Aging skin is a growing concern in the United States, and not surprisingly, patients continue to seek non-surgical procedures more frequently than surgical ones to treat their lines and wrinkles. According to the American Society for Aesthetic Plastic Surgery, 9.6 million non-surgical cosmetic procedures were performed last year compared to only 2.1 million surgical cosmetic procedures.1
Noninvasive treatments continue in popularity, and last year the top-5 nonsurgical procedures included botulinum toxin injections, hyaluronic acid fillers, laser hair removal, microdermabrasion, and intense pulsed light treatments.1 Additionally, consumers favor over-the-counter cosmeceuticals and prescription anti-aging medications for facial rejuvenation.
As dermatologists, we prescribe these products to enhance results obtained from in-office procedures and as part of a comprehensive anti-aging regimen. The use of topical tretinoin has been an established part of many anti-aging regimens. This article will review the latest data supporting the use of topical tretinoin for treating photodamaged skin.
Photodamage
Skin aging is caused by the cumulative effects of intrinsic and extrinsic aging. (See Table 1.) Intrinsic aging, or natural aging, occurs with time passage, while extrinsic aging is caused by environmental factors.
Chronic sun exposure is by far the most important extrinsic factor. Photoaging is characterized by unique changes in the skin including coarse and fine wrinkling, mottled hyperpigmentation, sallowness, lentigines, freckling, and telangiectasia. In more advanced cases, the cumulative effects of the sun induce ac-tinic keratoses and cause skin cancer.2,3
Histologically, photodamaged skin shows both epidermal and dermal changes. Sun-exposed skin experiences a thickening of the epidermis and stratum corneum. Epi-dermal pigment is prominent because of an increase in the number of melanosomes in melanocytes and more dispersion of pigment to keratinocytes. Additionally, epidermal cells may be focally irregular in size with nuclear atypia. The dermis shows solar elastosis, a hallmark of photoaging, and a deficiency in collagen I, III, and IV.
Much of the clinical stigmata associated with photodamage, including wrinkling, can be attributed to this loss of dermal connective tissue support.3,4
Pathogenesis of Photoaging
To briefly recap the pathogenesis of the photoaging process: Ultraviolet light affects skin through a series of cellular and molecular events. It activates signaling pathways that affect gene expression, including the protein kinase pathway.3 This pathway up-regulates nuclear transcription factors including activator protein 1 (AP-1) and nuclear transcription factor NF-_B. AP-1 is responsible for producing metalloproteinases (MMPs), the enzymes that break down collagen. AP-1 also impairs collagen synthesis by blocking the effects of transforming growth factor beta (TGF-_). NF-_B stimulates transcription of pro-inflammatory mediators including several interleukins and TNF-_. Through these molecular events, ultraviolet light reduces collagen synthesis and enhances collagen breakdown affecting both the functional and structural integrity of the skin. (See Figure 1 for more detail.)3
Photodamage in Skin of Color
It is known that pigment provides natural protection against ultraviolet light.3 Patients with dark skin are protected from sunburn and have a lower incidence of skin cancer, and they generally do not show the characteristic changes seen in fair-skinned individuals with photodamage. Accordingly, sun protection in patients with skin of color has not been emphasized.5
Recently, dermatologists have recognized that while photoaging is less visible on dark skin, it still exists.6 For patients with dark skin, photodamage manifests itself as hyperpigmentation that may be localized or diffuse. This hyperpigmentation is of cosmetic concern and can be difficult to treat.5 Accordingly, it is imperative for us to encourage our patients with skin of color to adopt sun protective behaviors and to seek treatment for photodamage when it occurs.
The Role of Retinoids in Preventing and Reversing Photodamage
Retinoids are important molecules that have revolutionized dermatologic therapy because of their biologic and therapeutic diversity.7 Retinoid effects include immunomodulation, angiogenesis, anti-inflammation, epithelial proliferation and differentiation, and cancer chemoprevention.7 Because of their diverse effects, retinoids are used to treat a variety of dermatologic disorders including acne, psoriasis, hyperpigmentation, rosacea, and photoaging.7 The first retinoid to be widely used was tretinoin, or all-trans-retinoic acid.
The application of tretinoin to the skin initiates a series of events that can both prevent and repair photodamage.8 When applied topically to the skin, tretinoin enters the cell and binds to nuclear hormone receptors including retinoic acid receptors (RARs) and retinoid X receptors (RXRs). It is this activated retinoid-receptor complex that regulates gene transcription, allowing retinoids to inhibit or activate certain gene expression.
