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Oral isotretinoin for acne: a complete overview (2022)
Alessia Villani, Francesca Nastro, Francesca Di Vico, Gabriella Fabbrocini, Maria Carmela Annunziata & Lucia Genco
ABSTRACT
Introduction: Acne is one of the most common and widespread skin conditions, affecting the health as much as patients’ quality of life. A wide variety of treatments for acne, topical and systemic, could be prescribed, depending on its degree of severity. Isotretinoin, a derivative of retinol, has been widely used for the treatment of severe forms of acne, and those forms do not respond to conventional treatments. In literature, there are several studies describing its efficacy, also reporting side-effects related to the drug; therefore, this has led the scientific community to request further studies qualifying its characteristics and comparing its efficacy and safety with other classic acne treatments, as well as with different treatment regimes, in order to find the dose with the best efficacy/safety ratio.
Areas covered: The aim of this article is to provide a complete overview on the use of oral isotretinoin for the treatment of acne describing the efficacy, safety, and tolerability of the drug.
Expert opinion: Oral isotretinoin represents a valid therapeutic alternative in treating severe and mild-to-moderate acne lesions, also reducing scarring damage. There are no standardized protocols regarding the use of oral isotretinoin and its association with other therapies; however, the correct patient selection and a tailored treatment protocol according to acne lesions severity and type should be considered in order to obtain optimal results.
1. Introduction
Acne is one of the most common and widespread skin conditions, affecting the health as much as patients’ quality of life (QoL) [1,2]. Several factors are involved in the pathogenesis of acne, with hyperkeratinization of follicles, excessive sebum production, inflammation, and proliferation of Propionibacterium acnes being the most important ones. The majority of acne vulgaris can be classified as mild (85%); however, about 15% of affected patients develop the severe form of acne, which can result in various forms of scarring [3,4]. Treatment options for acne include topical treatments (retinoids and antibiotics), systemic medications (oral retinoids, antibiotics, and hormones), and non-pharmacological methods such as phototherapy. Topical treatments are mostly used for mild-to-moderate forms of acne, whereas severe forms of acne require systemic treatments with oral isotretinoin representing the most effective one [5,6]. Isotretinoin, a derivative of retinol (vitamin A), has been introduced in the early 1980s and has been widely used for the treatment of severe forms of acne, and those forms not responding to conventional treatments. Although many studies describing its efficacy have been widely described, there are many articles reporting side-effects related to the drug; therefore, this has led the scientific community to request further studies qualifying its characteristics and comparing its efficacy and safety with other classic acne treatments, as well as with different treatment regimes, in order to find the dose with the best efficacy/safety ratio [7–9]. The objective of this review is to provide a complete overview of the use of oral isotretinoin for the treatment of acne vulgaris, used as a single therapy or in association with other treatments.
3. Pharmacokinetics and mechanism of action
Oral isotretinoin (13-cis retinoic acid) is a natural metabolite of vitamin A, approved for acne vulgaris in 1982 by the U.S. Food and Drug Administration (FDA) [7] and in 1983 by the European Medicines Agency (EMA) [8]. Being a highly lipophilic drug, its relative bioavailability increases if taken with food [9]. A novel formulation of isotretinoin, isotretinoin dose, use lipid agents to incorporate lipophilic isotretinoin and can be taken before and after meals [10]. The drug is excreted in feces and urines with the 13-cis-4-oxo-retinoic acid representing the main metabolite. In patients treated with isotretinoin at doses of 0.5–1 mg/kg/day, isotretinoin and its metabolites return to endogenous concentrations within 2 weeks after stopping treatment [11]. The efficacy of isotretinoin is due to its efficacy in reducing sebum production, and normalizing follicular keratinization, thus inhibiting Cutibacterium acnes growth through a retinoic acid receptor mechanism, but also through [12] a retinoic acid receptor-independent mechanism that causes cell cycle arrest and apoptosis in sebocytes [13]. The induction of key genes such as the tumor necrosis factor (TNF) and FOX01 is linked to the apoptosis of sebocytes and keratinocytes suppression [14,15]. Furthermore, isotretinoin has also anti-inflammatory effects due to the reduction in monocyte Toll-like receptor-2 expression, the inhibition of neutrophil and monocyte chemotaxis [16], and the reduction of pro-matrix metalloproteinase (MMP)- 9 and matrix metalloproteinase [17] in sebum. According to the European guidelines isotretinoin should be used in patients >12 years of age with severe papulopustular/moderate nodular acne and with severe nodular/conglobate acne that has or is not responding to systemic antibiotics and topical therapy [18]. Although the majority of clinical trials on acne treatment involve patients >12 years of age, there are severe cases in which the use of isotretinoin in patients aged <12 years could not be excluded [19,20].
