Special Topic Reversal of Skin Aging with Topical Retinoids Bradley A. Hubbard, M.D. Jacob G. Unger, M.D. Rod J. Rohrich, M.D. Dallas, Texas
Summary: Topical skin care and its place in plastic surgery today are often overlooked by clinicians formulating a plan for facial rejuvenation. Not only is it important to consider topical skin care as part of comprehensive care, but clinicians should also be educated with the data available in today's literature. This review aims to familiarize the reader with the biological processes of skin aging and evidence-based clinical outcomes afforded by various topical therapies. Furthermore, this review will focus on solar damage, the value of retinoids, and how they can be used in conjunction with forms of treatment such as chemical peel, dermabrasion, and lasers. Finally, guidelines will be provided to help the physician administer appropriate skin care based on the data presented. (Plast. Reconstr. Surg. 133: 481e, 2014.)
T
he pursuit to prevent or reverse human aging is as old as time itself. The shelves of pharmacies, department stores, and physicians’ offices are filled with a dizzying array of topical products aimed at skin rejuvenation. Unfortunately, the role of topical skin care is often overlooked, or worse, poorly understood by the plastic surgery community. This review aims to familiarize the reader with the biological processes of skin aging and evidence-based clinical outcomes afforded by topical retinoid therapy.
PHOTOAGING OF SKIN Molecular Level Ultraviolet radiation causes direct and indirect damage to skin. Direct damage results from absorption of the ultraviolet energy by DNA. Although ultraviolet B (290 to 320 nm) is most likely to induce pyrimidine base changes, ultraviolet A (320 to 400 nm) can also cause direct damage.1 Defects in mitochondrial DNA impair oxidative phosphorylation, leading to further oxidative stress on the entire cell.2 Although nuclear and mitochondrial DNA are affected, mitochondrial DNA repair mechanisms are less efficient and therefore more susceptible to permanent damage. Although ultraviolet A can directly induce DNA changes, most of its cell damage is indirect through the creation of reactive oxygen species and free radicals. Cells are designed to tolerate From the Department of Plastic Surgery, University of Texas Southwestern Medical Center. Received for publication March 14, 2013; accepted August 13, 2013. Copyright © 2014 by the American Society of Plastic Surgeons DOI: 10.1097/PRS.0000000000000043
an oxidative environment and protect themselves with DNA repair enzymes, enzymatic reduction proteins, and antioxidants.2 However, high metabolic demand, ultraviolet radiation, smoking, decreased cellular function with age, and other factors may overwhelm the system and oxidative damage results. Clinical Findings On a clinical level, the most common finding in naturally aged skin that has been protected from exposure to ultraviolet light is thin, dry, smooth, and unblemished skin. Photoaged skin (skin that has had marked exposure to ultraviolet light), in contrast, is characterized by fine and coarse wrinkles, roughness, laxity, sallowness, scaling, dryness, telangiectasia, and dyschromia (Fig. 1, left). There is also an increased frequency of benign, premalignant, and malignant lesions.3,4 Seborrheic keratoses are commonly associated with sun-exposed, aged skin.5 Histologic Findings Epidermis Aged photoprotected epidermis is usually thin, with decreased cellular turnover. There are minor abnormalities in keratinocyte maturation but a normal stratum corneum, in addition to a flattened contour of the rete pegs, increasing fragility, and susceptibility to shear stress forces (Fig. 2, above).5 Disclosure: None of authors has any commercial associations or financial disclosures that might pose or create a conflict of interest with information presented in this article.
www.PRSJournal.com
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Plastic and Reconstructive Surgery • April 2014
Fig. 1. Clinical photographs of photodamage pretreatment. (Left) Fine and coarse wrinkles, roughness, laxity, sallowness, scaling, telangiectasia, and dyschromia. (Center) After 1 year of nightly tretinoin 0.05% cream. (Right) After 5 years.
Photodamaged keratinocytes are characterized by atypia, loss of polarity (nonorderly maturation), slowed proliferation, and lessened cell signaling and response.6–8 Histologically,
Fig. 2. Photodamaged skin and photoprotected skin histology. (Reproduced with permission from Singh M, Griffiths CE. The use of retinoids in the treatment of photoaging. Dermatol Ther. 2006;19:297–305.)
