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Photodamage pilot study: A double-blind, vehicle-controlled study to assess the efficacy and safety of tazarotene 0.1% gel
Photodamage pilot study: A double-blind, vehicle-controlled study to assess the efficacy and safety of tazarotene 0.1% gel John Sefton, PhD,a Albert M. Kligman, MD, PhD,b Scott C. Kopper, BS,a John C. Lue, MS,a and John R. Gibson, MDa Irvine, California, and Philadelphia, Pennsylvania Background: Tazarotene, a potent acetylenic retinoid for topical use, might be expected to benefit photodamaged skin, including improving the classical signs of fine wrinkles, mottled hyperpigmentation, and roughness. Objective: Our purpose was to determine the efficacy and safety of tazarotene 0.1% gel in the treatment of photodamaged dorsal forearm skin. Methods: Ten healthy female volunteers, aged 45 to 65 years, with moderately photodamaged forearm skin applied tazarotene 0.1% gel to one arm and vehicle gel to the other once daily for 12 weeks. The study was a double-blind, randomized, paired-comparison evaluation conducted at a single site. Results: Tazarotene showed beneficial effects for several efficacy variables. It was more efficacious than vehicle in reducing skin roughness and fine wrinkling based on objective measurements. Tazarotene also corrected epidermal atrophy and atypia and improved skin hydration properties. Conclusion: In this 12-week pilot study tazarotene redressed abnormalities associated with photodamaged skin. (J Am Acad Dermatol 2000;43:656-63.)
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ll skin tends to undergo the changes brought about by intrinsic aging, but pathologic changes may also occur because of long-term sun exposure. Sun-induced changes, referred to as photodamage, are superimposed on the changes caused by chronologic aging, and are responsible for the many unwanted age-associated features of the skin’s appearance.1 Whereas intrinsically aged, sunprotected skin is thin, less elastic, but otherwise largely unblemished and smooth, photodamaged skin is characterized by fine and coarse wrinkles, roughness, laxity, sallowness, mottled hyperpigmentation, and telangiectasia.1,2 Histologic changes in photodamaged skin include epidermal atypia and atrophy, elastosis, increased melanogenesis, exces-
From Allergan, Inc, Irvine,a and the Department of Dermatology, University of Pennsylvania College of Medicine, Philadelphia.b Supported by Allergan, Inc. Accepted for publication April 13, 2000. Reprint requests: John Sefton, PhD, Allergan, Inc, Skin Care Clinical R&D, 2525 Dupont Dr, Irvine, CA 92612. E-mail: sefton_john@ allergan.com. Copyright © 2000 by the American Academy of Dermatology, Inc. 0190-9622/2000/$12.00 + 0 16/1/107938 doi:10.1067/mjd.2000.107938
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Abbreviations used: GAG: RAR: RXR: TEWL:
glycosaminoglycan retinoic acid receptor retinoid X receptor transepidermal water loss
sive deposition of glycosaminoglycans (GAGs), and decreased collagen.3-6 Topical tretinoin (all-trans-retinoic acid) has been shown to improve the clinical appearance of photodamaged skin.3,7 Histologically, tretinoin induces compaction of the stratum corneum, thickening of the epidermis (acanthosis), correction of atypia, increased granular layer thickness, increased dermal collagen, and angiogenesis.3,6,7 Retinoids elicit their effects at the molecular level by regulating gene transcription and affecting activities such as cellular differentiation and proliferation. Retinoids can act directly, by inducing transcription from genes whose promotor region contains retinoid response elements.8 Two such retinoidresponsive genes, TIG1 and TIG2 (tazaroteneinduced genes 1 and 2), have recently been described in skin. Their expression in psoriatic
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lesions is stimulated by the topical retinoid tazarotene, which is effective in the treatment of psoriasis.9 The exact mechanism by which genes like TIG1 and TIG2 function is not yet understood. Retinoids can also act indirectly, by inhibiting the transcription of certain genes.8 For example, it has recently been shown that pretreatment with tretinoin reduced the UVB-induced expression of collagen-degrading metalloproteinases in skin, presumably by antagonizing the UVB-induced transcription factor AP-1.5 Nuclear retinoic acid receptors belong to two families, the retinoic acid receptor (RAR) family and the retinoid X receptor (RXR) family, and each receptor family contains 3 receptor subtypes: α, β, and γ.8 Tretinoin is a nonselective retinoid which activates all RAR pathways (RARs α, β, and γ) directly and RXR pathways indirectly through conversion of all-trans retinoic acid to 9-cis retinoic acid (the natural ligand for RXRs).10 Tazarotene, on the other hand, is the first of a new generation of receptor-selective retinoids that selectively binds mainly to RAR β and γ and is unable to bind to RXRs directly or indirectly.8 It should be noted that the skin contains primarily RAR γ, and it is unknown whether the receptor selectivity of tazarotene would have any particular clinical significance in the treatment of skin disease, including the treatment of photodamage.11 This photodamage pilot study demonstrates that tazarotene does have beneficial effects in correcting some of the structural and functional changes of photodamaged skin.
STUDY DESIGN The study was initiated as a single-center, doubleblind, randomized, paired-comparison evaluating the efficacy and safety of tazarotene 0.1% gel compared with vehicle applied once daily for 12 weeks. Ten healthy female volunteers, aged 45 to 65 years, with moderately photodamaged forearm skin applied tazarotene 0.1% gel to one arm and vehicle gel to the opposite arm. The forearms of each subject showed clinical grades ranging from 2-4 on a scale of 1-5 for surface roughness, laxity, and mottled hyperpigmentation. A negative urine pregnancy test was required for women of childbearing potential. Subjects provided written informed consent. This study was conducted in compliance with the Code of Federal Regulations for institutional review boards and the Declaration of Helsinki.
