SUPPORTED BY AN UNRESTRICTED EDUCATIONAL GRANT FROM ORTHO DERMATOLOGICAL

Photoaging therapy with topical : an evidence-based analysis

Sewon Kang, MD, and John J. Voorhees, MD Ann Arbor, Michigan

Topical tretinoin is established as an effective treatment for photoaging. Yet some confu- sion still exists about the proper way to use this medication, confusion that can misguide physicians in their clinical approaches and patients in their treatment regimens. Most of the misinformation about tretinoin has been perpetuated from the early days of the drug, when its efficacy for treating the effects of photoaging was still in dispute. Significant advances in clinical and basic research in this area have dispelled much of the confusion, clearing the way for an evidence-based medical approach to tretinoin therapy for photoaging. This review summarizes recent relevant advances in tretinoin therapy to guide physicians in treating patients with this safe and effective hormone. To date, tretinoin remains the only therapeutic agent proved to repair photodamage. (J Am Acad Dermatol 1998;39:S55-61.)

The effectiveness of topical tretinoin for treat- ical community around the world. Along with the ing the effects of photoaging is now unchallenged. excitement it generated, a certain amount of skep- This acceptance, however, has come more than a ticism was initially expressed by many. Although decade after the initial reports by Cordero1 and several reasons may be cited for the mixed Kligman et al2 who described the potential utility response, the most important was probably the of topical tretinoin for photoaging, and it did not medical community’s unfamiliarity with photoag- occur without controversy. Although several large- ing at the time and a consequent inability to draw scale clinical studies have consistently demonstrat- clear distinctions between photoaging and natural ed the efficacy of tretinoin in treating photoaging aging of skin. After all, the clinical features of pho- and although basic research into its mechanism of toaging—dry, sallow skin; mottled or blotchy dys- action in human skin has greatly enhanced our pigmentation, and wrinkles4—are what most peo- understanding of its pharmacologic effects, mis- ple envision for skin of advanced age. Therefore it conceptions remain about the proper clinical use of is easy to see how the improvements brought about tretinoin. In this review, we highlight pertinent by tretinoin therapy could have been misconstrued data to clarify 5 commonly misunderstood aspects as a reversal of the aging process, a claim that was of tretinoin therapy for photoaging: (1) tretinoin- made more than once in the media and one that specific improvement in skin; (2) irritation associ- was understandably difficult to accept. With the ated with tretinoin treatment; (3) tretinoin treat- realization that even in individuals with marked ment in non–white persons; (4) sunlight and photoaging, their sun-protected skin was much tretinoin treatment; and (5) patient safety from sys- more youthful in appearance, a clearer distinction temic absorption. could be drawn between photoaging and intrin- When the original double-blind, vehicle-con- sic/chronologic aging. This distinction made it trolled study was published in 19883 that demon- easier for critics to accept that photoaged skin is strated that topical tretinoin improves the pheno- treatable with pharmacologic agents. The contro- typic features of photoaging, the report received versy was effectively resolved when several well- tremendous attention from the media and the med- controlled studies5-8 provided consistent, indis- putable evidence that tretinoin improves the effects of photoaging in human skin. From the Department of Dermatology, University of Michigan Medical Center. TRETINOIN SPECIFICITY OF PHOTOAGING Supported in part by the Babcock Dermatological Research Fund and a research agreement with Johnson & Johnson Corporation. REPAIR Reprint requests: Sewon Kang, MD, 1910 Taubman Center, 1500 E. Although the clinical efficacy of tretinoin for Medical Center Dr., Ann Arbor, MI 48109-0314. Copyright © 1998 by the American Academy of Dermatology, Inc. treatment of photoaged skin is now generally 0190-9622/98/$5.00 + 0 16/0/91349 accepted, some critics have argued that the