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the epidermal thickness is increased in unprotected skin. However, concomitant flattening of the rete ridges can give the appearance of decreased thickness or atrophy (Fig. 2, below).6 On the whole, melanocytes decrease in number, have shortened lifespans, and respond less to growth factors, resulting in guttate hypomelanosis.9 However, there can also be regions of increased melanocyte concentration, increased capacity for melanin production, and increased melanin deposition into keratinocytes (e.g., solar lentigines).5 Dermis Of note, ultraviolet B light is almost completely absorbed by the epidermis; thus, dermal photodamage is caused solely by ultraviolet A light. In photoprotected skin, there is a decrease in all cell type density and extracellular matrix contents. Collagen, elastin, glycosaminoglycan content, and fibroblast and Langerhans cell counts are all decreased.10 Photoaged dermis on the cellular level is marked by signs of chronic inflammation. Fibroblasts and Langerhans cells are decreased and surrounded by abundant inflammatory infiltrate, a condition termed heliodermatitis.11,12 Fibroblasts are morphologically abnormal and produce less collagen. Solar elastosis is the term used to describe the histologic appearance of the photoaged dermal
Volume 133, Number 4 • Topical Retinoids for Skin Aging extracellular matrix. This condition is characterized by an accumulation of amorphous, abnormal elastin material surrounding a decreased volume and disorganized array of wavy collagen fibrils.3,6 It is hypothesized that the abnormal elastin results from overproduction of normal elastin, which is subsequently degraded by the chronic inflammatory state.3 The other major components of extracellular matrix (glycoproteins and glycosaminoglycans) tend to diminish with age but are increased in photoaged skin.13 However, the increased glycosaminoglycans are not found in the papillary dermis and epidermis as usual; instead, they are deposited in the reticular dermis within the elastotic material.14 In this location, the glycosaminoglycans are not able to regulate hydration, leading to dry and leathery appearing skin.15
RETINOID THERAPY Retinoids are a family of compounds composed of vitamin A, its derivatives, and synthetic molecules acting through the same pathway. Since the 1940s, they have been used topically and orally for a multitude of skin conditions (primarily, acne). Retinoids’ ability to rejuvenate photoaged skin was popularized in the 1980s, in large part because of the work of Kligman et al.16–18 Classification of the retinoid family can be done using their chemical makeup (presence of aromatic groups), generation, natural or synthetic, and prescription or over-the-counter availability. Table 1 displays an exhaustive list of retinoids using many existing classifications.19 Table 1. Classification of Retinoids Generation
Retinoid
First (nonaromatic and naturally occurring)
Retinol (all-trans-retinol, vitamin A)† Retinyl-palmitate† Retinyl-propionate† Retinyl-retinoate† Retinyl N-formyl aspartamate† Retinyl-acetate† Retinaldehyde† Tretinoin (all-trans-retinoic acid)*† Isotretinoin (13-cis-retinoic acid)*† Alitretinoin (9-cis-retinoic acid)*† Second Etretinate‡ (monoaromatic) Acetretin* Third (polyaromatic) Adapalene*† Tazarotene*† Bexarotene* Fourth (pyranones) Seletinoid G*† Arotinoid* Eretin*
*Prescription only. †Studied for effects on skin aging. ‡U.S. Food and Drug Administration approval retracted.
Mechanism of Action Retinols are naturally existing elements acquired through diet. Retinol (vitamin A) is absorbed through the small intestine and transported to be stored as a retinol ester (palmitate, propionate, and acetate) or oxidized to tretinoin through a two-step process, with retinaldehyde serving as the intermediate. Tretinoin represents 50 percent of the active cellular form, with its metabolites (4-hydroxy-retinoic acid) and stereoisomers 9-cis-retinoic acid (alitretinoin) and 13-cis-retinoic acid (isotretinoin) making up the difference.20 Thus, in topical application, retinol, retinol esters, and retinaldehyde have to be converted to a more active form (tretinoin), whereas isotretinoin, alitretinoin, adapalene, tazarotene, and seletinoid G are applied in their active form. Histologic Retinoid Effects Retinoids increase collagen content in the upper papillary dermis by inhibiting collagen degradation and increasing collagen synthesis. Topical tretinoin application before ultraviolet irradiation has been shown to prevent matrix metalloproteinase production and collagen degradation.21 New type I procollagen biosynthesis is increased by retinoids.22,23 Histologically, increased collagen types I, III, and VII (dermal-epidermal anchoring fibrils) can be seen, as can reorganization of the dermal collagen into new woven bundles.24 Topical tretinoin has been shown to increase production of type I collagen by 80 percent in photoaged skin.25 It is thought that the increased collagen content indirectly stimulates normalization of the elastic tissue organization.26 Increased smoothness of skin or wrinkle effacement from tretinoin topical treatment results from epidermal hyperplasia, compaction of the stratum corneum, thickening of the granular layer, and increased epidermal and dermal glycosaminoglycan deposition. Tretinoin therapy has also been shown to improve wound healing. This is most likely the effect of improved cutaneous circulation, which has been demonstrated by laser Doppler velocimetry.27 Animal studies have also shown tretinoin to have an effect on cytokeratin 16, which is an important modulator of the wound healing process.28 However, to date, a direct cause-and-effect relationship has not been established. Tretinoin Clinical Evidence The typically studied treatment protocol is 0.05% tretinoin cream applied nightly. Using this
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Fig. 3. (Above, left) Photodamaged skin before tretinoin treatment. (Above, right) Photodamaged skin after 4 months of topical tretinoin treatment. Keratinocytes are more organized, the granular layer thickness is increased, the stratum corneum is more compact, and severe elastosis continues to be present. (Below) Photoaged skin after 9 months of topical tretinoin treatment. There is restoration of polarity, thickening of the granular layer, increased angiogenesis in the dermis, and decreased elastosis. (Slides reprinted with permission from Torras H. Retinoids in aging. Clin Dermatol. 1996;14:207–215.)
