British Journal of Dermatology (1990) 122, Supplement 35, 83-86.
Tretinoin therapy in photoageing: historical perspective J.J.LEYDEN University of Pennsylvania School of Medicine, Philadelphia, U,S,A,
SUMMARY
Tretinoin was shown in the late 1960s to be useful for the treatment of disorders associated with abnormal epithelial differentiation; however, because of irritation, retinoids were only slowly accepted. In the 1970s, evidence accumulated to show that topical tretinoin could modulate many of the abnormalities in the epidermis and dermis associated with photoageing. It has been shown in hairless mice that tretinoin can reverse dermal elastosis with the formation of new collagen and this has led to clinical trials being carried out in man. Randomized, controlled trials have shown that topical tretinoin is effective in the treatment of photoaged skin.
Tropical tretinoin therapy was first shown to be successful in treating a variety of disorders involving epidermal keratinization in the early 1960s by Stuttgen, who reported that, despite local irritation, therapeutic responses in ichthyosis were encouraging.^'^ Although these results were confirmed by Beer,^ the use of topical tretinoin failed to gain widespread acceptance because of the irritation produced by the concentrations and formulations used in these studies. Kligman et al.'*' later demonstrated that topical tretinoin was effective in the treatment of acne and that the therapeutic response was not related to irritation. Their results suggested that tretinoin affected the sebaceous follicular epithelium, resulting in a more rapid desquamation process, which led to the elimination of comedones. Local irritation was again a common sideeffect and was probably due to the use of a hydro-alcoholic formulation. In the late 1960s and early 1970s, there were several reports on the efficacy of topical tretinoin treatment in a variety of disorders ranging from psoriasis, lichen planus, Darier's disease, keratoacanthoma and cutaneous carcinogenesis;'"^ thus, the age of topical retinoid therapy had arrived. These clinical observations led to investigative work in dermatological laboratories throughout the world. The central question was how could a single molecule affect so many seemingly disparate conditions? By the late 1970s, the age of retinoid therapy had been extended with the introduction of oral treatment. The demonstration of profound clinical effects in acne, psoriasis, ichthyosis and other disorders of keratinization are important landmarks in dermatology.'""'' Correspondence: J,J,Leyden, M.D,, Professor of Dermatology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, U,S,A,
83
84
J.J.Leyden EFFECTS ON CELL DIFFERENTIATION
At the same time as interest in tretinoin for the treatment ofa variety of cutaneous disorders was growing research laboratories turned their attention to its effects on cell differentiation and carcinogenesis, and they began to discover a variety of pharmacological and biochemical effects in epithelial systems. These results indicated that the primary physiological effects involved cellular differentiation and genomic expression. Several lines of research suggested that a primary mechanism of action of tretinoin and other retinoids in modulating cell differentiation is related to their effects on the expression of oncogenes and peptide growth factors. The effects of retinoic acid on cell differentiation have been reviewed in several publications.'^'^^ The precise mechanisms by which tretinoin affects cell differentiation in a variety of disorders is as yet unknown and further studies are indicated. As extensive clinical and basic research had shown that tretinoin could modulate abnormal epithelial differentiation, it was not surprising when topical tretinoin was found to be effective in treating one aspect of what is now known as photoageing, i.e. actinic keratosis, and was even shown to be useful in the treatment of basal squamous cell carcinomas. Beginning with the work of Stiittgen,^ several studies have demonstrated the efficacy of topical tretinoin, both alone and in combination with 5-fluorouracil, in the treatment of actinic keratoses. '^"^ ^ The known effects of tretinoin on cell differentiation and gene expression provide a framework for possible mechanisms by which this therapeutic effect could be achieved. The usefulness of topical tretinoin in improving some of the dermal changes associated with chronic UV-induced damage, such as elastosis and wrinkling, is not immediately apparent. There is, however, now a considerable amount of data to indicate that tretinoin has profound effects on the dermis and retinoids have been reported to stimulate wound repair due to enhanced collagen formation and can reverse the effects of corticosteroids and salicylates in wound healing.'^'^^ ANIMAL STUDIES