S55 Journal of the American Academy of Dermatology S56 Kang and Voorhees August 1998 improvement observed in skin cannot be credited clinical improvement of photoaged skin. On the to tretinoin per se. This skepticism stems from the contrary, equally impressive clinical results may fact that skin irritation, also known as “ be achieved with sparing but diligent use of dermatitis,” frequently accompanies topical appli- tretinoin, an approach that minimizes retinoid der- cation of tretinoin. Though data were lacking to matitis. One recent study reported that a 48-week support these contentions, and some critics regimen of treatment once-daily with 0.05% claimed that improvement in photoaging was sec- tretinoin emollient cream, followed by treatment 3 ondary to nonspecific irritation associated with times weekly for an additional 24 weeks, main- topical application of tretinoin and not a result of tained and, in some cases, even enhanced the retinoid-specific action in skin. improvements in photoaged skin.11 Treatment The facts about the efficacy of tretinoin therapy once-a-week with tretinoin was less effective in were finally clarified with the publication of a sustaining the clinical improvement achieved by large, single-center study involving nearly 100 the initial treatment regimen of tretinoin once- subjects.9 Study participants were randomized into daily. In the same study, some reversal of the ben- 3 treatment groups, treated with 0.1% tretinoin, eficial effects of tretinoin treatment was observed 0.025% tretinoin, or vehicle cream. The results after discontinuation of therapy for 24 weeks, indicated that treatment with either 0.1% or which indicates the need to continue tretinoin ther- 0.025% tretinoin induced statistically significant apy to maintain clinical improvement. improvement in the effects of photoaging, com- pared with vehicle treatment. There were no sig- RECEPTORS MEDIATE THE nificant differences in the overall clinical efficacy BIOLOGIC EFFECTS OF TRETINOIN of treatment with 0.1% versus 0.025% concentra- Although improvements in photoaged skin are tions of tretinoin. However, the degree of irritation, attributable to retinoid therapy and not a result of a defined as erythema and scaling of mild or greater nonspecific irritant reaction, it was not initially severity on 2 or more occasions during treatment, clear how tretinoin’s effects are mediated in differed markedly between the 2 treatment groups: human skin. We provide a brief overview of this the 0.1% tretinoin-treated group exhibited an avenue of research here, but readers are referred to approximately threefold greater incidence of irrita- a recent review for a more comprehensive discus- tion than the 0.025% tretinoin-treated group. sion of the subject.12 If clinical improvement of photoaged skin was, The mechanism by which tretinoin (all-trans- in fact, secondary to skin irritation caused by retinoic acid) induces its biologic effects was not tretinoin as some critics claimed, then the effects well understood until recently. The discovery of produced by 0.1% tretinoin treatment should have retinoic acid receptors (RARs) in 198713,14 was the been significantly greater than those produced by first demonstration of the existence of a tretinoin- 0.025% tretinoin treatment because of significant- specific gene transcription factor, a landmark find- ly greater irritation expected at the higher concen- ing that lead to the realization that tretinoin is a tration. However, the absence of any correlation hormone. RARs are similar to steroid/thyroid hor- between clinical efficacy and level of irritation mone receptors in terms of molecular composition points to the conclusion that tretinoin’s irritant and function. As such, RARs have distinct DNA properties are clearly distinguishable from its ben- and retinoid-binding domains, and they function in eficial effects on photoaged skin. In a separate pairs, either pairs of identical receptors called study by Kligman et al,10 which used an animal homodimers or pairs of different receptors called model of photoaging, tretinoin effectively effaced heterodimers. In human skin, RARs partner with wrinkles, whereas topically applied irritants had retinoid X receptors (RXRs) to form heterodimeric no effect, which supports the results of the study complexes.15,16 The RAR-γ subtype accounts for on human subjects. approximately 90% of RARs in human epidermis, The consistent results of both animal and although the RXR-α subtype accounts for roughly human studies have clear implications for clinical 90% of RXRs.15 For the most part, normal human practice, the most important being that it is unnec- skin is regulated by paired heterodimers composed essary to push tretinoin use to the