protocol, epidermal thickening and improvement in fine wrinkles may be seen as soon as 3 months (Level II Evidence).29,30 After 6 months of therapy, improvements in fine and coarse wrinkling, sallowness, dyschromia, roughness, and laxity have been observed (Level I Evidence).31–35 However, at 6 months, improvement is limited to the epidermis, as no changes in dermal collagen or elastosis were seen (Figs. 1, center, and 2, above, right). Bhawan et al. confirmed that dermal changes were not seen at 6 months, and continued treatment for 12 months, at which point formation of new collagen fibers and reduction in elastoic material was seen (Figs. 1, right, and 3, below).36 The optimal dosing of tretinoin is a balance between efficacy and side effects, known as the retinoid reaction. The retinoid reaction consists of erythema, scaling, xerosis, and pruritus. These side effects are dose dependent. They are seen in the majority of patients using 0.05% concentrations daily and in upward of 90 percent of patients treated with 0.1% concentrations. However, the side-effect severity tends to subside over time.29 To reduce the incidence or severity of the retinoid reaction, several studies have been performed
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with lower concentrations of tretinoin. After 6 months of therapy, two large, vehicle-controlled, double-blind, randomized trials have shown superior epidermal improvement using a 0.05% concentration compared with 0.01%.32,33 Griffiths et al. compared 0.1% and 0.025% concentrations in a similarly designed study over 8 months and found no statistically significant difference in epidermal changes. Not surprisingly, the 0.025% concentration had far fewer adverse effects.37 Thus, it appears that concentrations of 0.025% to 0.1% have equivalent efficacy for epidermal improvement at 6 to 8 months. Lower concentrations of tretinoin have also been studied with longer treatment durations. Olsen and colleagues followed 298 patients randomized to daily application of 0.05%, 0.01%, or vehicle for 11 months. Statistical improvement over the vehicle preparation was identical for both tretinoin concentrations in clinical and histologic evaluations.38 Similarly, Nyirady et al. performed a double-blind, vehicle-controlled comparison of 0.02% and 0.05% tretinoin cream for 24 months and found no statistically significant difference in clinical improvement.39 Thus, these studies have
Volume 133, Number 4 • Topical Retinoids for Skin Aging indicated that with prolonged therapy there may not be any advantage to using treatments with higher concentration levels. Because of the delayed gratification of clinical improvement and concurrent incidence of adverse effects, patient noncompliance and discontinuation of therapy are not uncommon with tretinoin therapy. This has stimulated investigation of high-strength tretinoin treatment. Kligman and colleagues have been the strongest proponents of this style of therapy. In 1998, their group studied 50 women using 0.25% tretinoin cream every other night for 2 weeks followed thereafter by nightly application. Not only did they find the therapy to be well tolerated by patients, but also the clinical and histologic improvement after 4 to 6 weeks was similar to their results of patients who underwent 12 months of 0.05% daily application. Specifically, fine wrinkling, hyperpigmentation, elasticity, hydration, vascularity, and new collagen deposition were witnessed.40 In 2004, Kligman and Draelos studied 32 women with 0.25% tretinoin for 4 weeks. Again, early onset of epidermal and dermal changes was witnessed, in a process they have termed “rapid retinization.” Perhaps more interesting, the retinoid reaction was markedly diminished within only 2 weeks of treatment.41 To date, randomized controlled trials using rapid retinization concepts have yet to be performed. The safety and efficacy of a lifetime prescription of tretinoin are less well understood, as no study to date has greater than 6-year follow-up. After 48 months of 0.05% cream, Olsen et al. randomized 126 patients to once-weekly application, three-times-weekly application, or discontinuation of therapy. Three-times-weekly therapy was found to preserve fine wrinkle improvement better than once-weekly therapy. Discontinuation of therapy resulted in significant reversal of the antiaging effect.42 Therefore, discontinuation or significant truncation of tretinoin therapy appears to result in reversal of effect to some extent. Ellis et al. followed patients for 22 months using 0.1% and 0.05% concentrations. Their firstyear results were similar to the above-noted studies. However, epidermal thickness decreased gradually from its 6-month peak (although it was greater than before treatment), mitotic figures decreased, and the compact stratum corneum reverted to its pretreatment basket-weave pattern.43 A 4-year study of patients using variable concentrations of tretinoin, but all using 0.025% for the last 19 months, found slightly different results. Epidermal thickness did decrease slightly between 1 and 4 years, but the granular layer thickness and stratum corneum