METHODS Subjects applied the assigned treatments once daily, in the morning after bathing, for 12 weeks. Treatment with tazarotene or vehicle was randomized to the left or right arm in blocks of 4. Subjects
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were evaluated at weeks 0 (baseline), 1, 4, 8, and 12. Emollient use was allowed. Subjects were instructed to use the same emollient, provided by the investigator. Subjects were asked to avoid excessive sun exposure, to wear protective clothing, and to apply a thin layer of sun protection factor (SPF) 15 waterproof and PABA-free sunscreen (provided by the investigator) to both arms at least 30 minutes after drug application. It should be noted that the study was carried out in the Philadelphia area during a period from early September to mid-December. It is unknown whether there was a seasonal effect that could have affected the results, but presumably subjects received limited exposure to sunlight during this period. Noninvasive procedures The skin area to be evaluated for each response measurement procedure (see below) was clearly identified and every effort was made to carry out all future measurements on the same areas of each arm. The same anatomic site was evaluated on the right and left forearms. It should be noted that the exact clinical significance of each parameter measured is not known. Colorimetry. Skin color was measured with a chromameter (model CR200, Minolta, Osaka, Japan) according to the Commission International de l’Eclairage (CIE) system using the L*a*b* color coordinates. Light from a xenon flash lamp illuminates a 1-cm diameter circular area of the skin and the reflected, 3-color decomposed light is analyzed for its intensity (luminosity, ∆L*) and the color components red-green (∆a*) and blue-yellow (∆b*).12 Erythema is measured on the red-green scale and pigment is measured on the luminosity scale. Before the start of a series of measurements the chromameter was calibrated by means of a standard white tile. After 15 minutes acclimation at a room temperature of 70°F ± 0.5°F and a relative humidity of 35% ± 5%, the measurements on skin were made. At weeks 0 and 12, 3 readings were recorded for each arm, and the average used. Dermaspectrometry. Erythema and melanin indices were obtained with a Dermaspectrometer (Cortex Technology, Hadsund, Denmark) which measures ratios of incident and narrow-band reflected light (red and green).12 Three readings were recorded and the average used. Transepidermal water loss. An evaporimeter (EP2, Servo Med, Stockholm, Sweden) was used to measure transepidermal water loss (TEWL) according to published guidelines.13 Skin blood flow. A Laser Doppler flowmeter (Periflux model PF3, Perimed AB, Järfälla, Sweden)
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Table I. Gross observations
Roughness Tazarotene 0.1% gel Vehicle Laxity Tazarotene 0.1% gel Vehicle Mottling Tazarotene 0.1% gel Vehicle
Week 0 (baseline value)
Week 12 (change from baseline)
3.6 ± 1.0 3.6 ± 1.0
–1.0 ± 0.9* –0.9 ± 0.6*
3.2 ± 0.6 3.2 ± 0.6
–0.8 ± 0.8 –0.3 ± 0.7
4.1 ± 0.7 4.1 ± 0.7
–1.2 ± 1.0* –1.1 ± 0.9*
*Statistically significant change compared with baseline.
was used to measure blood flow, expressed in perfusion units. Three readings were recorded at each time point and the average used. Skin conductance. Skin conductance, which reflects hydration of the stratum corneum, was measured with a Skicon 200 (IBS, Tokyo, Japan) and expressed in micro-Siemens. This method was used to determine the hydration state, hygroscopicity (ie, the propensity of the stratum corneum to take up water; sorption), water-holding capacity (ie, the ability of the stratum corneum to retain water) and desorption rates of the skin.14 Desquamation index. A thin layer of the stratum corneum was removed using an adhesive coated disc (D-Squame, CuDerm, Dallas, Tex) to determine the degree of scaling, which reflects the level of dryness of the skin.15 The desquamation index, which quantifies the degree of scaling, was calculated from measurements of both the percentage of area covered by corneocytes and the distribution of scales, according to 5 levels of thickness, in the sample removed with the D-Squame disc.16 Gross observation of mottling, roughness, and laxity. The following scales were used for grading these features: Roughness (degree of scaling and surface texture)—very smooth (1), mostly smooth (2), slightly rough (3), rough (4), very rough (5). Laxity (ability to spring back after pinching the skin)—very tight (1), somewhat tight (2), somewhat loose (3), loose (4), very loose (5). Mottled hyperpigmentation (a combination of lentigines and hyperpigmented and hypopigmented spots)—very even (1), mostly even with few blotches (2), blotchy (3), mostly blotchy (4), very blotchy (5). One set of readings was recorded for each side (dorsal and volar) of each arm at every visit by two dermatologists, independently. Surface replicas. Silicone skin molds of the treated skin areas were obtained at weeks 0 and 12.
The silicone skin molds were evaluated independently by a third party (Advanced Scientific Imaging Inc, Northport, NY), who remained unaware of which treatment had been used on which arm. The replicas were evaluated by digital image analysis. Each replica was illuminated by an Olympus TL-2 lamp at a 25° angle and scanned using a charged couple device (ccd) video camera. Two hundred fifty-six lines were scanned on each replica for analysis of the total developed surface. Shadows generated by this lighting reflect topographic fine lines and wrinkles. The images (size, shape, and number of the shadows) were digitized, enabling a calculation of the following: depth of wrinkles, number of peaks, average roughness, surface area, plateau area, average plateau width, and surface microrelief.17 High-resolution photography. Two types of photography were used: ultraviolet photography to demonstrate possible changes in pigmentation of dyspigmented areas and polarized light photography for analysis of details of surface microtopography. One photograph of each type was taken of each arm at weeks 0 and 12. Ultrasound. A 20 MHz ultrasound Dermascan C (Cortex Technology) was used at weeks 0 and 12 to characterize echogenicity of the dermis and skin thickness. Cutometry. The biomechanical properties of the skin were characterized at baseline and after 12 weeks, using a Cutometer SEM575 (CourageKhazaka GmbH, Cologne, Germany), a suction device which measures viscoelasticity of the skin. Invasive procedures At weeks 0 and 12, a 4-mm punch biopsy was taken from the dorsal side of each forearm. Each biopsy specimen was fixed in 10% neutral buffered formalin, and bisected. One half was embedded in paraffin, and the other in soft methacrylate according to the JB-4 method. The following histologic characteristics were evaluated in stained sections: general architecture (using hematoxylin and eosin), elastosis (using Luna’s stain), presence of GAGs (using Hale’s stain), and melanin content (using Fontana’s stain). Epidermal and epidermal plus dermal skin thickness were also measured. Safety measures Adverse events were monitored by a dermatologist. No subjects were of childbearing potential. Statistical analysis Demographic and safety data were summarized with descriptive statistics, frequency tables, and case listings. An intent-to-treat analysis was applied to all
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D Fig 1. Two-dimensional image analysis of a silicone skin replica for tazarotene and vehicletreated forearms (patient 108). A and B, Skin before treatment with tazarotene 0.1% gel (A) and after 12 weeks of treatment (B), showing increased overall smoothness because of significant decreases in microrelief, and the number of wrinkle peaks and valleys. C and D, Skin before treatment with vehicle gel (C) and after 12 weeks of treatment (D) showing minimal changes in skin smoothness.