point that brisk of RAR-γ and RXR-α. In the presence of the RAR- retinoid dermatitis develops to achieve maximum specific retinoid (eg, all-trans-retinoic acid, or Journal of the American Academy of Dermatology Volume 39, Number 2, Part 3 Kang and Voorhees S57 tretinoin), the heterodimers bind to specific DNA clinical and histologic changes after 4 days of con- sequences, known collectively as the retinoic acid tinuous occlusion, there is a difference in the time response element (RARE), in the promoter region of onset. Tretinoin induces these changes after 2 of genes that are regulated by tretinoin and in this days; SLS takes longer.23 The rapid onset with manner regulate the transcriptional activity of tretinoin therapy suggests that tretinoin has a tretinoin-responsive genes. The heterodimer direct effect on cutaneous cells (ie, mediated by requires only the RAR-specific retinoid to bind to receptors), whereas the effects of SLS are indirect the RARE and initiate transcriptional activity; the and caused by secondary phenomena. This possi- presence of an RXR-binding retinoid, such as 9- bility was confirmed in experiments with geneti- cis-retinoic acid, does not confer additional trans- cally engineered mice that expressed mutant RXR- activation induced by the RAR retinoid. However, α receptors. In these transgenic mice, the expres- for the (RAR/RXR) heterodimer to function, the sion of dominant negative RXR-α mutant proteins RXR protein must be physically present to associ- was targeted to the suprabasal layers of the epider- ate with the RAR protein. mis by the keratin 10 promoter. Because mutant Currently, it has been determined that RXR-α are capable of dimerizing with wild-type tretinoin’s actions in the skin are primarily, and RARs, one consequence of mutant receptor over probably solely, mediated by these retinoid recep- expression is a functional deficiency of RARs. tors. Because the receptors are transcription fac- Normal RARs are tied up with mutant RXR-α in tors, tretinoin must accomplish its effects in skin heterodimers, with the end result that skin is defi- through regulated gene expression. Although ini- cient in functional retinoid receptors. In the skin of tially only RARE-containing genes are activated in the transgenic mice deficient in functional RARs, response to tretinoin, some of the protein products topical application of tretinoin does not induce the of these genes are believed to activate other non- epidermal hyperplasia and desquamation typically RARE-containing genes in a cascading fashion, seen, indicating that the tretinoin-induced epider- producing the diverse array of retinoid actions in mal hyperproliferative response and peeling are skin. indeed receptor mediated.24 These findings sug- Recently we reviewed evidence that dermal col- gest that any retinoid, natural or synthetic, that can lagen may be the central player in the pathogenesis bind to and activate the RARs will induce the epi- of photoaging.17 Partial restoration of dermal colla- dermal hyperplasia and desquamation response in gen that had been reduced in photoaged skin is skin. Claims that synthetic can provide observed after topical tretinoin use,18 which is an clinical efficacy without the concomitant peeling example of a tretinoin-initiated cascade whose end response should therefore be viewed with extreme result is wrinkle effacement at the clinical level. skepticism, because they are inherently contradic- tory, according to current knowledge. PEELING COMPONENT OF TRETINOIN The erythema component of retinoid dermatitis IRRITATION IS ALSO RECEPTOR MEDIATED appears not to be receptor mediated. Topical appli- Repeated topical applications of tretinoin pre- cation of all-trans to human skin induces dictably produce a skin reaction resembling irrita- epidermal hyperplasia and expression of the tion. This reaction is characterized by redness and RARE-containing cellular retinoic acid-binding desquamation, signs that correspond histologically protein-II gene mRNA.19 The ability of all-trans to alterations in the stratum corneum and epider- retinol to elicit histologic and molecular effects mal hyperplasia.9,19,20 Similar clinical and histo- identical to those produced by tretinoin can be logic findings can be observed after 4 days of explained by the conversion of retinol to trace occlusive therapy with tretinoin or sodium lauryl amounts of tretinoin. Despite evidence that retinol sulfate (SLS).21 These histologic changes result treatment activates RARs, it is unassociated