compaction were unchanged.44 Lastly, Kligman et al. followed patients for 5 to 6 years using 0.05% concentration daily. In this group of patients, they found continued improvement over time in the dermis and epidermis. Specifically, they found a widening Grenz layer, decreased elastotic tissue, increased fibroblast density, and decreased dermal glycosaminoglycan.45 No conclusion can be drawn as to the best maintenance therapy dosing or concentration of tretinoin. Current evidence regarding the long-term effect of tretinoin on epidermal thickness and compaction of the stratum corneum is contradictory. However, evidence does suggest that continued tretinoin therapy is necessary to prolong, maintain, or possibly improve on early clinical gains in dyschromia and reversal of solar elastosis. Isotretinoin Molecular/Histologic Evidence Isotretinoin (13-cis-retinoic acid) is a stereoisomer of retinoic acid. It is known to bind to cellular retinoic acid–binding protein intracellularly and bind all retinoic acid receptor subtypes directly. However, some debate exists as to whether its topical effect is, in some part, attributable to conversion to tretinoin in vivo.46 Clinical Evidence The clinical evidence for the effect of isotretinoin on photoaging is less than that of tretinoin but nonetheless significant. Three groups have performed large (n = 776, n = 326, and n = 800) double-blind, vehicle-controlled, randomized trials using 0.1% cream for 9 months.47–49 All demonstrated statistically significant clinical improvement in wrinkling pigmentation, sallowness, and texture compared with controls starting at 12 weeks. However, no significant changes were found in the dermis in terms of elastosis reduction or fibroblast density. It should be noted that the duration of each study was only 9 months; thus, long-term dermal effects are unknown. Side effects were local and severe in only 5 to 10 percent. Plasma concentration of isotretinoin was not increased over the 36-week study period. Alirezai et al. studied the effect of twice-daily 0.1% isotretinoin cream on actinic keratoses.50 In a vehicle-controlled study, two-thirds of patients were found to have a greater than 33 percent reduction in precancerous growths in 6 months. More recently, oral isotretinoin therapy has been investigated for efficacy in the treatment of photoaging. Although there was some early level II evidence of subjective clinical improvement,
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Plastic and Reconstructive Surgery • April 2014 Bagatin et al. have recently called these results into question with better controls and objective assessment measures.51–53 In their 2010 phase II trial, 32 women were randomized to sunscreen and moisturizer, or 20 mg of isotretinoin orally three times per week plus sunscreen and moisturizer. The oral isotretinoin group was found to have no clinical benefit on profilometry, corneometry, skin elasticity tests, or histologic examination. In addition to the significant side-effect and safety concerns associated with oral isotretinoin therapy, current evidence is discouraging for the efficacy of oral isotretinoin in facial aging. Retinol (Vitamin A) Molecular/Histologic Evidence Retinol is commonly used as a component in cosmeceutical products. Its potential in the treatment of antiaging was realized in 1995, when Kang et al. first showed the ability of retinol to induce epidermal thickening with little irritation. The drastic reduction in the retinoid reaction is attributable to the replacement of retinoic acid’s carboxyl group with a hydroxyl group. Unfortunately, retinol is very unstable when exposed to light, oxygen, heat, lipid-peroxidation, and water, reducing its bioavailability.54 Furthermore, retinol must be converted to tretinoin in vivo to become biologically active.55 From these shortcomings, it has been speculated that retinol is 20-fold less effective than tretinoin, and the dermal concentration of tretinoin is 1000-fold less than that seen when topically applying the proper drug.56 Some have hypothesized that if retinol were applied at concentrations high enough to have similar effects as tretinoin, the side-effect profile would be similar. Clinical Evidence To date, evidence on the use of retinol in photoaged skin is limited to small controlled trials of limited duration. Piérard-Franchimont et al. conducted the first controlled clinical trial with retinol and demonstrated significant improvement in fine wrinkles after 12 weeks of treatment.57 Varani and colleagues studied 1% retinol on 53 patients with photoaged skin compared with a vehicle control. They found statistically significant histologic improvement at 7 days.58 Kafi et al. conducted a randomized, double-blind, vehicle-controlled study of 0.4% retinol in the upper arm skin of 23 patients. They found significant improvement in subjective fine wrinkles and histologic improvement.59 It should be noted that the commonly researched retinol concentrations range from
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0.4% to 1%, compared with the average over-thecounter products, which contain 0.08% or less.60 Retinyl Esters and Derivatives Molecular/Histologic Evidence Like retinol, its esters and derivatives must undergo in vivo conversion to the active form, tretinoin. Their creation has been stimulated by the side effects of tretinoin therapy and the instability of retinol. Clinical Evidence Retinyl propionate was the first clinically studied retinol ester. Green et al. conducted a double-blind, randomized, placebo-controlled trial with 80 patients using retinyl propionate cream. Fifty-nine patients completed the 48-week study. No subjective or objective data suggested improvement compared with the vehicle control.61 Retinyl palpitate was studied indirectly by Watson et al., who compared commercially available skin creams; one contained retinyl palmitate (concentration,
Summary: Topical skin care and its place in plastic surgery today are often overlooked by clinicians formulating a plan for facial rejuvenation. Not only is it important to consider topical skin care as part of comprehensive care, but clinicians should also be educated with the data available in today's literature. This review aims to familiarize the reader with the biological processes of skin aging and evidence-based clinical outcomes afforded by various topical therapies. Furthermore, this review will focus on solar damage, the value of retinoids, and how they can be used in conjunction with forms of treatment such as chemical peel, dermabrasion, and lasers. Finally, guidelines will be provided to help the physician administer appropriate skin care based on the data presented. (Plast. Reconstr. Surg. 133: 481e, 2014.)