efficacy and safety variables. Data from all subjects, randomized to treatment, were included in the statistical analysis. For the efficacy variables, the Wilcoxon signed rank test for paired designs was performed to detect treatment differences. Week 12 was considered the main end point. Within each treatment group, change from baseline was calculated at each scheduled follow-up visit. Within-group comparisons to baseline were performed by the Wilcoxon signed rank test. All statistical tests were performed using a twosided significance level of 0.05. Data were summarized for each adverse event as treatment-related, unrelated, or regardless of cause. The data were analyzed using SAS release 6.08 by SAS Institute, Inc. It should be noted that there was no adjustment for multiplicity (ie, multiple parameters) in this small pilot study, which may increase the likelihood of a false statistically significant result. However, adjust-
ment of the P value to account for multiplicity can be performed by the reader by employing techniques such as the Bonferroni method.
RESULTS Gross observations Both tazarotene 0.1% gel and vehicle were associated with significant smoothening and reduced mottling on the dorsal aspect of the forearms after 12 weeks of treatment compared with baseline (P < .05) (Table I). Laxity in tazarotene-treated skin was improved after 12 weeks of treatment, compared with baseline (P = .06). However, there were no significant between-group differences for any of the gross observations (Table I). Silicone replicas Image analysis of the silicone molds obtained at week 0 and week 12 enabled measurement changes
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Table II. Silicone replicas
No. of valleys Tazarotene 0.1% gel Vehicle Distribution of plateaus Tazarotene 0.1% gel Vehicle No. of peaks Tazarotene 0.1% gel Vehicle Average plateau width (µm) Tazarotene 0.1% gel Vehicle Surface microrelief Tazarotene 0.1% gel Vehicle Total plateau area (mm2) Tazarotene 0.1% gel Vehicle Ratio plateau area/ total surface area Tazarotene 0.1% gel Vehicle
Table IV. Miscellaneous measurements Week 0 (baseline value)
Week 12 (change from baseline)
13.9 ± 6.3 11.5 ± 4.7
–8.0 ± 7.9* –0.6 ± 5.6
62.9 ± 12.7 68.3 ± 8.9
17.5 ± 18.3* 1.7 ± 12.7
23.3 ± 6.6 20.2 ± 4.4
–9.5 ± 10.6* –1.1 ± 7.1
288 ± 165 286 ± 56
227 ± 324 76 ± 279
1.2 ± 0.5 1.1 ± 0.2
–0.3 ± 0.4 –0.1 ± 0.4
14.4 ± 2.4 15.4 ± 1.5
3.2 ± 3.3* 0.5 ± 2.0
54.2 ± 12.8 58.8 ± 6.9
16.6 ± 16.8* 2.7 ± 12.2
*Statistically significant change compared with baseline.
Week 12 (change from baseline)
7.8 ± 1.5 7.7 ± 1.5
0.5 ± 2.3 –0.9 ± 1.1*
0.016 ± 0.001 0.016 ± 0.001
–0.001 ± 0.001* –0.001 ± 0.001*
10.6 ± 3.0 10.2 ± 2.7
–1.1 ± 2.7 –1.7 ± 2.4*
35.2 ± 3.3 34.5 ± 2.8
–1.9 ± 2.2* –2.0 ± 1.9*
0.15 ± 0.04 0.12 ± 0.04
0.16 ± 0.04 0.14 ± 0.05
9.3 ± 2.3 9.6 ± 2.7
16.6 ± 32.6* 4.1 ± 9.2
3.5 ± 0.6 3.5 ± 0.6
6.9 ± 7.0*† 1.8 ± 1.4*
*Statistically significant change compared with baseline. †Statistically significant difference between treatment groups.
Table III. Skin thickness Week 0 (baseline value)
Epidermis (µm) Tazarotene 0.1% gel Vehicle Stratum corneum‡ (µm) Tazarotene 0.1% gel Vehicle
Erythema (colorimetry) Tazarotene 0.1% gel Vehicle Pigment (colorimetry) Tazarotene 0.1% gel Vehicle Erythema (dermaspectrometry) Tazarotene 0.1% gel Vehicle Melanin (dermaspectrometry) Tazarotene 0.1% gel Vehicle Desquamation index Tazarotene 0.1% gel Vehicle Skin blood flow (perfusion units) Tazarotene 0.1% gel Vehicle TEWL (g/m2/h) Tazarotene 0.1% gel Vehicle
Week 0 (baseline value)
Week 12 (final value)
53 ± 6 60 ± 10
100 ± 37*† 67 ± 13
65 ± 22 65 ± 33
36.5 ± 21.2 46.9 ± 24
*Statistically significant difference compared with baseline. †Statistically significant difference between treatment groups. ‡Stratum corneum thickness values reflect measurements taken after biopsy handling and processing. These values may not accurately reflect in vivo thickness.