with from increased proliferation of keratinocytes, as clinical erythema.19 indicated by a greater number of mitotic figures, and enhanced expression of differentiation mark- TRETINOIN THERAPY IN NON–WHITE ers.3,19,22 Collectively, these epidermal changes PERSONS IS SAFE AND EFFECTIVE lead to clinical desquamation and peeling. It is a well-established clinical fact that individ- Although both tretinoin and SLS induce similar uals with greater baseline constitutive skin pig- Journal of the American Academy of Dermatology S58 Kang and Voorhees August 1998 mentation are more prone to the development of UV radiation, may contribute to this response. patches of dyspigmentation (called postinflamma- With daily use of tretinoin, the stratum corneum tory hyper- or hypopigmentation) at sites of skin becomes thinner but more compact.3,6,7 To what inflammation. Because topical tretinoin therapy is extent thinning of the stratum corneum affects commonly associated with “retinoid dermatitis,” photosensitivity is unknown. However, formal there has been legitimate concern about inducing phototesting of individuals treated with oral postinflammatory dyspigmentation at sites of (which must be converted to tretinoin retinoid dermatitis, especially in darker-skinned to be effective) has failed to demonstrate any sig- individuals. However, controlled studies25-27 in nificant changes in photosensitivity (minimal ery- which black patients and Asian patients were treat- thema dose).29,30 ed with 0.1% tretinoin cream have consistently The only evidence that tretinoin may have pho- demonstrated that such undesirable dyspigmenta- tocarcinogenic potential comes from animal stud- tion does not occur. Remarkably, one study ies. In albino and hairless mice, the application of showed that topical tretinoin can be effectively tretinoin has been reported to promote UVB- used to treat postinflammatory hyperpigmentation induced carcinogenesis.31,32 Opposite effects, caused by inflammatory conditions such as acne or demonstrating that tretinoin inhibits growth and in folliculitis in black patients.25 In our experience, some cases cause regression of UVB-induced tretinoin therapy rarely causes hyperpigmentation, tumors, have also been reported in hairless and when it does, the undesirable effects are treat- mice.33,34 This evidence suggests that the carcino- able with continued use of tretinoin. Furthermore, genic effects of tretinoin may be limited to suscep- the incidence of hyperpigmentation is not more tible animals under laboratory conditions. The prevalent in black patients and Asian patients. gross inadequacy of commonly used rodent mod- Indeed, these individuals tolerate topical tretinoin, els for studying photocarcinogenesis in human even the 0.1% strength, as well as, if not better skin was recently demonstrated in a study in which than, white patients. Given this evidence, tretinoin human skin was grafted onto mice with severe therapy for individuals with darker skin pigmenta- combined immunodeficiency (SCID). In this tion can be recommended with confidence. study, human carcinomas developed only rarely (3.6%) and only in grafts that were first tumor ini- SUN EXPOSURE AND TRETINOIN THERAPY tiated (with dimethyl(a)benzanthracene) before Two concerns have been raised regarding sun being irradiated with UVB. On the other hand, exposure during tretinoin therapy: photosensitivity murine carcinomas were commonly observed in and photocarcinogenesis. Skin treated with topical all UVB-irradiated SCID mice grafted with human tretinoin does respond differently to solar radiation skin, whether they were dimethyl(a)benzanthra- than untreated skin does. However, the differences cene initiated (23%) or not (45%), before irradia- in response need to be clarified. Under controlled tion.35 These results indicate that UVB is much conditions, when human skin that has been pre- more potent in mouse skin than in human skin, treated with topical tretinoin is irradiated with UV either as a complete carcinogen or as a promoter. light of a defined energy, there is no effect on the Furthermore, these findings demonstrate the ten- minimal erythema dose.28 These results clearly dency of rodent models to overestimate the car- indicate that tretinoin has no phototoxic activity cinogenic potential of tested agents in human skin. and that it does not possess sunscreen properties In humans, there is no evidence to date that either.28 Patients undergoing topical tretinoin ther- tretinoin is carcinogenic. On the