Kligman et al.^^ tested the hypothesis that topical tretinoin could be useful in treating UVinduced dermal elastosis. Using the hairless mouse as a model, they showed that UVB irradiation produced similar changes to those found in photodamaged skin. In mice treated with topical tretinoin, large numbers of fibroblasts appeared and new collagen was formed in the upper dermis with a 'pushing down' of potentially elastotic material deeper into the dermis. They also demonstrated dose-response improvements, both in terms of concentration of tretinoin and duration of treatment, whereas control experiments using irritants such as croton oil, salicylic acid, propyleneglycol and sodium lauryl sulphate did not result in dermal repair, thus indicating that the response to topical tretinoin was a pharmacological one rather than due to non-specific wound repair. CLINICAL STUDIES
At the same time as the development of the hairless mouse skin model and the demonstration that topical tretinoin could reverse many of the changes seen in the dermis, clinical use of topical tretinoin was initiated in a newly established clinic at the University of Pennsylvania that was devoted to the study and treatment of ageing skin. In the initial stages, open clinical studies were carried out on hundreds of patients using different concentrations and formulations of topical tretinoin, with clinical assessment mainly involving visual comparison of photographs. Over
History of retinoid therapy in photoageing 85 several years, convincing evidence emerged that topical tretinoin was useful in moderating many of the changes associated with photoageing, and these findings led to extensive studies in which the clinical and histological effects of tretinoin on photodamaged facial and forearm skin were determined.^^ When tretinoin-treated tissue was examined by light and electron microscopy it was shown that: epidermal atrophy was replaced by hyperplasia; atypia and other changes of dysplasia were reversed; melanosomes were dispersed; new collagen deposition took place in the papillary dermis; and, possibly, angioneogenesis occurred. Physiological studies demonstrated that bloodflowwas increased, with greater permeability and reactivity of the skin. It was concluded that topical tretinoin is capable of at least partially reversing many of the structural changes associated with chronic UV-induced damage and that these changes bring about visible clinical improvement. Subsequently, Weiss et al.^* demonstrated similar clinical and histological changes in a double-blind clinical trial. Their findings created enormous interest and response from the lay press, which has continued to this day. Since these observations, further controlled clinical trials have been conducted both in the U.S.A. and in Europe. These studies have extended the understanding of possible mechanisms by which tretinoin can modulate photoageing.
REFERENCES 1 Stuttgen G, Krause H, Der Nachweis von trikiummarkiertem Vitamin A in den Schichten der Haut nach lokaler Applikation, Hautarzt 1959; 10: 504-6, 2 Stuttgen G, Zur Lokalbehandlung von Keratosen mit Vitamin-A Saure, Dermatologica 1962; 124: 65-80, 3 Beer P, Umersuchungen uber die Wirkung der Vitamin-A Saure, Dermatologica 1962; 124: 192-5, 4 Kligman AM, Fulton JE Jr, Plewig G, Topical vitamin A acid in acne vulgaris. Arch Dermatol 1969; 99: 469-76, 5 Orfanos CE, Schmidt HW, Mahrle G et al. Retinoic acid in psoriasis: its value for topical therapy with and without corticosteroids, Br J Dermatol 1973; 88: 167-82. 6 Frost P, Battistini F. Retinoic acid for the therapy of psoriasis, Acta Derm Venereol (Stockh) 1975; S5(Suppl): 154-60, 7 Prutkin L, The effect of vitamin A acid on hyperkeratinization and the keratoacanthoma, J Invest Dermatol 1967; 49: 165-72, 8 Gunther S. Retinoic acid in the treatment of lichen planus. Dermatologica 1971; 143: 315-18, 9 Frost P, Weinstein GD, Topical administration of vitamin A acid for ichthyosiform dermatoses andpsoriasis.J/^w Med Assoc 1969; 207: 1863-8, 10 Peck GL, Yoder FW, Olsen TG et al. Treatment of Darier's disease, lamellar ichthyosis, pityriasis rubra pilaris, cystic acne, and basal cell carcinoma with oral 13-cis-retinoic acid. Dermatologica 1978; I57(suppl): 11-12. 11 Peck GL, Olsen TG, Yoder FW et al. Prolonged remissions of cystic and conglobate acne with 13-cis-retinoic acid, N EnglJ Med 1979; 300: 329-33. 