in number of wrinkles, number of peaks, average roughness, surface area, plateau area, average plateau width, and surface microrelief (Fig 1) (Table II). Tazarotene caused significant decreases in the number of valleys compared with baseline (P = .008) and the number of peaks compared with baseline (P = .04) (Table II), indicating smoothening of the skin surface. In the distribution of plateaus (transitional areas between wrinkles) as well as in the calculated area of all plateaus, tazarotene also produced significant improvement compared with baseline
(P = .02 in both cases). The changes induced by vehicle were slight and not statistically significant. Because of the small number of subjects, there were no significant differences between the treatment groups (Table II). Skin thickness Differences in skin thickness between the two treatment groups could not be detected by ultrasound measurements. However, histologic determinations of epidermal thickness showed a significant increase in epidermal thickness after 12 weeks of tazarotene treatment (a mean increase of 90%), compared with vehicle (a mean increase of 14%, P = .008) (Table III). There were no significant betweengroup differences in stratum corneum thickness. Fig 2 illustrates the histologic changes associated with tazarotene and vehicle in biopsy specimens. Miscellaneous measurements At the end of 12 weeks, there were some small decreases in erythema associated with both treatments as determined by colorimetry and dermaspectrometry, but the differences between the
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C
D
Fig 2. Changes associated with tazarotene and vehicle treatment (patient 108). A, Photomicrograph of a 4-mm punch biopsy specimen taken at week 0 (baseline) showing epidermal thickness and part of dermis before vehicle treatment. B, Photomicrograph of punch biopsy specimen taken at week 0 (baseline) showing epidermal thickness and part of dermis before tazarotene treatment. C, Photomicrograph of biopsy specimen after 12 weeks of treatment with vehicle, showing minimal epidermal thickening. D, Photomicrograph of biopsy specimen after 12 weeks of treatment with tazarotene, showing significant epidermal thickening.
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Table V. Conductance measurements
Skin hydration Tazarotene 0.1% gel Vehicle Hygroscopicity Tazarotene 0.1% gel Vehicle Water holding capacity Tazarotene 0.1% gel Vehicle Desorption rate constant Tazarotene 0.1% gel Vehicle
Week 0 (baseline value) (µS)
Week 12 (final value) (µS)
24.9 ± 12.7 19.9 ± 10.1
39.9 ± 18.9* 35.8 ± 22.4*
732 ± 232 711 ± 201
1074 ± 409*† 792 ± 368
232 ± 143 204 ± 123
353 ± 164*† 215 ± 129
2.29 ± 0.49 2.42 ± 0.43
2.16 ± 0.40 2.23 ± 0.59
*Statistically significant change compared with baseline. †Statistically significant difference between treatment groups.
treatment groups were not statistically significant (Table IV). The apparent melanin content of skin as determined by dermaspectrometry was reduced to some degree with both treatments, but again the differences between treatment groups were not significant. No statistically significant differences in the desquamation index were observed after 12 weeks of tazarotene or vehicle treatment. Skin blood flow was significantly increased after 12 weeks by tazarotene treatment (P = .02), but the difference between the treatment groups was not significant. TEWL showed a significant increase with tazarotene treatment compared with vehicle treatment (P = .03) after 12 weeks. Conductance measurements Measurements of skin conductance showed several statistically significant differences between treatments at weeks 0 and 12 (Table V). First, tazarotene caused a significant increase in hygroscopicity at week 12 compared with vehicle (P = .01) and compared with baseline (P = .02). Tazarotene-treated skin also showed a significant increase in water-holding capacity at week 12 compared with vehicle (P = .01) and compared with baseline (P = .03). There were no significant differences in skin hydration between the two treatment groups, though both groups showed an increase over time, compared with baseline (P = .003 and P = .04, respectively). Histologic observations The punch biopsy specimens taken at week 12 were evaluated histologically in a blinded fashion by the investigator (A. M. K.) who provided descriptive summaries of the changes associated with treatment
for each patient. A positive response included the following constellation of epidermal changes: • Acanthosis, an increased number of cell layers comprising the viable epidermis, resulting in a thicker epidermis • Hyperplastic keratinocytes, indicating higher metabolic activity and more rapid epidermal proliferation • Correction of atypia, with keratinocytes more uniform in size, shape, and staining properties • Correction of polarity, with more orderly differentiation as cells move upward • Widened intercellular spaces, due to accumulation of hyaluronic acid • Sparser and less heavily pigmented melanin granules, which should contribute to a bleaching of hyperpigmented spots • A thinner and more compact stratum corneum as a result of exfoliation of horny cells • A granular layer, 2 to 4 cells in thickness and with prominent, larger, more numerous granules When all these changes were present to a marked degree, the investigator scored the changes as +++. Moderate changes were scored as ++; slight changes were scored as +. It needs to be added here that the investigator could in essence break the study blind based on these histologic evaluations. Of the 10 subjects in the study, 3 scored +++ responses, 4 scored ++, and 1 scored + with tazarotene. One subject dropped out of the study, and another showed no change. Vehicle-treated sites showed no discernible effects. Other histologic evaluations The Fontana stain showed a moderate to marked depigmenting effect with decreased pigmentation on the tazarotene-treated sites in 6 of 8 subjects. Vehicle-treated sites showed no discernible effects. The Luna and Hale stains did not expose differences in elastosis or deposition of GAGs, respectively, between the treatment groups. Safety data All subjects experienced local side effects on the tazarotene-treated sites, ranging from mild to moderate erythema; typical of retinoid-induced dermatitis. Because of this fact, the investigator could in essence break the study blind. No subjects dropped out of the study because of adverse events. All adverse events resolved within 2 weeks after discontinuing treatment. No serious adverse events were observed.
