inherently paralleled efficacy for topical retinoids nor the idea that adverse events were due to insufficient retinoid receptor subtype selectivity have proven to be true. Half a century of research has resulted in new generations of retinoids with improved stability (primarily through structural modification) and greater tolerability (largely a result of improved formulation technologies).