12 Sporn MB, Roberts AB, Roche NS et a/. Mechanism of action of retinoids. J Am Acad Dermatol 1986; 15: 756-64, 13 Chytil F, Retinoic acid; biochemistry and metabolism, J Am Acad Dermatol 1986; 15; 741-7, 14 Bollag W, Ott F, Retinoic acid: topical treatment of senile or actinic keratoses and basal cell carcinomas. Agents Actions 1970; i: 172-5. 15 Purcell SM, Pierce DK, Dixon SL et al. Chemoprevention of actinic keratoses with topical all-tra«j-retinoic acid. J Invest Dermatol 1986; 86: 501, 16 Robinson TA, Kligman AM, Treatment of solar keratoses with retinoic acid and 5-fluorouracil, BrJ Dermatol 1975; 92: 703-6, 17 Peck GL. Topical tretinoin in actinic keratosis and basal cell carcinoma, J Am Acad Dermatol 1986; 15: 829-35, 18 Lee KH, Tong TG, Mechanism of action of retinyl compounds on wound healing, H, Effect of active retinyl derivatives on granuloma formation, J Pharm Sci 1970; 59: 1195-7, 19 Hunt TK, Ehrlich HP, Garcia JA et al. Effect of vitamin A on reversing the inhibitory effect of cortisone on healing of open wounds in animals and man, Ann Surg 1969J 170: 633-41, 20 Lee KH, Studies on the mechanism of action of salicylates, HL Effect of vitamin A on the wound healing retardation of aspirin, J Pharm Sci 1968; 57: 1238-40,
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21 BrinkerhofT CE, McMillan RM, Dayer JM et a/. Inhibition by retinoic acid of collagenase production in rheumatoid synovial cells, N EnglJ Med 1980; 303: 432-6, 22 Kligman LH, Chen HD, Kligman AM, Topical retinoic acid enhances the repair of ultraviolet damaged dermal connective tissue. Connect Tissue Res 1984; 12: 139-50, 23 Kligman AM, Grove GL, Hirose R et al. Topical tretinoin for photoaged skin, J Am Acad Dermatol 1986; 15: 8365924 Weiss JS, Ellis CN, Headington JT et al. Topical tretinoin improves photoaged i)dn.J Am Med Assoc 1988; 4:31-6,
Tretinoin therapy in photoageing: historical perspective J.J.LEYDEN University of Pennsylvania School of Medicine, Philadelphia, U,S,A,
SUMMARY
Tretinoin was shown in the late 1960s to be useful for the treatment of disorders associated with abnormal epithelial differentiation; however, because of irritation, retinoids were only slowly accepted. In the 1970s, evidence accumulated to show that topical tretinoin could modulate many of the abnormalities in the epidermis and dermis associated with photoageing. It has been shown in hairless mice that tretinoin can reverse dermal elastosis with the formation of new collagen and this has led to clinical trials being carried out in man. Randomized, controlled trials have shown that topical tretinoin is effective in the treatment of photoaged skin.
Tropical tretinoin therapy was first shown to be successful in treating a variety of disorders involving epidermal keratinization in the early 1960s by Stuttgen, who reported that, despite local irritation, therapeutic responses in ichthyosis were encouraging.^'^ Although these results were confirmed by Beer,^ the use of topical tretinoin failed to gain widespread acceptance because of the irritation produced by the concentrations and formulations used in these studies. Kligman et al.'*' later demonstrated that topical tretinoin was effective in the treatment of acne and that the therapeutic response was not related to irritation. Their results suggested that tretinoin affected the sebaceous follicular epithelium, resulting in a more rapid desquamation process, which led to the elimination of comedones. Local irritation was again a common sideeffect and was probably due to the use of a hydro-alcoholic formulation. In the late 1960s and early 1970s, there were several reports on the efficacy of topical tretinoin treatment in a variety of disorders ranging from psoriasis, lichen planus, Darier's disease, keratoacanthoma and cutaneous carcinogenesis;'"^ thus, the age of topical retinoid therapy had arrived. These clinical observations led to investigative work in dermatological laboratories throughout the world. The central question was how could a single molecule affect so many seemingly disparate conditions? By the late 1970s, the age of retinoid therapy had been extended with the introduction of oral treatment. The demonstration of profound clinical effects in acne, psoriasis, ichthyosis and other disorders of keratinization are important landmarks in dermatology.'""'' Correspondence: J,J,Leyden, M.D,, Professor of Dermatology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, U,S,A,
83
84
J.J.Leyden EFFECTS ON CELL DIFFERENTIATION