T
he pursuit to prevent or reverse human aging is as old as time itself. The shelves of pharmacies, department stores, and physicians’ offices are filled with a dizzying array of topical products aimed at skin rejuvenation. Unfortunately, the role of topical skin care is often overlooked, or worse, poorly understood by the plastic surgery community. This review aims to familiarize the reader with the biological processes of skin aging and evidence-based clinical outcomes afforded by topical retinoid therapy.
PHOTOAGING OF SKIN Molecular Level Ultraviolet radiation causes direct and indirect damage to skin. Direct damage results from absorption of the ultraviolet energy by DNA. Although ultraviolet B (290 to 320 nm) is most likely to induce pyrimidine base changes, ultraviolet A (320 to 400 nm) can also cause direct damage.1 Defects in mitochondrial DNA impair oxidative phosphorylation, leading to further oxidative stress on the entire cell.2 Although nuclear and mitochondrial DNA are affected, mitochondrial DNA repair mechanisms are less efficient and therefore more susceptible to permanent damage. Although ultraviolet A can directly induce DNA changes, most of its cell damage is indirect through the creation of reactive oxygen species and free radicals. Cells are designed to tolerate From the Department of Plastic Surgery, University of Texas Southwestern Medical Center. Received for publication March 14, 2013; accepted August 13, 2013. Copyright © 2014 by the American Society of Plastic Surgeons DOI: 10.1097/PRS.0000000000000043
an oxidative environment and protect themselves with DNA repair enzymes, enzymatic reduction proteins, and antioxidants.2 However, high metabolic demand, ultraviolet radiation, smoking, decreased cellular function with age, and other factors may overwhelm the system and oxidative damage results. Clinical Findings On a clinical level, the most common finding in naturally aged skin that has been protected from exposure to ultraviolet light is thin, dry, smooth, and unblemished skin. Photoaged skin (skin that has had marked exposure to ultraviolet light), in contrast, is characterized by fine and coarse wrinkles, roughness, laxity, sallowness, scaling, dryness, telangiectasia, and dyschromia (Fig. 1, left). There is also an increased frequency of benign, premalignant, and malignant lesions.3,4 Seborrheic keratoses are commonly associated with sun-exposed, aged skin.5 Histologic Findings Epidermis Aged photoprotected epidermis is usually thin, with decreased cellular turnover. There are minor abnormalities in keratinocyte maturation but a normal stratum corneum, in addition to a flattened contour of the rete pegs, increasing fragility, and susceptibility to shear stress forces (Fig. 2, above).5 Disclosure: None of authors has any commercial associations or financial disclosures that might pose or create a conflict of interest with information presented in this article.
www.PRSJournal.com
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Plastic and Reconstructive Surgery • April 2014
Fig. 1. Clinical photographs of photodamage pretreatment. (Left) Fine and coarse wrinkles, roughness, laxity, sallowness, scaling, telangiectasia, and dyschromia. (Center) After 1 year of nightly tretinoin 0.05% cream. (Right) After 5 years.
Photodamaged keratinocytes are characterized by atypia, loss of polarity (nonorderly maturation), slowed proliferation, and lessened cell signaling and response.6–8 Histologically,
Fig. 2. Photodamaged skin and photoprotected skin histology. (Reproduced with permission from Singh M, Griffiths CE. The use of retinoids in the treatment of photoaging. Dermatol Ther. 2006;19:297–305.)