DISCUSSION This pilot study is the first to evaluate the effects of tazarotene on photodamaged skin. The changes
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observed were consistent with the known effects of topical retinoids, namely decreases in skin roughness and reductions in fine wrinkling (reflected mainly by measurements on silicone replicas). Enhanced architecture, including the correction of epidermal atrophy and atypia, was observed as well. Five of the 7 measurements calculated by image analysis of the silicone replicas showed a significant change in the tazarotene-treated group (compared with baseline), whereas in the vehicle group no significance in any of the measurements was found. This parallels the skin replica analysis studies of photodamaged skin after application of tretinoin emollient cream reported by Grove et al.17 The increase in TEWL is an effect typical of topically applied retinoids and is thought to be associated with a perturbation of the stratum corneum water barrier function.18,19 It is also possible that the increase in TEWL could be related to the increased skin blood flow in tazarotene-treated skin. The lack of between-group significance for some of the parameters in the tazarotene versus vehicle pilot study is probably due to the small sample size (n = 10), as well as the short treatment time frame. Most tretinoin photodamage studies were conducted for 6 months to 1 year, with some studies continuing for 4 years.17,20,21 Because tretinoin studies show increasing improvement as treatment continues from month 3 to month 6, continued improvement with tazarotene in studies with a duration of more than 12 weeks might be expected.7 A recently completed 24-week study examining the effects of tazarotene cream on photodamaged skin showed a significant reduction in the severity of several clinical signs of photodamage with tazarotene, compared with vehicle.
CONCLUSIONS In this small pilot study, tazarotene 0.1% gel was associated with improvement in some of the signs of photodamage, such as reduced skin roughness and fine wrinkling, after treatment for a period of 12 weeks. Beneficial histologic changes also occurred in the epidermis and stratum corneum. Further studies are needed to assess tazarotene’s efficacy and tolerability in longer-term studies. REFERENCES 1. Gilchrest BA. Skin aging and photoaging: an overview. J Am Acad Dermatol 1989;21:610-3. 2. Lavker RM. Cutaneous aging: chronologic versus photoaging. In: Gilchrest BA, editor. Photodamage. Malden (MA): Blackwell Science; 1995. p. 123-35.
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3. Kligman AM, Grove GL, Hirose R, Leyden JJ. Topical tretinoin for photoaged skin. J Am Acad Dermatol 1986;15:836-59. 4. Braverman IM, Fonferko E. Studies in cutaneous aging: I. The elastic fiber network. J Invest Dermatol 1982;78:434-43. 5. Fisher G, Datta SC, Talwar HS, Wang ZQ, Varani J, Kang S, et al. Molecular basis of sun-induced premature skin ageing and retinoid antagonism. Nature 1996;379:335-9. 6. Kang S, Fisher GJ,Voorhees JJ. Photoaging and topical tretinoin. Arch Dermatol 1997;133:1280-4. 7. Weinstein GD, Nigra TP, Pochi PE, Savin RC, Allan A, Benik K, et al. Topical tretinoin for treatment of photodamaged skin. Arch Dermatol 1991;127:659-65. 8. Chandraratna RAS. Tazarotene-first of a new generation of receptor-selective retinoids. Br J Dermatol 1996;135:18-25. 9. Nagpal S, Patel S, Jacobe H, DiSepio D, Ghosn C, Malhotra M, et al. Tazarotene-induced gene 2 (TIG2), a novel retinoid-responsive gene in skin. J Invest Dermatol 1997;109:91-5. 10. Levin AA, Sturzenbecker LJ, Kazmer S, Bosakowski T, Huselton C, Allenby G, et al. 9-Cis retinoic acid stereoisomer binds and activates the nuclear receptor RXRα . Nature 1992;355:359-61. 11. Fisher GJ, Talwar HS, Xiao JH, Datta SC, Reddy AP, Gaub MP, et al. Immunological identification and functional quantitation of retinoic acid and retinoid X receptor proteins in human skin. J Biol Chem 1994;269:20629-35. 12. Takiwaki H, Serup J. Measurement of color parameters of psoriatic plaques by narrow-band reflectance spectrophotometry and tristimulus colorimetry. Skin Pharmacol 1994;7:145-50. 13. Pinnagoda J, Tupker RA, Agner T, Serup J. Guidelines for transepidermal water loss (TEWL) measurement. Contact Dermatitis 1990;22:164-78. 14. Tagami H, Kanamaru Y, Inoue K, Suehisa S, Inoue F, Iwatsuki K, et al. Water sorption-desorption test of the skin in vivo for functional assessment of the stratum corneum. J Invest Dermatol 1982;78:425-8. 15. Serup J, Winther A, Blichmann C. A simple method for the study of scale pattern and effects of a moisturizer-quantitative and quantitative evaluation by D-Squame® tape compared with parameters of epidermal hydration. Clin Exp Dermatol 1989;14:277-82. 16. Schatz H, Altmeyer PJ, Kligman AM. Dry skin and scaling evaluated by D-Squames and image analysis. In: Serup J, Jemec GBE, editors. Handbook of non-invasive methods and the skin. Boca Raton (FL): CRC Press; 1995. p. 154-5. 17. Grove GL, Grove MJ, Leyden JJ, Lufrano L, Schwab B, Perry BH, et al. Skin replica analysis of photodamaged skin after therapy with tretinoin emollient cream. J Am Acad Dermatol 1991;25: 231-7. 18. Tagami H, Tadaki T, Obata M, Koyama J. Functional assessment of the stratum corneum under the influence of oral retinoid (etretinate) in guinea-pigs and humans: comparison with topical retinoic acid treatment. Br J Dermatol 1992;127:470-5. 19. Effendy I, Kwangsukstith C, Lee LY, Maibach HI. Functional changes in human stratum corneum induced by topical glycolic acid: comparison with all-trans retinoic acid. Acta Derm Venereol 1995;75:455-8. 20. Olsen EA, Katz HI, Levine N, Nigra TP, Pochi PE, Savin RC, et al. Tretinoin emollient cream for photodamaged skin: results of 48-week, multicenter, double-blind studies. J Am Acad Dermatol 1997;37:217-26. 21. Bhawan J, Olsen E, Lufrano L,Thorne EG, Schwab B, Gilchrest BA. Histologic evaluation of the long term effects of tretinoin on photodamaged skin. J Dermatol Sci 1996;11:177-82.