At the same time as interest in tretinoin for the treatment ofa variety of cutaneous disorders was growing research laboratories turned their attention to its effects on cell differentiation and carcinogenesis, and they began to discover a variety of pharmacological and biochemical effects in epithelial systems. These results indicated that the primary physiological effects involved cellular differentiation and genomic expression. Several lines of research suggested that a primary mechanism of action of tretinoin and other retinoids in modulating cell differentiation is related to their effects on the expression of oncogenes and peptide growth factors. The effects of retinoic acid on cell differentiation have been reviewed in several publications.'^'^^ The precise mechanisms by which tretinoin affects cell differentiation in a variety of disorders is as yet unknown and further studies are indicated. As extensive clinical and basic research had shown that tretinoin could modulate abnormal epithelial differentiation, it was not surprising when topical tretinoin was found to be effective in treating one aspect of what is now known as photoageing, i.e. actinic keratosis, and was even shown to be useful in the treatment of basal squamous cell carcinomas. Beginning with the work of Stiittgen,^ several studies have demonstrated the efficacy of topical tretinoin, both alone and in combination with 5-fluorouracil, in the treatment of actinic keratoses. '^"^ ^ The known effects of tretinoin on cell differentiation and gene expression provide a framework for possible mechanisms by which this therapeutic effect could be achieved. The usefulness of topical tretinoin in improving some of the dermal changes associated with chronic UV-induced damage, such as elastosis and wrinkling, is not immediately apparent. There is, however, now a considerable amount of data to indicate that tretinoin has profound effects on the dermis and retinoids have been reported to stimulate wound repair due to enhanced collagen formation and can reverse the effects of corticosteroids and salicylates in wound healing.'^'^^ ANIMAL STUDIES
Kligman et al.^^ tested the hypothesis that topical tretinoin could be useful in treating UVinduced dermal elastosis. Using the hairless mouse as a model, they showed that UVB irradiation produced similar changes to those found in photodamaged skin. In mice treated with topical tretinoin, large numbers of fibroblasts appeared and new collagen was formed in the upper dermis with a 'pushing down' of potentially elastotic material deeper into the dermis. They also demonstrated dose-response improvements, both in terms of concentration of tretinoin and duration of treatment, whereas control experiments using irritants such as croton oil, salicylic acid, propyleneglycol and sodium lauryl sulphate did not result in dermal repair, thus indicating that the response to topical tretinoin was a pharmacological one rather than due to non-specific wound repair. CLINICAL STUDIES
At the same time as the development of the hairless mouse skin model and the demonstration that topical tretinoin could reverse many of the changes seen in the dermis, clinical use of topical tretinoin was initiated in a newly established clinic at the University of Pennsylvania that was devoted to the study and treatment of ageing skin. In the initial stages, open clinical studies were carried out on hundreds of patients using different concentrations and formulations of topical tretinoin, with clinical assessment mainly involving visual comparison of photographs. Over
History of retinoid therapy in photoageing 85 several years, convincing evidence emerged that topical tretinoin was useful in moderating many of the changes associated with photoageing, and these findings led to extensive studies in which the clinical and histological effects of tretinoin on photodamaged facial and forearm skin were determined.^^ When tretinoin-treated tissue was examined by light and electron microscopy it was shown that: epidermal atrophy was replaced by hyperplasia; atypia and other changes of dysplasia were reversed; melanosomes were dispersed; new collagen deposition took place in the papillary dermis; and, possibly, angioneogenesis occurred. Physiological studies demonstrated that bloodflowwas increased, with greater permeability and reactivity of the skin. It was concluded that topical tretinoin is capable of at least partially reversing many of the structural changes associated with chronic UV-induced damage and that these changes bring about visible clinical improvement. Subsequently, Weiss et al.^* demonstrated similar clinical and histological changes in a double-blind clinical trial. Their findings created enormous interest and response from the lay press, which has continued to this day. Since these observations, further controlled clinical trials have been conducted both in the U.S.A. and in Europe. These studies have extended the understanding of possible mechanisms by which tretinoin can modulate photoageing.