Studies in human skin demonstrate that pretreatment with topical tretinoin mitigates UVR-induced expression of AP-1.4 This down-regulates production of collagen degrading enzymes allowing tretinoin to preserve dermal collagen. Additionally, when collagen loss has already occurred, the application of topical tretinoin induces type I and type III procollagen gene expression.9 These combined effects explain how tretinoin boosts dermal collagen, leaving skin smoother and less wrinkled.
The histologic effects of tretinoin on photodamaged skin were first reported by Bhawan et al in 1991. Tretinoin increases epidermal thickness, increases granular layer thickness, decreases epidermal melanin content, and promotes stratum corneum compaction.10
Clinical Efficacy of Tretinoin in Treating Photodamaged Skin
Kligman and colleagues were the first to observe that patients using tretinoin to treat acne also saw a softening of periorbital wrinkles.11 These early observations set off controversy among dermatologists, many of whom were skeptical. Since that time, numerous studies have confirmed the beneficial effects of tretinoin on photoaged skin including making skin smoother, lightening hyperpigmentation, and effacing wrinkles.
The first double-blind vehicle-controlled study on tretinoin for photoaged skin was reported by Weiss et al in 1988.12 In this trial, patients used 0.1% tretinoin cream once daily for 4 months on facial and forearm skin. While patients in the tretinoin group demonstrated a statistically significant improvement in coarse wrinkles, roughness, and lentigines, irritation was reported by 92% of subjects in the test group.
To determine if irritation is necessary for efficacy, two concentrations of tretinoin cream (0.l% and 0.025%) were compared.13 In this study, subjects applied the tretinoin once daily for 48 weeks. Investigators found that while clinical improvement was equal in both groups, patients using the lower concentration cream had far less irritation. Nyirady et al compared the irritation factor of several commonly used retinoid formulations.14 Sixty healthy adults were randomized to six groups:
1. tretinoin cream 0.02%
2. tretinoin emollient cream 0.05%
3. tretinoin cream 0.05%
4. tretinoin cream 0.1%
5. tazarotene cream 0.1%
6. tazarotene gel 0.1%.
Patients were treated three times weekly for 3 weeks and evaluated using an irritation score. This study demonstrated that tretinoin cream 0.02% was the least irritating of the six preparations studied. (See Figure 2.)14
Tretinoin cream 0.02% has been studied in four well-controlled, multi-center clinical trials and one single-center, randomized, controlled trial. All clinical trials were 24 weeks long. A total of 324 patients were treated with tretinoin cream 0.02%, and 332 patients were treated with vehicle cream. In addition, all patients were required to use comprehensive skin protection and sun avoidance during the clinical trials.15 Two of the five clinical trials demonstrated efficacy in reducing the appearance of fine facial wrinkling after 6 months of treatment. (See Figure 3.)
A long-term clinical trial was also conducted with tretinoin cream 0.02% to determine the effects after 1 year of treatment.16 Eighty-five percent of patients treated with tretinoin cream 0.02% considered themselves “improved” compared with baseline, and 19% considered themselves “much improved.” No patients had worsening of their photodamaged skin. In addition, this study demonstrated a reduction in fine wrinkling, which improved in the 52 weeks of the study.16 Figure 4 summarizes the principal efficacy results of both the 24-week and 52-week studies. Overall, both patients and physicians saw improvements in overall appearance, severity of photodamage, and fine wrinkling with the use of tretinoin cream 0.02%.16 In addition, the safety data from the long-term clinical trial demonstrated that tretinoin cream 0.02% was generally well tolerated and had a favorable safety profile. Signs and symptoms of irritation peaked at 4 weeks and then declined to baseline by 8 weeks. Overall, 43% of patients reported skin irritation during the 52-week trial, but the irritation was generally mild. Only 6% of patients discontinued the long-term trial due to adverse events.16
Safety of Tretinoin for Photodamaged Skin
Because oral tretinoin is associated with significant teratogenicity, Shapiro et al evaluated the pharmacokinetic and pharmacodynamic action of topically applied tretinoin emollient cream.17 When applied to human skin, only 2% of tretinoin emollient cream was absorbed after one dose or after 28 days of daily dosing, and 1.1% was absorbed after 1 year of therapy.17 The authors concluded that this level of penetration is enough for topical effectiveness, but not for systemic risk of teratogenicity.
Clinical trials have determined that tretinoin is safe to use and that while minor irritation including redness and flaking may occur, it generally diminishes in the first few weeks of therapy. The author generally suggested that patients start by applying tretinoin every other night or even every third night for the first few weeks and avoid aggressive exfoliation and the use of abrasive scrubs and masks. Using the emollient formulations of tretinoin and lower concentration products will also minimize irritation for first- time users.