A
ll skin tends to undergo the changes brought about by intrinsic aging, but pathologic changes may also occur because of long-term sun exposure. Sun-induced changes, referred to as photodamage, are superimposed on the changes caused by chronologic aging, and are responsible for the many unwanted age-associated features of the skin’s appearance.1 Whereas intrinsically aged, sunprotected skin is thin, less elastic, but otherwise largely unblemished and smooth, photodamaged skin is characterized by fine and coarse wrinkles, roughness, laxity, sallowness, mottled hyperpigmentation, and telangiectasia.1,2 Histologic changes in photodamaged skin include epidermal atypia and atrophy, elastosis, increased melanogenesis, exces-
From Allergan, Inc, Irvine,a and the Department of Dermatology, University of Pennsylvania College of Medicine, Philadelphia.b Supported by Allergan, Inc. Accepted for publication April 13, 2000. Reprint requests: John Sefton, PhD, Allergan, Inc, Skin Care Clinical R&D, 2525 Dupont Dr, Irvine, CA 92612. E-mail: sefton_john@ allergan.com. Copyright © 2000 by the American Academy of Dermatology, Inc. 0190-9622/2000/$12.00 + 0 16/1/107938 doi:10.1067/mjd.2000.107938
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Abbreviations used: GAG: RAR: RXR: TEWL:
glycosaminoglycan retinoic acid receptor retinoid X receptor transepidermal water loss
sive deposition of glycosaminoglycans (GAGs), and decreased collagen.3-6 Topical tretinoin (all-trans-retinoic acid) has been shown to improve the clinical appearance of photodamaged skin.3,7 Histologically, tretinoin induces compaction of the stratum corneum, thickening of the epidermis (acanthosis), correction of atypia, increased granular layer thickness, increased dermal collagen, and angiogenesis.3,6,7 Retinoids elicit their effects at the molecular level by regulating gene transcription and affecting activities such as cellular differentiation and proliferation. Retinoids can act directly, by inducing transcription from genes whose promotor region contains retinoid response elements.8 Two such retinoidresponsive genes, TIG1 and TIG2 (tazaroteneinduced genes 1 and 2), have recently been described in skin. Their expression in psoriatic
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lesions is stimulated by the topical retinoid tazarotene, which is effective in the treatment of psoriasis.9 The exact mechanism by which genes like TIG1 and TIG2 function is not yet understood. Retinoids can also act indirectly, by inhibiting the transcription of certain genes.8 For example, it has recently been shown that pretreatment with tretinoin reduced the UVB-induced expression of collagen-degrading metalloproteinases in skin, presumably by antagonizing the UVB-induced transcription factor AP-1.5 Nuclear retinoic acid receptors belong to two families, the retinoic acid receptor (RAR) family and the retinoid X receptor (RXR) family, and each receptor family contains 3 receptor subtypes: α, β, and γ.8 Tretinoin is a nonselective retinoid which activates all RAR pathways (RARs α, β, and γ) directly and RXR pathways indirectly through conversion of all-trans retinoic acid to 9-cis retinoic acid (the natural ligand for RXRs).10 Tazarotene, on the other hand, is the first of a new generation of receptor-selective retinoids that selectively binds mainly to RAR β and γ and is unable to bind to RXRs directly or indirectly.8 It should be noted that the skin contains primarily RAR γ, and it is unknown whether the receptor selectivity of tazarotene would have any particular clinical significance in the treatment of skin disease, including the treatment of photodamage.11 This photodamage pilot study demonstrates that tazarotene does have beneficial effects in correcting some of the structural and functional changes of photodamaged skin.
STUDY DESIGN The study was initiated as a single-center, doubleblind, randomized, paired-comparison evaluating the efficacy and safety of tazarotene 0.1% gel compared with vehicle applied once daily for 12 weeks. Ten healthy female volunteers, aged 45 to 65 years, with moderately photodamaged forearm skin applied tazarotene 0.1% gel to one arm and vehicle gel to the opposite arm. The forearms of each subject showed clinical grades ranging from 2-4 on a scale of 1-5 for surface roughness, laxity, and mottled hyperpigmentation. A negative urine pregnancy test was required for women of childbearing potential. Subjects provided written informed consent. This study was conducted in compliance with the Code of Federal Regulations for institutional review boards and the Declaration of Helsinki.