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the epidermal thickness is increased in unprotected skin. However, concomitant flattening of the rete ridges can give the appearance of decreased thickness or atrophy (Fig. 2, below).6 On the whole, melanocytes decrease in number, have shortened lifespans, and respond less to growth factors, resulting in guttate hypomelanosis.9 However, there can also be regions of increased melanocyte concentration, increased capacity for melanin production, and increased melanin deposition into keratinocytes (e.g., solar lentigines).5 Dermis Of note, ultraviolet B light is almost completely absorbed by the epidermis; thus, dermal photodamage is caused solely by ultraviolet A light. In photoprotected skin, there is a decrease in all cell type density and extracellular matrix contents. Collagen, elastin, glycosaminoglycan content, and fibroblast and Langerhans cell counts are all decreased.10 Photoaged dermis on the cellular level is marked by signs of chronic inflammation. Fibroblasts and Langerhans cells are decreased and surrounded by abundant inflammatory infiltrate, a condition termed heliodermatitis.11,12 Fibroblasts are morphologically abnormal and produce less collagen. Solar elastosis is the term used to describe the histologic appearance of the photoaged dermal
Volume 133, Number 4 • Topical Retinoids for Skin Aging extracellular matrix. This condition is characterized by an accumulation of amorphous, abnormal elastin material surrounding a decreased volume and disorganized array of wavy collagen fibrils.3,6 It is hypothesized that the abnormal elastin results from overproduction of normal elastin, which is subsequently degraded by the chronic inflammatory state.3 The other major components of extracellular matrix (glycoproteins and glycosaminoglycans) tend to diminish with age but are increased in photoaged skin.13 However, the increased glycosaminoglycans are not found in the papillary dermis and epidermis as usual; instead, they are deposited in the reticular dermis within the elastotic material.14 In this location, the glycosaminoglycans are not able to regulate hydration, leading to dry and leathery appearing skin.15
RETINOID THERAPY Retinoids are a family of compounds composed of vitamin A, its derivatives, and synthetic molecules acting through the same pathway. Since the 1940s, they have been used topically and orally for a multitude of skin conditions (primarily, acne). Retinoids’ ability to rejuvenate photoaged skin was popularized in the 1980s, in large part because of the work of Kligman et al.16–18 Classification of the retinoid family can be done using their chemical makeup (presence of aromatic groups), generation, natural or synthetic, and prescription or over-the-counter availability. Table 1 displays an exhaustive list of retinoids using many existing classifications.19 Table 1. Classification of Retinoids Generation
Retinoid
First (nonaromatic and naturally occurring)
Retinol (all-trans-retinol, vitamin A)† Retinyl-palmitate† Retinyl-propionate† Retinyl-retinoate† Retinyl N-formyl aspartamate† Retinyl-acetate† Retinaldehyde† Tretinoin (all-trans-retinoic acid)*† Isotretinoin (13-cis-retinoic acid)*† Alitretinoin (9-cis-retinoic acid)*† Second Etretinate‡ (monoaromatic) Acetretin* Third (polyaromatic) Adapalene*† Tazarotene*† Bexarotene* Fourth (pyranones) Seletinoid G*† Arotinoid* Eretin*
*Prescription only. †Studied for effects on skin aging. ‡U.S. Food and Drug Administration approval retracted.
Mechanism of Action Retinols are naturally existing elements acquired through diet. Retinol (vitamin A) is absorbed through the small intestine and transported to be stored as a retinol ester (palmitate, propionate, and acetate) or oxidized to tretinoin through a two-step process, with retinaldehyde serving as the intermediate. Tretinoin represents 50 percent of the active cellular form, with its metabolites (4-hydroxy-retinoic acid) and stereoisomers 9-cis-retinoic acid (alitretinoin) and 13-cis-retinoic acid (isotretinoin) making up the difference.20 Thus, in topical application, retinol, retinol esters, and retinaldehyde have to be converted to a more active form (tretinoin), whereas isotretinoin, alitretinoin, adapalene, tazarotene, and seletinoid G are applied in their active form. Histologic Retinoid Effects Retinoids increase collagen content in the upper papillary dermis by inhibiting collagen degradation and increasing collagen synthesis. Topical tretinoin application before ultraviolet irradiation has been shown to prevent matrix metalloproteinase production and collagen degradation.21 New type I procollagen biosynthesis is increased by retinoids.22,23 Histologically, increased collagen types I, III, and VII (dermal-epidermal anchoring fibrils) can be seen, as can reorganization of the dermal collagen into new woven bundles.24 Topical tretinoin has been shown to increase production of type I collagen by 80 percent in photoaged skin.25 It is thought that the increased collagen content indirectly stimulates normalization of the elastic tissue organization.26 Increased smoothness of skin or wrinkle effacement from tretinoin topical treatment results from epidermal hyperplasia, compaction of the stratum corneum, thickening of the granular layer, and increased epidermal and dermal glycosaminoglycan deposition. Tretinoin therapy has also been shown to improve wound healing. This is most likely the effect of improved cutaneous circulation, which has been demonstrated by laser Doppler velocimetry.27 Animal studies have also shown tretinoin to have an effect on cytokeratin 16, which is an important modulator of the wound healing process.28 However, to date, a direct cause-and-effect relationship has not been established. Tretinoin Clinical Evidence The typically studied treatment protocol is 0.05% tretinoin cream applied nightly. Using this
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Fig. 3. (Above, left) Photodamaged skin before tretinoin treatment. (Above, right) Photodamaged skin after 4 months of topical tretinoin treatment. Keratinocytes are more organized, the granular layer thickness is increased, the stratum corneum is more compact, and severe elastosis continues to be present. (Below) Photoaged skin after 9 months of topical tretinoin treatment. There is restoration of polarity, thickening of the granular layer, increased angiogenesis in the dermis, and decreased elastosis. (Slides reprinted with permission from Torras H. Retinoids in aging. Clin Dermatol. 1996;14:207–215.)