One safety issue that continues to be a concern among patients is the anecdotal report that tretinoin causes increased sun sensitivity. This notion leads to compliance issues among outdoor enthusiasts who think they get too much sun exposure to use tretinoin. Nyirady and Grossman conducted two randomized, double-blind, placebo-controlled studies with 35 healthy volunteers to determine if tretinoin caused phototoxicity and/or photoallergy.18 Patients were treated with 0.05% tretinoin cream on test patches and then subjected to UV irradiation. These studies demonstrated that neither 0.05% tretinoin emollient cream nor vehicle caused phototoxic or photoallergic reactions. The authors suggest that the increased sun sensitivity of some patients may result from the diminished ability of the skin to deflect UV light.18
Efficacy of Tretinoin in Combination with Other Dermatologic Procedures
Because tretinoin is effective for the treatment of photodamaged skin, a number of studies have examined whether tretinoin in combination with other dermatologic procedures, such as dermabrasion, chemical peels, or electroepilation, may shorten the recovery time from these procedures.19,20,21,22 A review of the literature by Nyirady et al looked at studies addressing the use of tretinoin in combination with dermatologic procedures.
Most dermatologic surgeons use tretinoin preoperatively and postoperatively when performing resurfacing procedures. It is generally agreed that tretinoin is of benefit in wound healing and in reducing the incidence of post-operative complications such as hyperpigmentation and milia formation. This article provides an excellent review of the literature on this type of combination therapy.19 The Guidelines of Care on Chemical Peeling published in 1995 by the American Academy of Dermatology recommended pre and postoperative treatment with tretinoin.23
Two studies have examined the use of tretinoin before trichloroacetic acid (TCA) peel and show conflicting results.21,24 Hevia and colleagues conducted a double-blind, placebo-controlled study with 16 patients. These patients were treated daily with 0.1% tretinoin and placebo on the left and right sides of the face, forearms, and hands for 14 days prior to a 35% TCA peel. This study showed that the face healed the fastest and that pretreatment with tretinoin led to enhanced healing time. However, there was no significant difference in clinical outcomes in those pretreated with tretinoin and those achieved with TCA peel only.21 The other study, conducted by Humphreys and colleagues, examined 16 men with actinic damage, including actinic keratoses.24 Eight patients were pretreated with tretinoin for 6 weeks prior to 40% TCA peel. Some improvements were seen for all patients, but more rapid and even frosting was observed in the tretinoin-treated patient. Overall, these researchers found that treatment with tretinoin did not enhance the efficacy of the TCA peel. 24
More studies on combined therapy are warranted.
A Helpful Tool
Despite public health warnings about sun exposure, a significant portion of the U.S. population still gets too much sun exposure. Whether the exposure is recreational or occupational, the results are cumulative. Retinoids can be used to help prevent and repair the damage seen from photodamage as they act on a molecular level to mitigate many of the untoward effects of UVR on the skin.
Aging skin is a growing concern in the United States, and not surprisingly, patients continue to seek non-surgical procedures more frequently than surgical ones to treat their lines and wrinkles. According to the American Society for Aesthetic Plastic Surgery, 9.6 million non-surgical cosmetic procedures were performed last year compared to only 2.1 million surgical cosmetic procedures.1
Noninvasive treatments continue in popularity, and last year the top-5 nonsurgical procedures included botulinum toxin injections, hyaluronic acid fillers, laser hair removal, microdermabrasion, and intense pulsed light treatments.1 Additionally, consumers favor over-the-counter cosmeceuticals and prescription anti-aging medications for facial rejuvenation.
As dermatologists, we prescribe these products to enhance results obtained from in-office procedures and as part of a comprehensive anti-aging regimen. The use of topical tretinoin has been an established part of many anti-aging regimens. This article will review the latest data supporting the use of topical tretinoin for treating photodamaged skin.
Photodamage
Skin aging is caused by the cumulative effects of intrinsic and extrinsic aging. (See Table 1.) Intrinsic aging, or natural aging, occurs with time passage, while extrinsic aging is caused by environmental factors.