METHODS Subjects applied the assigned treatments once daily, in the morning after bathing, for 12 weeks. Treatment with tazarotene or vehicle was randomized to the left or right arm in blocks of 4. Subjects
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were evaluated at weeks 0 (baseline), 1, 4, 8, and 12. Emollient use was allowed. Subjects were instructed to use the same emollient, provided by the investigator. Subjects were asked to avoid excessive sun exposure, to wear protective clothing, and to apply a thin layer of sun protection factor (SPF) 15 waterproof and PABA-free sunscreen (provided by the investigator) to both arms at least 30 minutes after drug application. It should be noted that the study was carried out in the Philadelphia area during a period from early September to mid-December. It is unknown whether there was a seasonal effect that could have affected the results, but presumably subjects received limited exposure to sunlight during this period. Noninvasive procedures The skin area to be evaluated for each response measurement procedure (see below) was clearly identified and every effort was made to carry out all future measurements on the same areas of each arm. The same anatomic site was evaluated on the right and left forearms. It should be noted that the exact clinical significance of each parameter measured is not known. Colorimetry. Skin color was measured with a chromameter (model CR200, Minolta, Osaka, Japan) according to the Commission International de l’Eclairage (CIE) system using the L*a*b* color coordinates. Light from a xenon flash lamp illuminates a 1-cm diameter circular area of the skin and the reflected, 3-color decomposed light is analyzed for its intensity (luminosity, ∆L*) and the color components red-green (∆a*) and blue-yellow (∆b*).12 Erythema is measured on the red-green scale and pigment is measured on the luminosity scale. Before the start of a series of measurements the chromameter was calibrated by means of a standard white tile. After 15 minutes acclimation at a room temperature of 70°F ± 0.5°F and a relative humidity of 35% ± 5%, the measurements on skin were made. At weeks 0 and 12, 3 readings were recorded for each arm, and the average used. Dermaspectrometry. Erythema and melanin indices were obtained with a Dermaspectrometer (Cortex Technology, Hadsund, Denmark) which measures ratios of incident and narrow-band reflected light (red and green).12 Three readings were recorded and the average used. Transepidermal water loss. An evaporimeter (EP2, Servo Med, Stockholm, Sweden) was used to measure transepidermal water loss (TEWL) according to published guidelines.13 Skin blood flow. A Laser Doppler flowmeter (Periflux model PF3, Perimed AB, Järfälla, Sweden)
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Table I. Gross observations
Roughness Tazarotene 0.1% gel Vehicle Laxity Tazarotene 0.1% gel Vehicle Mottling Tazarotene 0.1% gel Vehicle
Week 0 (baseline value)
Week 12 (change from baseline)
3.6 ± 1.0 3.6 ± 1.0
–1.0 ± 0.9* –0.9 ± 0.6*
3.2 ± 0.6 3.2 ± 0.6
–0.8 ± 0.8 –0.3 ± 0.7
4.1 ± 0.7 4.1 ± 0.7
–1.2 ± 1.0* –1.1 ± 0.9*
*Statistically significant change compared with baseline.
was used to measure blood flow, expressed in perfusion units. Three readings were recorded at each time point and the average used. Skin conductance. Skin conductance, which reflects hydration of the stratum corneum, was measured with a Skicon 200 (IBS, Tokyo, Japan) and expressed in micro-Siemens. This method was used to determine the hydration state, hygroscopicity (ie, the propensity of the stratum corneum to take up water; sorption), water-holding capacity (ie, the ability of the stratum corneum to retain water) and desorption rates of the skin.14 Desquamation index. A thin layer of the stratum corneum was removed using an adhesive coated disc (D-Squame, CuDerm, Dallas, Tex) to determine the degree of scaling, which reflects the level of dryness of the skin.15 The desquamation index, which quantifies the degree of scaling, was calculated from measurements of both the percentage of area covered by corneocytes and the distribution of scales, according to 5 levels of thickness, in the sample removed with the D-Squame disc.16 Gross observation of mottling, roughness, and laxity. The following scales were used for grading these features: Roughness (degree of scaling and surface texture)—very smooth (1), mostly smooth (2), slightly rough (3), rough (4), very rough (5). Laxity (ability to spring back after pinching the skin)—very tight (1), somewhat tight (2), somewhat loose (3), loose (4), very loose (5). Mottled hyperpigmentation (a combination of lentigines and hyperpigmented and hypopigmented spots)—very even (1), mostly even with few blotches (2), blotchy (3), mostly blotchy (4), very blotchy (5). One set of readings was recorded for each side (dorsal and volar) of each arm at every visit by two dermatologists, independently. Surface replicas. Silicone skin molds of the treated skin areas were obtained at weeks 0 and 12.
The silicone skin molds were evaluated independently by a third party (Advanced Scientific Imaging Inc, Northport, NY), who remained unaware of which treatment had been used on which arm. The replicas were evaluated by digital image analysis. Each replica was illuminated by an Olympus TL-2 lamp at a 25° angle and scanned using a charged couple device (ccd) video camera. Two hundred fifty-six lines were scanned on each replica for analysis of the total developed surface. Shadows generated by this lighting reflect topographic fine lines and wrinkles. The images (size, shape, and number of the shadows) were digitized, enabling a calculation of the following: depth of wrinkles, number of peaks, average roughness, surface area, plateau area, average plateau width, and surface microrelief.17 High-resolution photography. Two types of photography were used: ultraviolet photography to demonstrate possible changes in pigmentation of dyspigmented areas and polarized light photography for analysis of details of surface microtopography. One photograph of each type was taken of each arm at weeks 0 and 12. Ultrasound. A 20 MHz ultrasound Dermascan C (Cortex Technology) was used at weeks 0 and 12 to characterize echogenicity of the dermis and skin thickness. Cutometry. The biomechanical properties of the skin were characterized at baseline and after 12 weeks, using a Cutometer SEM575 (CourageKhazaka GmbH, Cologne, Germany), a suction device which measures viscoelasticity of the skin. Invasive procedures At weeks 0 and 12, a 4-mm punch biopsy was taken from the dorsal side of each forearm. Each biopsy specimen was fixed in 10% neutral buffered formalin, and bisected. One half was embedded in paraffin, and the other in soft methacrylate according to the JB-4 method. The following histologic characteristics were evaluated in stained sections: general architecture (using hematoxylin and eosin), elastosis (using Luna’s stain), presence of GAGs (using Hale’s stain), and melanin content (using Fontana’s stain). Epidermal and epidermal plus dermal skin thickness were also measured. Safety measures Adverse events were monitored by a dermatologist. No subjects were of childbearing potential. Statistical analysis Demographic and safety data were summarized with descriptive statistics, frequency tables, and case listings. An intent-to-treat analysis was applied to all
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A
B
C
D Fig 1. Two-dimensional image analysis of a silicone skin replica for tazarotene and vehicletreated forearms (patient 108). A and B, Skin before treatment with tazarotene 0.1% gel (A) and after 12 weeks of treatment (B), showing increased overall smoothness because of significant decreases in microrelief, and the number of wrinkle peaks and valleys. C and D, Skin before treatment with vehicle gel (C) and after 12 weeks of treatment (D) showing minimal changes in skin smoothness.
efficacy and safety variables. Data from all subjects, randomized to treatment, were included in the statistical analysis. For the efficacy variables, the Wilcoxon signed rank test for paired designs was performed to detect treatment differences. Week 12 was considered the main end point. Within each treatment group, change from baseline was calculated at each scheduled follow-up visit. Within-group comparisons to baseline were performed by the Wilcoxon signed rank test. All statistical tests were performed using a twosided significance level of 0.05. Data were summarized for each adverse event as treatment-related, unrelated, or regardless of cause. The data were analyzed using SAS release 6.08 by SAS Institute, Inc. It should be noted that there was no adjustment for multiplicity (ie, multiple parameters) in this small pilot study, which may increase the likelihood of a false statistically significant result. However, adjust-
ment of the P value to account for multiplicity can be performed by the reader by employing techniques such as the Bonferroni method.