REFERENCES 1 Stuttgen G, Krause H, Der Nachweis von trikiummarkiertem Vitamin A in den Schichten der Haut nach lokaler Applikation, Hautarzt 1959; 10: 504-6, 2 Stuttgen G, Zur Lokalbehandlung von Keratosen mit Vitamin-A Saure, Dermatologica 1962; 124: 65-80, 3 Beer P, Umersuchungen uber die Wirkung der Vitamin-A Saure, Dermatologica 1962; 124: 192-5, 4 Kligman AM, Fulton JE Jr, Plewig G, Topical vitamin A acid in acne vulgaris. Arch Dermatol 1969; 99: 469-76, 5 Orfanos CE, Schmidt HW, Mahrle G et al. Retinoic acid in psoriasis: its value for topical therapy with and without corticosteroids, Br J Dermatol 1973; 88: 167-82. 6 Frost P, Battistini F. Retinoic acid for the therapy of psoriasis, Acta Derm Venereol (Stockh) 1975; S5(Suppl): 154-60, 7 Prutkin L, The effect of vitamin A acid on hyperkeratinization and the keratoacanthoma, J Invest Dermatol 1967; 49: 165-72, 8 Gunther S. Retinoic acid in the treatment of lichen planus. Dermatologica 1971; 143: 315-18, 9 Frost P, Weinstein GD, Topical administration of vitamin A acid for ichthyosiform dermatoses andpsoriasis.J/^w Med Assoc 1969; 207: 1863-8, 10 Peck GL, Yoder FW, Olsen TG et al. Treatment of Darier's disease, lamellar ichthyosis, pityriasis rubra pilaris, cystic acne, and basal cell carcinoma with oral 13-cis-retinoic acid. Dermatologica 1978; I57(suppl): 11-12. 11 Peck GL, Olsen TG, Yoder FW et al. Prolonged remissions of cystic and conglobate acne with 13-cis-retinoic acid, N EnglJ Med 1979; 300: 329-33. 12 Sporn MB, Roberts AB, Roche NS et a/. Mechanism of action of retinoids. J Am Acad Dermatol 1986; 15: 756-64, 13 Chytil F, Retinoic acid; biochemistry and metabolism, J Am Acad Dermatol 1986; 15; 741-7, 14 Bollag W, Ott F, Retinoic acid: topical treatment of senile or actinic keratoses and basal cell carcinomas. Agents Actions 1970; i: 172-5. 15 Purcell SM, Pierce DK, Dixon SL et al. Chemoprevention of actinic keratoses with topical all-tra«j-retinoic acid. J Invest Dermatol 1986; 86: 501, 16 Robinson TA, Kligman AM, Treatment of solar keratoses with retinoic acid and 5-fluorouracil, BrJ Dermatol 1975; 92: 703-6, 17 Peck GL. Topical tretinoin in actinic keratosis and basal cell carcinoma, J Am Acad Dermatol 1986; 15: 829-35, 18 Lee KH, Tong TG, Mechanism of action of retinyl compounds on wound healing, H, Effect of active retinyl derivatives on granuloma formation, J Pharm Sci 1970; 59: 1195-7, 19 Hunt TK, Ehrlich HP, Garcia JA et al. Effect of vitamin A on reversing the inhibitory effect of cortisone on healing of open wounds in animals and man, Ann Surg 1969J 170: 633-41, 20 Lee KH, Studies on the mechanism of action of salicylates, HL Effect of vitamin A on the wound healing retardation of aspirin, J Pharm Sci 1968; 57: 1238-40,
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21 BrinkerhofT CE, McMillan RM, Dayer JM et a/. Inhibition by retinoic acid of collagenase production in rheumatoid synovial cells, N EnglJ Med 1980; 303: 432-6, 22 Kligman LH, Chen HD, Kligman AM, Topical retinoic acid enhances the repair of ultraviolet damaged dermal connective tissue. Connect Tissue Res 1984; 12: 139-50, 23 Kligman AM, Grove GL, Hirose R et al. Topical tretinoin for photoaged skin, J Am Acad Dermatol 1986; 15: 8365924 Weiss JS, Ellis CN, Headington JT et al. Topical tretinoin improves photoaged i)dn.J Am Med Assoc 1988; 4:31-6,