Chronic sun exposure is by far the most important extrinsic factor. Photoaging is characterized by unique changes in the skin including coarse and fine wrinkling, mottled hyperpigmentation, sallowness, lentigines, freckling, and telangiectasia. In more advanced cases, the cumulative effects of the sun induce ac-tinic keratoses and cause skin cancer.2,3
Histologically, photodamaged skin shows both epidermal and dermal changes. Sun-exposed skin experiences a thickening of the epidermis and stratum corneum. Epi-dermal pigment is prominent because of an increase in the number of melanosomes in melanocytes and more dispersion of pigment to keratinocytes. Additionally, epidermal cells may be focally irregular in size with nuclear atypia. The dermis shows solar elastosis, a hallmark of photoaging, and a deficiency in collagen I, III, and IV.
Much of the clinical stigmata associated with photodamage, including wrinkling, can be attributed to this loss of dermal connective tissue support.3,4
Pathogenesis of Photoaging
To briefly recap the pathogenesis of the photoaging process: Ultraviolet light affects skin through a series of cellular and molecular events. It activates signaling pathways that affect gene expression, including the protein kinase pathway.3 This pathway up-regulates nuclear transcription factors including activator protein 1 (AP-1) and nuclear transcription factor NF-_B. AP-1 is responsible for producing metalloproteinases (MMPs), the enzymes that break down collagen. AP-1 also impairs collagen synthesis by blocking the effects of transforming growth factor beta (TGF-_). NF-_B stimulates transcription of pro-inflammatory mediators including several interleukins and TNF-_. Through these molecular events, ultraviolet light reduces collagen synthesis and enhances collagen breakdown affecting both the functional and structural integrity of the skin. (See Figure 1 for more detail.)3
Photodamage in Skin of Color
It is known that pigment provides natural protection against ultraviolet light.3 Patients with dark skin are protected from sunburn and have a lower incidence of skin cancer, and they generally do not show the characteristic changes seen in fair-skinned individuals with photodamage. Accordingly, sun protection in patients with skin of color has not been emphasized.5
Recently, dermatologists have recognized that while photoaging is less visible on dark skin, it still exists.6 For patients with dark skin, photodamage manifests itself as hyperpigmentation that may be localized or diffuse. This hyperpigmentation is of cosmetic concern and can be difficult to treat.5 Accordingly, it is imperative for us to encourage our patients with skin of color to adopt sun protective behaviors and to seek treatment for photodamage when it occurs.
The Role of Retinoids in Preventing and Reversing Photodamage
Retinoids are important molecules that have revolutionized dermatologic therapy because of their biologic and therapeutic diversity.7 Retinoid effects include immunomodulation, angiogenesis, anti-inflammation, epithelial proliferation and differentiation, and cancer chemoprevention.7 Because of their diverse effects, retinoids are used to treat a variety of dermatologic disorders including acne, psoriasis, hyperpigmentation, rosacea, and photoaging.7 The first retinoid to be widely used was tretinoin, or all-trans-retinoic acid.
The application of tretinoin to the skin initiates a series of events that can both prevent and repair photodamage.8 When applied topically to the skin, tretinoin enters the cell and binds to nuclear hormone receptors including retinoic acid receptors (RARs) and retinoid X receptors (RXRs). It is this activated retinoid-receptor complex that regulates gene transcription, allowing retinoids to inhibit or activate certain gene expression.
Studies in human skin demonstrate that pretreatment with topical tretinoin mitigates UVR-induced expression of AP-1.4 This down-regulates production of collagen degrading enzymes allowing tretinoin to preserve dermal collagen. Additionally, when collagen loss has already occurred, the application of topical tretinoin induces type I and type III procollagen gene expression.9 These combined effects explain how tretinoin boosts dermal collagen, leaving skin smoother and less wrinkled.
The histologic effects of tretinoin on photodamaged skin were first reported by Bhawan et al in 1991. Tretinoin increases epidermal thickness, increases granular layer thickness, decreases epidermal melanin content, and promotes stratum corneum compaction.10
Clinical Efficacy of Tretinoin in Treating Photodamaged Skin
Kligman and colleagues were the first to observe that patients using tretinoin to treat acne also saw a softening of periorbital wrinkles.11 These early observations set off controversy among dermatologists, many of whom were skeptical. Since that time, numerous studies have confirmed the beneficial effects of tretinoin on photoaged skin including making skin smoother, lightening hyperpigmentation, and effacing wrinkles.
The first double-blind vehicle-controlled study on tretinoin for photoaged skin was reported by Weiss et al in 1988.12 In this trial, patients used 0.1% tretinoin cream once daily for 4 months on facial and forearm skin. While patients in the tretinoin group demonstrated a statistically significant improvement in coarse wrinkles, roughness, and lentigines, irritation was reported by 92% of subjects in the test group.