4. Effectiveness of isotretinoin
4.1. Isotretinoin: different treatment regimens compared
4.2. Isotretinoin vs isotretinoin in association with other systemic treatments
4.3. Isotretinoin vs oral antibiotics and/or topical agents
4.4. Isotretinoin vs isotretinoin in association with physical treatment
5. Adverse events
5.1. Cutaneous adverse reaction
5.2. Extracutaneous adverse reaction
6. Laboratory evaluation
7. Predictive markers of therapeutic response
8. Expert opinion
Acne vulgaris is a common inflammatory skin disorder mostly affecting young patients and highly impacting their quality of life. It sometimes represents a risk factor for depression, anxiety, and in severe cases, even suicides [1– 3,111]. A wide variety of topical and systemic treatments do exist with oral isotretinoin being one of the most common and effective ones. A prompt treatment, reducing inflammation, in particular for moderate-to-severe forms of acne should be always considered in order to avoid permanent consequences such as scarring and pigmentary changes [111]. Oral isotretinoin represents a valid and cost-effective therapeutic alternative in treating severe and mild-to-moderate acne lesions, also reducing scarring damage [5]. Oral isotretinoin has been used for the treatment of acne for more than 40 years, and no serious side effects have ever been reported to cause discontinuation, proving its safety and efficacy. It is currently the only drug that can cure acne and maintain the result with even a single cycle, provided that the protocol is followed properly, i.e. until complete remission of the symptoms plus a further month thereafter. In fact, recurrence occurs when the lesions are still in an inflammatory phase, as long as the recommended cumulative dose is not exceeded. As reported in our review, new effective oral isotretinoin formulations and new dosing regimens, including low-dose isotretinoin (0.1–0.3 mg/kg daily) or intermittent protocols have been proposed in order to reduce dose-dependent drug-related adverse events, avoiding treatment discontinuation [6]. Knowledge of the appropriate dose of the drug, periodic laboratory evaluation, the adoption of contraceptive methods in females, and a correct lifestyle have positive effects on the treatment process. To date, several studies have also demonstrated the objective efficacy of isotretinoin in reducing acne severity grading when used in association with other topical or systemic treatments. A synergistic effect has been also described for the association of oral isotretinoin with physical treatments, such as laser therapy, in improving acne scars lesions; in our clinical practice, oral isotretinoin has been widely used alone, only associated with topical products as hydrants and antibiotic creams. The superiority of the synergistic effect is demonstrated by the rapidity and degree of improvement, the reduction of the recovery time, and the higher patients’ grade of satisfaction compared to the treatment used alone. There are no standardized protocols regarding the use of oral isotretinoin and its association with other therapies; however, the correct patient selection and a tailored treatment protocol with specific planning of treatment sessions according to acne lesions severity and type should be considered in order to obtain optimal results.
Alessia Villani, Francesca Nastro, Francesca Di Vico, Gabriella Fabbrocini, Maria Carmela Annunziata & Lucia Genco
ABSTRACT
Introduction: Acne is one of the most common and widespread skin conditions, affecting the health as much as patients’ quality of life. A wide variety of treatments for acne, topical and systemic, could be prescribed, depending on its degree of severity. Isotretinoin, a derivative of retinol, has been widely used for the treatment of severe forms of acne, and those forms do not respond to conventional treatments. In literature, there are several studies describing its efficacy, also reporting side-effects related to the drug; therefore, this has led the scientific community to request further studies qualifying its characteristics and comparing its efficacy and safety with other classic acne treatments, as well as with different treatment regimes, in order to find the dose with the best efficacy/safety ratio.
Areas covered: The aim of this article is to provide a complete overview on the use of oral isotretinoin for the treatment of acne describing the efficacy, safety, and tolerability of the drug.
Expert opinion: Oral isotretinoin represents a valid therapeutic alternative in treating severe and mild-to-moderate acne lesions, also reducing scarring damage. There are no standardized protocols regarding the use of oral isotretinoin and its association with other therapies; however, the correct patient selection and a tailored treatment protocol according to acne lesions severity and type should be considered in order to obtain optimal results.
1. Introduction
Acne is one of the most common and widespread skin conditions, affecting the health as much as patients’ quality of life (QoL) [1,2]. Several factors are involved in the pathogenesis of acne, with hyperkeratinization of follicles, excessive sebum production, inflammation, and proliferation of Propionibacterium acnes being the most important ones. The majority of acne vulgaris can be classified as mild (85%); however, about 15% of affected patients develop the severe form of acne, which can result in various forms of scarring [3,4]. Treatment options for acne include topical treatments (retinoids and antibiotics), systemic medications (oral retinoids, antibiotics, and hormones), and non-pharmacological methods such as phototherapy. Topical treatments are mostly used for mild-to-moderate forms of acne, whereas severe forms of acne require systemic treatments with oral isotretinoin representing the most effective one [5,6]. Isotretinoin, a derivative of retinol (vitamin A), has been introduced in the early 1980s and has been widely used for the treatment of severe forms of acne, and those forms not responding to conventional treatments. Although many studies describing its efficacy have been widely described, there are many articles reporting side-effects related to the drug; therefore, this has led the scientific community to request further studies qualifying its characteristics and comparing its efficacy and safety with other classic acne treatments, as well as with different treatment regimes, in order to find the dose with the best efficacy/safety ratio [7–9]. The objective of this review is to provide a complete overview of the use of oral isotretinoin for the treatment of acne vulgaris, used as a single therapy or in association with other treatments.