protocol, epidermal thickening and improvement in fine wrinkles may be seen as soon as 3 months (Level II Evidence).29,30 After 6 months of therapy, improvements in fine and coarse wrinkling, sallowness, dyschromia, roughness, and laxity have been observed (Level I Evidence).31–35 However, at 6 months, improvement is limited to the epidermis, as no changes in dermal collagen or elastosis were seen (Figs. 1, center, and 2, above, right). Bhawan et al. confirmed that dermal changes were not seen at 6 months, and continued treatment for 12 months, at which point formation of new collagen fibers and reduction in elastoic material was seen (Figs. 1, right, and 3, below).36 The optimal dosing of tretinoin is a balance between efficacy and side effects, known as the retinoid reaction. The retinoid reaction consists of erythema, scaling, xerosis, and pruritus. These side effects are dose dependent. They are seen in the majority of patients using 0.05% concentrations daily and in upward of 90 percent of patients treated with 0.1% concentrations. However, the side-effect severity tends to subside over time.29 To reduce the incidence or severity of the retinoid reaction, several studies have been performed
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with lower concentrations of tretinoin. After 6 months of therapy, two large, vehicle-controlled, double-blind, randomized trials have shown superior epidermal improvement using a 0.05% concentration compared with 0.01%.32,33 Griffiths et al. compared 0.1% and 0.025% concentrations in a similarly designed study over 8 months and found no statistically significant difference in epidermal changes. Not surprisingly, the 0.025% concentration had far fewer adverse effects.37 Thus, it appears that concentrations of 0.025% to 0.1% have equivalent efficacy for epidermal improvement at 6 to 8 months. Lower concentrations of tretinoin have also been studied with longer treatment durations. Olsen and colleagues followed 298 patients randomized to daily application of 0.05%, 0.01%, or vehicle for 11 months. Statistical improvement over the vehicle preparation was identical for both tretinoin concentrations in clinical and histologic evaluations.38 Similarly, Nyirady et al. performed a double-blind, vehicle-controlled comparison of 0.02% and 0.05% tretinoin cream for 24 months and found no statistically significant difference in clinical improvement.39 Thus, these studies have
Volume 133, Number 4 • Topical Retinoids for Skin Aging indicated that with prolonged therapy there may not be any advantage to using treatments with higher concentration levels. Because of the delayed gratification of clinical improvement and concurrent incidence of adverse effects, patient noncompliance and discontinuation of therapy are not uncommon with tretinoin therapy. This has stimulated investigation of high-strength tretinoin treatment. Kligman and colleagues have been the strongest proponents of this style of therapy. In 1998, their group studied 50 women using 0.25% tretinoin cream every other night for 2 weeks followed thereafter by nightly application. Not only did they find the therapy to be well tolerated by patients, but also the clinical and histologic improvement after 4 to 6 weeks was similar to their results of patients who underwent 12 months of 0.05% daily application. Specifically, fine wrinkling, hyperpigmentation, elasticity, hydration, vascularity, and new collagen deposition were witnessed.40 In 2004, Kligman and Draelos studied 32 women with 0.25% tretinoin for 4 weeks. Again, early onset of epidermal and dermal changes was witnessed, in a process they have termed “rapid retinization.” Perhaps more interesting, the retinoid reaction was markedly diminished within only 2 weeks of treatment.41 To date, randomized controlled trials using rapid retinization concepts have yet to be performed. The safety and efficacy of a lifetime prescription of tretinoin are less well understood, as no study to date has greater than 6-year follow-up. After 48 months of 0.05% cream, Olsen et al. randomized 126 patients to once-weekly application, three-times-weekly application, or discontinuation of therapy. Three-times-weekly therapy was found to preserve fine wrinkle improvement better than once-weekly therapy. Discontinuation of therapy resulted in significant reversal of the antiaging effect.42 Therefore, discontinuation or significant truncation of tretinoin therapy appears to result in reversal of effect to some extent. Ellis et al. followed patients for 22 months using 0.1% and 0.05% concentrations. Their firstyear results were similar to the above-noted studies. However, epidermal thickness decreased gradually from its 6-month peak (although it was greater than before treatment), mitotic figures decreased, and the compact stratum corneum reverted to its pretreatment basket-weave pattern.43 A 4-year study of patients using variable concentrations of tretinoin, but all using 0.025% for the last 19 months, found slightly different results. Epidermal thickness did decrease slightly between 1 and 4 years, but the granular layer thickness and stratum corneum