To determine if irritation is necessary for efficacy, two concentrations of tretinoin cream (0.l% and 0.025%) were compared.13 In this study, subjects applied the tretinoin once daily for 48 weeks. Investigators found that while clinical improvement was equal in both groups, patients using the lower concentration cream had far less irritation. Nyirady et al compared the irritation factor of several commonly used retinoid formulations.14 Sixty healthy adults were randomized to six groups:
1. tretinoin cream 0.02%
2. tretinoin emollient cream 0.05%
3. tretinoin cream 0.05%
4. tretinoin cream 0.1%
5. tazarotene cream 0.1%
6. tazarotene gel 0.1%.
Patients were treated three times weekly for 3 weeks and evaluated using an irritation score. This study demonstrated that tretinoin cream 0.02% was the least irritating of the six preparations studied. (See Figure 2.)14
Tretinoin cream 0.02% has been studied in four well-controlled, multi-center clinical trials and one single-center, randomized, controlled trial. All clinical trials were 24 weeks long. A total of 324 patients were treated with tretinoin cream 0.02%, and 332 patients were treated with vehicle cream. In addition, all patients were required to use comprehensive skin protection and sun avoidance during the clinical trials.15 Two of the five clinical trials demonstrated efficacy in reducing the appearance of fine facial wrinkling after 6 months of treatment. (See Figure 3.)
A long-term clinical trial was also conducted with tretinoin cream 0.02% to determine the effects after 1 year of treatment.16 Eighty-five percent of patients treated with tretinoin cream 0.02% considered themselves “improved” compared with baseline, and 19% considered themselves “much improved.” No patients had worsening of their photodamaged skin. In addition, this study demonstrated a reduction in fine wrinkling, which improved in the 52 weeks of the study.16 Figure 4 summarizes the principal efficacy results of both the 24-week and 52-week studies. Overall, both patients and physicians saw improvements in overall appearance, severity of photodamage, and fine wrinkling with the use of tretinoin cream 0.02%.16 In addition, the safety data from the long-term clinical trial demonstrated that tretinoin cream 0.02% was generally well tolerated and had a favorable safety profile. Signs and symptoms of irritation peaked at 4 weeks and then declined to baseline by 8 weeks. Overall, 43% of patients reported skin irritation during the 52-week trial, but the irritation was generally mild. Only 6% of patients discontinued the long-term trial due to adverse events.16
Safety of Tretinoin for Photodamaged Skin
Because oral tretinoin is associated with significant teratogenicity, Shapiro et al evaluated the pharmacokinetic and pharmacodynamic action of topically applied tretinoin emollient cream.17 When applied to human skin, only 2% of tretinoin emollient cream was absorbed after one dose or after 28 days of daily dosing, and 1.1% was absorbed after 1 year of therapy.17 The authors concluded that this level of penetration is enough for topical effectiveness, but not for systemic risk of teratogenicity.
Clinical trials have determined that tretinoin is safe to use and that while minor irritation including redness and flaking may occur, it generally diminishes in the first few weeks of therapy. The author generally suggested that patients start by applying tretinoin every other night or even every third night for the first few weeks and avoid aggressive exfoliation and the use of abrasive scrubs and masks. Using the emollient formulations of tretinoin and lower concentration products will also minimize irritation for first- time users.
One safety issue that continues to be a concern among patients is the anecdotal report that tretinoin causes increased sun sensitivity. This notion leads to compliance issues among outdoor enthusiasts who think they get too much sun exposure to use tretinoin. Nyirady and Grossman conducted two randomized, double-blind, placebo-controlled studies with 35 healthy volunteers to determine if tretinoin caused phototoxicity and/or photoallergy.18 Patients were treated with 0.05% tretinoin cream on test patches and then subjected to UV irradiation. These studies demonstrated that neither 0.05% tretinoin emollient cream nor vehicle caused phototoxic or photoallergic reactions. The authors suggest that the increased sun sensitivity of some patients may result from the diminished ability of the skin to deflect UV light.18
Efficacy of Tretinoin in Combination with Other Dermatologic Procedures
Because tretinoin is effective for the treatment of photodamaged skin, a number of studies have examined whether tretinoin in combination with other dermatologic procedures, such as dermabrasion, chemical peels, or electroepilation, may shorten the recovery time from these procedures.19,20,21,22 A review of the literature by Nyirady et al looked at studies addressing the use of tretinoin in combination with dermatologic procedures.