3. Pharmacokinetics and mechanism of action
Oral isotretinoin (13-cis retinoic acid) is a natural metabolite of vitamin A, approved for acne vulgaris in 1982 by the U.S. Food and Drug Administration (FDA) [7] and in 1983 by the European Medicines Agency (EMA) [8]. Being a highly lipophilic drug, its relative bioavailability increases if taken with food [9]. A novel formulation of isotretinoin, isotretinoin dose, use lipid agents to incorporate lipophilic isotretinoin and can be taken before and after meals [10]. The drug is excreted in feces and urines with the 13-cis-4-oxo-retinoic acid representing the main metabolite. In patients treated with isotretinoin at doses of 0.5–1 mg/kg/day, isotretinoin and its metabolites return to endogenous concentrations within 2 weeks after stopping treatment [11]. The efficacy of isotretinoin is due to its efficacy in reducing sebum production, and normalizing follicular keratinization, thus inhibiting Cutibacterium acnes growth through a retinoic acid receptor mechanism, but also through [12] a retinoic acid receptor-independent mechanism that causes cell cycle arrest and apoptosis in sebocytes [13]. The induction of key genes such as the tumor necrosis factor (TNF) and FOX01 is linked to the apoptosis of sebocytes and keratinocytes suppression [14,15]. Furthermore, isotretinoin has also anti-inflammatory effects due to the reduction in monocyte Toll-like receptor-2 expression, the inhibition of neutrophil and monocyte chemotaxis [16], and the reduction of pro-matrix metalloproteinase (MMP)- 9 and matrix metalloproteinase [17] in sebum. According to the European guidelines isotretinoin should be used in patients >12 years of age with severe papulopustular/moderate nodular acne and with severe nodular/conglobate acne that has or is not responding to systemic antibiotics and topical therapy [18]. Although the majority of clinical trials on acne treatment involve patients >12 years of age, there are severe cases in which the use of isotretinoin in patients aged <12 years could not be excluded [19,20].
4. Effectiveness of isotretinoin
4.1. Isotretinoin: different treatment regimens compared
4.2. Isotretinoin vs isotretinoin in association with other systemic treatments
4.3. Isotretinoin vs oral antibiotics and/or topical agents
4.4. Isotretinoin vs isotretinoin in association with physical treatment
5. Adverse events
5.1. Cutaneous adverse reaction
5.2. Extracutaneous adverse reaction
6. Laboratory evaluation
7. Predictive markers of therapeutic response
8. Expert opinion
Acne vulgaris is a common inflammatory skin disorder mostly affecting young patients and highly impacting their quality of life. It sometimes represents a risk factor for depression, anxiety, and in severe cases, even suicides [1– 3,111]. A wide variety of topical and systemic treatments do exist with oral isotretinoin being one of the most common and effective ones. A prompt treatment, reducing inflammation, in particular for moderate-to-severe forms of acne should be always considered in order to avoid permanent consequences such as scarring and pigmentary changes [111]. Oral isotretinoin represents a valid and cost-effective therapeutic alternative in treating severe and mild-to-moderate acne lesions, also reducing scarring damage [5]. Oral isotretinoin has been used for the treatment of acne for more than 40 years, and no serious side effects have ever been reported to cause discontinuation, proving its safety and efficacy. It is currently the only drug that can cure acne and maintain the result with even a single cycle, provided that the protocol is followed properly, i.e. until complete remission of the symptoms plus a further month thereafter. In fact, recurrence occurs when the lesions are still in an inflammatory phase, as long as the recommended cumulative dose is not exceeded. As reported in our review, new effective oral isotretinoin formulations and new dosing regimens, including low-dose isotretinoin (0.1–0.3 mg/kg daily) or intermittent protocols have been proposed in order to reduce dose-dependent drug-related adverse events, avoiding treatment discontinuation [6]. Knowledge of the appropriate dose of the drug, periodic laboratory evaluation, the adoption of contraceptive methods in females, and a correct lifestyle have positive effects on the treatment process. To date, several studies have also demonstrated the objective efficacy of isotretinoin in reducing acne severity grading when used in association with other topical or systemic treatments. A synergistic effect has been also described for the association of oral isotretinoin with physical treatments, such as laser therapy, in improving acne scars lesions; in our clinical practice, oral isotretinoin has been widely used alone, only associated with topical products as hydrants and antibiotic creams. The superiority of the synergistic effect is demonstrated by the rapidity and degree of improvement, the reduction of the recovery time, and the higher patients’ grade of satisfaction compared to the treatment used alone. There are no standardized protocols regarding the use of oral isotretinoin and its association with other therapies; however, the correct patient selection and a tailored treatment protocol with specific planning of treatment sessions according to acne lesions severity and type should be considered in order to obtain optimal results.