contrary, topical apy do occasionally complain of uncomfortable tretinoin may provide protection against UV- sensations when their skin is exposed to sunlight. induced premalignant lesions.36,37 These sensations often occur within minutes of We have recently demonstrated that doses of being in the sun, which suggests that the reaction UV light too low to cause visible skin reddening is quite different from the sunburn reaction that are still capable of activating the enzymatic normally occurs hours after excessive sun expo- machinery that leads to photoaging.28 Therefore sure. Furthermore, the sensations are more notice- minimizing sun exposure must be an important able in hot environments than in cold ones, indi- part of any photoaging treatment program, to pre- cating that heat (infrared radiation), rather than vent its further progression. Pretreatment with Journal of the American Academy of Dermatology Volume 39, Number 2, Part 3 Kang and Voorhees S59 tretinoin markedly inhibits UV induction of matrix unlikely that 4-hydroxylation and inactivation will metalloproteinases at the mRNA, protein, and occur before absorption. enzyme activity levels.28 Recently, these changes were demonstrated visually by the use of ribo- SUMMARY probe in situ hybridization, immunohistology, and Photoaging is a treatable condition that in situ zymography techniques,38 collectively pro- responds favorably to treatment with topical viding the first solid evidence for prevention of tretinoin. The improvement in photoaged skin is photoaging by tretinoin. tretinoin specific, not secondary to irritation. Indeed, marked clinical improvement can be SYSTEMIC ABSORPTION OF TOPICAL achieved without excessive use of tretinoin, there- TRETINOIN by minimizing the occurrence of skin irritation. When administered systemically, tretinoin is a However, some skin peeling, or desquamation, is potent teratogen, like isotretinoin and . unavoidable (except by dose reduction), because Because more younger women are using topical the epidermal hyperproliferative response is RAR tretinoin both for treatment and presumed preven- mediated. Based on evidence from controlled stud- tion of photoaging,28,38 there has been great con- ies, non-white patients tolerate topical tretinoin cern about whether tretinoin, topically adminis- treatment well. Postinflammatory dyspigmenta- tered, also has teratogenic potential. Existing data tions are only rarely observed. Increased “photo- on teratogenicity of topical tretinoin use have, for sensitivity” during tretinoin use appears to be an the most part, been collected from patients who enhanced neurosensory response to infrared irradi- were being treated for acne. In a large population- ation, rather than a phototoxic or an accelerated based study, no significant increase in the rate of sunburn response. No increased risk of photocar- fetal malformation was observed in the tretinoin- cinogenesis has been detected in humans with treated group during the first trimester of pregnan- tretinoin treatment. Finally, according to published cy, as compared with those without the exposure.39 epidemiologic data, tretinoin therapy involves no Consistent with this finding were results from a increased risk of teratogenicity at the typical dose controlled study in which 0.025% tretinoin gel was used to treat photoaging. Nevertheless, because applied daily to the face, neck, and upper part of spontaneous malformation of the fetus occasional- the chest for 14 days. Fluctuations in plasma lev- ly occurs in “normal” pregnancies, it is probably els of endogenous retinoids were lower than those prudent to postpone tretinoin therapy for patients of diurnal and nutritional factors.40 Taken togeth- who are actively trying to conceive, to avoid er, the data on routine clinical use of topical wrongful blame for congenital defects that may tretinoin indicate that there is no increased risk for occur by chance. In summary, topical tretinoin is pregnant women. an effective agent that can be used safely and wise- The cytochrome P-450 enzyme, retinoic acid 4- ly to treat photoaging when the clinical approach hydroxylase, metabolizes tretinoin to 4-hydroxy is based on existing scientific knowledge. retinoic acid, which is inactive. Very recently, this enzyme was cloned and identified as a novel We thank Patti Bayhan for secretarial assistance. 41,42 cytochrome P-450 (CYP26). Human skin not REFERENCES only expresses the enzyme but, after exposure to 1. 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