Most dermatologic surgeons use tretinoin preoperatively and postoperatively when performing resurfacing procedures. It is generally agreed that tretinoin is of benefit in wound healing and in reducing the incidence of post-operative complications such as hyperpigmentation and milia formation. This article provides an excellent review of the literature on this type of combination therapy.19 The Guidelines of Care on Chemical Peeling published in 1995 by the American Academy of Dermatology recommended pre and postoperative treatment with tretinoin.23
Two studies have examined the use of tretinoin before trichloroacetic acid (TCA) peel and show conflicting results.21,24 Hevia and colleagues conducted a double-blind, placebo-controlled study with 16 patients. These patients were treated daily with 0.1% tretinoin and placebo on the left and right sides of the face, forearms, and hands for 14 days prior to a 35% TCA peel. This study showed that the face healed the fastest and that pretreatment with tretinoin led to enhanced healing time. However, there was no significant difference in clinical outcomes in those pretreated with tretinoin and those achieved with TCA peel only.21 The other study, conducted by Humphreys and colleagues, examined 16 men with actinic damage, including actinic keratoses.24 Eight patients were pretreated with tretinoin for 6 weeks prior to 40% TCA peel. Some improvements were seen for all patients, but more rapid and even frosting was observed in the tretinoin-treated patient. Overall, these researchers found that treatment with tretinoin did not enhance the efficacy of the TCA peel. 24
More studies on combined therapy are warranted.
A Helpful Tool
Despite public health warnings about sun exposure, a significant portion of the U.S. population still gets too much sun exposure. Whether the exposure is recreational or occupational, the results are cumulative. Retinoids can be used to help prevent and repair the damage seen from photodamage as they act on a molecular level to mitigate many of the untoward effects of UVR on the skin.
Aging skin is a growing concern in the United States, and not surprisingly, patients continue to seek non-surgical procedures more frequently than surgical ones to treat their lines and wrinkles. According to the American Society for Aesthetic Plastic Surgery, 9.6 million non-surgical cosmetic procedures were performed last year compared to only 2.1 million surgical cosmetic procedures.1
Noninvasive treatments continue in popularity, and last year the top-5 nonsurgical procedures included botulinum toxin injections, hyaluronic acid fillers, laser hair removal, microdermabrasion, and intense pulsed light treatments.1 Additionally, consumers favor over-the-counter cosmeceuticals and prescription anti-aging medications for facial rejuvenation.
As dermatologists, we prescribe these products to enhance results obtained from in-office procedures and as part of a comprehensive anti-aging regimen. The use of topical tretinoin has been an established part of many anti-aging regimens. This article will review the latest data supporting the use of topical tretinoin for treating photodamaged skin.
Photodamage
Skin aging is caused by the cumulative effects of intrinsic and extrinsic aging. (See Table 1.) Intrinsic aging, or natural aging, occurs with time passage, while extrinsic aging is caused by environmental factors.
Chronic sun exposure is by far the most important extrinsic factor. Photoaging is characterized by unique changes in the skin including coarse and fine wrinkling, mottled hyperpigmentation, sallowness, lentigines, freckling, and telangiectasia. In more advanced cases, the cumulative effects of the sun induce ac-tinic keratoses and cause skin cancer.2,3
Histologically, photodamaged skin shows both epidermal and dermal changes. Sun-exposed skin experiences a thickening of the epidermis and stratum corneum. Epi-dermal pigment is prominent because of an increase in the number of melanosomes in melanocytes and more dispersion of pigment to keratinocytes. Additionally, epidermal cells may be focally irregular in size with nuclear atypia. The dermis shows solar elastosis, a hallmark of photoaging, and a deficiency in collagen I, III, and IV.
Much of the clinical stigmata associated with photodamage, including wrinkling, can be attributed to this loss of dermal connective tissue support.3,4
Pathogenesis of Photoaging
To briefly recap the pathogenesis of the photoaging process: Ultraviolet light affects skin through a series of cellular and molecular events. It activates signaling pathways that affect gene expression, including the protein kinase pathway.3 This pathway up-regulates nuclear transcription factors including activator protein 1 (AP-1) and nuclear transcription factor NF-_B. AP-1 is responsible for producing metalloproteinases (MMPs), the enzymes that break down collagen. AP-1 also impairs collagen synthesis by blocking the effects of transforming growth factor beta (TGF-_). NF-_B stimulates transcription of pro-inflammatory mediators including several interleukins and TNF-_. Through these molecular events, ultraviolet light reduces collagen synthesis and enhances collagen breakdown affecting both the functional and structural integrity of the skin. (See Figure 1 for more detail.)3
Photodamage in Skin of Color
It is known that pigment provides natural protection against ultraviolet light.3 Patients with dark skin are protected from sunburn and have a lower incidence of skin cancer, and they generally do not show the characteristic changes seen in fair-skinned individuals with photodamage. Accordingly, sun protection in patients with skin of color has not been emphasized.5
Recently, dermatologists have recognized that while photoaging is less visible on dark skin, it still exists.6 For patients with dark skin, photodamage manifests itself as hyperpigmentation that may be localized or diffuse. This hyperpigmentation is of cosmetic concern and can be difficult to treat.5 Accordingly, it is imperative for us to encourage our patients with skin of color to adopt sun protective behaviors and to seek treatment for photodamage when it occurs.