compaction were unchanged.44 Lastly, Kligman et al. followed patients for 5 to 6 years using 0.05% concentration daily. In this group of patients, they found continued improvement over time in the dermis and epidermis. Specifically, they found a widening Grenz layer, decreased elastotic tissue, increased fibroblast density, and decreased dermal glycosaminoglycan.45 No conclusion can be drawn as to the best maintenance therapy dosing or concentration of tretinoin. Current evidence regarding the long-term effect of tretinoin on epidermal thickness and compaction of the stratum corneum is contradictory. However, evidence does suggest that continued tretinoin therapy is necessary to prolong, maintain, or possibly improve on early clinical gains in dyschromia and reversal of solar elastosis. Isotretinoin Molecular/Histologic Evidence Isotretinoin (13-cis-retinoic acid) is a stereoisomer of retinoic acid. It is known to bind to cellular retinoic acid–binding protein intracellularly and bind all retinoic acid receptor subtypes directly. However, some debate exists as to whether its topical effect is, in some part, attributable to conversion to tretinoin in vivo.46 Clinical Evidence The clinical evidence for the effect of isotretinoin on photoaging is less than that of tretinoin but nonetheless significant. Three groups have performed large (n = 776, n = 326, and n = 800) double-blind, vehicle-controlled, randomized trials using 0.1% cream for 9 months.47–49 All demonstrated statistically significant clinical improvement in wrinkling pigmentation, sallowness, and texture compared with controls starting at 12 weeks. However, no significant changes were found in the dermis in terms of elastosis reduction or fibroblast density. It should be noted that the duration of each study was only 9 months; thus, long-term dermal effects are unknown. Side effects were local and severe in only 5 to 10 percent. Plasma concentration of isotretinoin was not increased over the 36-week study period. Alirezai et al. studied the effect of twice-daily 0.1% isotretinoin cream on actinic keratoses.50 In a vehicle-controlled study, two-thirds of patients were found to have a greater than 33 percent reduction in precancerous growths in 6 months. More recently, oral isotretinoin therapy has been investigated for efficacy in the treatment of photoaging. Although there was some early level II evidence of subjective clinical improvement,
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Plastic and Reconstructive Surgery • April 2014 Bagatin et al. have recently called these results into question with better controls and objective assessment measures.51–53 In their 2010 phase II trial, 32 women were randomized to sunscreen and moisturizer, or 20 mg of isotretinoin orally three times per week plus sunscreen and moisturizer. The oral isotretinoin group was found to have no clinical benefit on profilometry, corneometry, skin elasticity tests, or histologic examination. In addition to the significant side-effect and safety concerns associated with oral isotretinoin therapy, current evidence is discouraging for the efficacy of oral isotretinoin in facial aging. Retinol (Vitamin A) Molecular/Histologic Evidence Retinol is commonly used as a component in cosmeceutical products. Its potential in the treatment of antiaging was realized in 1995, when Kang et al. first showed the ability of retinol to induce epidermal thickening with little irritation. The drastic reduction in the retinoid reaction is attributable to the replacement of retinoic acid’s carboxyl group with a hydroxyl group. Unfortunately, retinol is very unstable when exposed to light, oxygen, heat, lipid-peroxidation, and water, reducing its bioavailability.54 Furthermore, retinol must be converted to tretinoin in vivo to become biologically active.55 From these shortcomings, it has been speculated that retinol is 20-fold less effective than tretinoin, and the dermal concentration of tretinoin is 1000-fold less than that seen when topically applying the proper drug.56 Some have hypothesized that if retinol were applied at concentrations high enough to have similar effects as tretinoin, the side-effect profile would be similar. Clinical Evidence To date, evidence on the use of retinol in photoaged skin is limited to small controlled trials of limited duration. Piérard-Franchimont et al. conducted the first controlled clinical trial with retinol and demonstrated significant improvement in fine wrinkles after 12 weeks of treatment.57 Varani and colleagues studied 1% retinol on 53 patients with photoaged skin compared with a vehicle control. They found statistically significant histologic improvement at 7 days.58 Kafi et al. conducted a randomized, double-blind, vehicle-controlled study of 0.4% retinol in the upper arm skin of 23 patients. They found significant improvement in subjective fine wrinkles and histologic improvement.59 It should be noted that the commonly researched retinol concentrations range from
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0.4% to 1%, compared with the average over-thecounter products, which contain 0.08% or less.60 Retinyl Esters and Derivatives Molecular/Histologic Evidence Like retinol, its esters and derivatives must undergo in vivo conversion to the active form, tretinoin. Their creation has been stimulated by the side effects of tretinoin therapy and the instability of retinol. Clinical Evidence Retinyl propionate was the first clinically studied retinol ester. Green et al. conducted a double-blind, randomized, placebo-controlled trial with 80 patients using retinyl propionate cream. Fifty-nine patients completed the 48-week study. No subjective or objective data suggested improvement compared with the vehicle control.61 Retinyl palpitate was studied indirectly by Watson et al., who compared commercially available skin creams; one contained retinyl palmitate (concentration,