The Role of Retinoids in Preventing and Reversing Photodamage
Retinoids are important molecules that have revolutionized dermatologic therapy because of their biologic and therapeutic diversity.7 Retinoid effects include immunomodulation, angiogenesis, anti-inflammation, epithelial proliferation and differentiation, and cancer chemoprevention.7 Because of their diverse effects, retinoids are used to treat a variety of dermatologic disorders including acne, psoriasis, hyperpigmentation, rosacea, and photoaging.7 The first retinoid to be widely used was tretinoin, or all-trans-retinoic acid.
The application of tretinoin to the skin initiates a series of events that can both prevent and repair photodamage.8 When applied topically to the skin, tretinoin enters the cell and binds to nuclear hormone receptors including retinoic acid receptors (RARs) and retinoid X receptors (RXRs). It is this activated retinoid-receptor complex that regulates gene transcription, allowing retinoids to inhibit or activate certain gene expression.
Studies in human skin demonstrate that pretreatment with topical tretinoin mitigates UVR-induced expression of AP-1.4 This down-regulates production of collagen degrading enzymes allowing tretinoin to preserve dermal collagen. Additionally, when collagen loss has already occurred, the application of topical tretinoin induces type I and type III procollagen gene expression.9 These combined effects explain how tretinoin boosts dermal collagen, leaving skin smoother and less wrinkled.
The histologic effects of tretinoin on photodamaged skin were first reported by Bhawan et al in 1991. Tretinoin increases epidermal thickness, increases granular layer thickness, decreases epidermal melanin content, and promotes stratum corneum compaction.10
Clinical Efficacy of Tretinoin in Treating Photodamaged Skin
Kligman and colleagues were the first to observe that patients using tretinoin to treat acne also saw a softening of periorbital wrinkles.11 These early observations set off controversy among dermatologists, many of whom were skeptical. Since that time, numerous studies have confirmed the beneficial effects of tretinoin on photoaged skin including making skin smoother, lightening hyperpigmentation, and effacing wrinkles.
The first double-blind vehicle-controlled study on tretinoin for photoaged skin was reported by Weiss et al in 1988.12 In this trial, patients used 0.1% tretinoin cream once daily for 4 months on facial and forearm skin. While patients in the tretinoin group demonstrated a statistically significant improvement in coarse wrinkles, roughness, and lentigines, irritation was reported by 92% of subjects in the test group.
To determine if irritation is necessary for efficacy, two concentrations of tretinoin cream (0.l% and 0.025%) were compared.13 In this study, subjects applied the tretinoin once daily for 48 weeks. Investigators found that while clinical improvement was equal in both groups, patients using the lower concentration cream had far less irritation. Nyirady et al compared the irritation factor of several commonly used retinoid formulations.14 Sixty healthy adults were randomized to six groups:
1. tretinoin cream 0.02%
2. tretinoin emollient cream 0.05%
3. tretinoin cream 0.05%
4. tretinoin cream 0.1%
5. tazarotene cream 0.1%
6. tazarotene gel 0.1%.
Patients were treated three times weekly for 3 weeks and evaluated using an irritation score. This study demonstrated that tretinoin cream 0.02% was the least irritating of the six preparations studied. (See Figure 2.)14
Tretinoin cream 0.02% has been studied in four well-controlled, multi-center clinical trials and one single-center, randomized, controlled trial. All clinical trials were 24 weeks long. A total of 324 patients were treated with tretinoin cream 0.02%, and 332 patients were treated with vehicle cream. In addition, all patients were required to use comprehensive skin protection and sun avoidance during the clinical trials.15 Two of the five clinical trials demonstrated efficacy in reducing the appearance of fine facial wrinkling after 6 months of treatment. (See Figure 3.)
A long-term clinical trial was also conducted with tretinoin cream 0.02% to determine the effects after 1 year of treatment.16 Eighty-five percent of patients treated with tretinoin cream 0.02% considered themselves “improved” compared with baseline, and 19% considered themselves “much improved.” No patients had worsening of their photodamaged skin. In addition, this study demonstrated a reduction in fine wrinkling, which improved in the 52 weeks of the study.16 Figure 4 summarizes the principal efficacy results of both the 24-week and 52-week studies. Overall, both patients and physicians saw improvements in overall appearance, severity of photodamage, and fine wrinkling with the use of tretinoin cream 0.02%.16 In addition, the safety data from the long-term clinical trial demonstrated that tretinoin cream 0.02% was generally well tolerated and had a favorable safety profile. Signs and symptoms of irritation peaked at 4 weeks and then declined to baseline by 8 weeks. Overall, 43% of patients reported skin irritation during the 52-week trial, but the irritation was generally mild. Only 6% of patients discontinued the long-term trial due to adverse events.16
Safety of Tretinoin for Photodamaged Skin
Because oral tretinoin is associated with significant teratogenicity, Shapiro et al evaluated the pharmacokinetic and pharmacodynamic action of topically applied tretinoin emollient cream.17 When applied to human skin, only 2% of tretinoin emollient cream was absorbed after one dose or after 28 days of daily dosing, and 1.1% was absorbed after 1 year of therapy.17 The authors concluded that this level of penetration is enough for topical effectiveness, but not for systemic risk of teratogenicity.
Clinical trials have determined that tretinoin is safe to use and that while minor irritation including redness and flaking may occur, it generally diminishes in the first few weeks of therapy. The author generally suggested that patients start by applying tretinoin every other night or even every third night for the first few weeks and avoid aggressive exfoliation and the use of abrasive scrubs and masks. Using the emollient formulations of tretinoin and lower concentration products will also minimize irritation for first- time users.
One safety issue that continues to be a concern among patients is the anecdotal report that tretinoin causes increased sun sensitivity. This notion leads to compliance issues among outdoor enthusiasts who think they get too much sun exposure to use tretinoin. Nyirady and Grossman conducted two randomized, double-blind, placebo-controlled studies with 35 healthy volunteers to determine if tretinoin caused phototoxicity and/or photoallergy.18 Patients were treated with 0.05% tretinoin cream on test patches and then subjected to UV irradiation. These studies demonstrated that neither 0.05% tretinoin emollient cream nor vehicle caused phototoxic or photoallergic reactions. The authors suggest that the increased sun sensitivity of some patients may result from the diminished ability of the skin to deflect UV light.18
Efficacy of Tretinoin in Combination with Other Dermatologic Procedures
Because tretinoin is effective for the treatment of photodamaged skin, a number of studies have examined whether tretinoin in combination with other dermatologic procedures, such as dermabrasion, chemical peels, or electroepilation, may shorten the recovery time from these procedures.19,20,21,22 A review of the literature by Nyirady et al looked at studies addressing the use of tretinoin in combination with dermatologic procedures.
Most dermatologic surgeons use tretinoin preoperatively and postoperatively when performing resurfacing procedures. It is generally agreed that tretinoin is of benefit in wound healing and in reducing the incidence of post-operative complications such as hyperpigmentation and milia formation. This article provides an excellent review of the literature on this type of combination therapy.19 The Guidelines of Care on Chemical Peeling published in 1995 by the American Academy of Dermatology recommended pre and postoperative treatment with tretinoin.23
Two studies have examined the use of tretinoin before trichloroacetic acid (TCA) peel and show conflicting results.21,24 Hevia and colleagues conducted a double-blind, placebo-controlled study with 16 patients. These patients were treated daily with 0.1% tretinoin and placebo on the left and right sides of the face, forearms, and hands for 14 days prior to a 35% TCA peel. This study showed that the face healed the fastest and that pretreatment with tretinoin led to enhanced healing time. However, there was no significant difference in clinical outcomes in those pretreated with tretinoin and those achieved with TCA peel only.21 The other study, conducted by Humphreys and colleagues, examined 16 men with actinic damage, including actinic keratoses.24 Eight patients were pretreated with tretinoin for 6 weeks prior to 40% TCA peel. Some improvements were seen for all patients, but more rapid and even frosting was observed in the tretinoin-treated patient. Overall, these researchers found that treatment with tretinoin did not enhance the efficacy of the TCA peel. 24
More studies on combined therapy are warranted.
A Helpful Tool
Despite public health warnings about sun exposure, a significant portion of the U.S. population still gets too much sun exposure. Whether the exposure is recreational or occupational, the results are cumulative. Retinoids can be used to help prevent and repair the damage seen from photodamage as they act on a molecular level to mitigate many of the untoward effects of UVR on the skin.