RESULTS Gross observations Both tazarotene 0.1% gel and vehicle were associated with significant smoothening and reduced mottling on the dorsal aspect of the forearms after 12 weeks of treatment compared with baseline (P < .05) (Table I). Laxity in tazarotene-treated skin was improved after 12 weeks of treatment, compared with baseline (P = .06). However, there were no significant between-group differences for any of the gross observations (Table I). Silicone replicas Image analysis of the silicone molds obtained at week 0 and week 12 enabled measurement changes
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Table II. Silicone replicas
No. of valleys Tazarotene 0.1% gel Vehicle Distribution of plateaus Tazarotene 0.1% gel Vehicle No. of peaks Tazarotene 0.1% gel Vehicle Average plateau width (µm) Tazarotene 0.1% gel Vehicle Surface microrelief Tazarotene 0.1% gel Vehicle Total plateau area (mm2) Tazarotene 0.1% gel Vehicle Ratio plateau area/ total surface area Tazarotene 0.1% gel Vehicle
Table IV. Miscellaneous measurements Week 0 (baseline value)
Week 12 (change from baseline)
13.9 ± 6.3 11.5 ± 4.7
–8.0 ± 7.9* –0.6 ± 5.6
62.9 ± 12.7 68.3 ± 8.9
17.5 ± 18.3* 1.7 ± 12.7
23.3 ± 6.6 20.2 ± 4.4
–9.5 ± 10.6* –1.1 ± 7.1
288 ± 165 286 ± 56
227 ± 324 76 ± 279
1.2 ± 0.5 1.1 ± 0.2
–0.3 ± 0.4 –0.1 ± 0.4
14.4 ± 2.4 15.4 ± 1.5
3.2 ± 3.3* 0.5 ± 2.0
54.2 ± 12.8 58.8 ± 6.9
16.6 ± 16.8* 2.7 ± 12.2
*Statistically significant change compared with baseline.
Week 12 (change from baseline)
7.8 ± 1.5 7.7 ± 1.5
0.5 ± 2.3 –0.9 ± 1.1*
0.016 ± 0.001 0.016 ± 0.001
–0.001 ± 0.001* –0.001 ± 0.001*
10.6 ± 3.0 10.2 ± 2.7
–1.1 ± 2.7 –1.7 ± 2.4*
35.2 ± 3.3 34.5 ± 2.8
–1.9 ± 2.2* –2.0 ± 1.9*
0.15 ± 0.04 0.12 ± 0.04
0.16 ± 0.04 0.14 ± 0.05
9.3 ± 2.3 9.6 ± 2.7
16.6 ± 32.6* 4.1 ± 9.2
3.5 ± 0.6 3.5 ± 0.6
6.9 ± 7.0*† 1.8 ± 1.4*
*Statistically significant change compared with baseline. †Statistically significant difference between treatment groups.
Table III. Skin thickness Week 0 (baseline value)
Epidermis (µm) Tazarotene 0.1% gel Vehicle Stratum corneum‡ (µm) Tazarotene 0.1% gel Vehicle
Erythema (colorimetry) Tazarotene 0.1% gel Vehicle Pigment (colorimetry) Tazarotene 0.1% gel Vehicle Erythema (dermaspectrometry) Tazarotene 0.1% gel Vehicle Melanin (dermaspectrometry) Tazarotene 0.1% gel Vehicle Desquamation index Tazarotene 0.1% gel Vehicle Skin blood flow (perfusion units) Tazarotene 0.1% gel Vehicle TEWL (g/m2/h) Tazarotene 0.1% gel Vehicle
Week 0 (baseline value)
Week 12 (final value)
53 ± 6 60 ± 10
100 ± 37*† 67 ± 13
65 ± 22 65 ± 33
36.5 ± 21.2 46.9 ± 24
*Statistically significant difference compared with baseline. †Statistically significant difference between treatment groups. ‡Stratum corneum thickness values reflect measurements taken after biopsy handling and processing. These values may not accurately reflect in vivo thickness.
in number of wrinkles, number of peaks, average roughness, surface area, plateau area, average plateau width, and surface microrelief (Fig 1) (Table II). Tazarotene caused significant decreases in the number of valleys compared with baseline (P = .008) and the number of peaks compared with baseline (P = .04) (Table II), indicating smoothening of the skin surface. In the distribution of plateaus (transitional areas between wrinkles) as well as in the calculated area of all plateaus, tazarotene also produced significant improvement compared with baseline
(P = .02 in both cases). The changes induced by vehicle were slight and not statistically significant. Because of the small number of subjects, there were no significant differences between the treatment groups (Table II). Skin thickness Differences in skin thickness between the two treatment groups could not be detected by ultrasound measurements. However, histologic determinations of epidermal thickness showed a significant increase in epidermal thickness after 12 weeks of tazarotene treatment (a mean increase of 90%), compared with vehicle (a mean increase of 14%, P = .008) (Table III). There were no significant betweengroup differences in stratum corneum thickness. Fig 2 illustrates the histologic changes associated with tazarotene and vehicle in biopsy specimens. Miscellaneous measurements At the end of 12 weeks, there were some small decreases in erythema associated with both treatments as determined by colorimetry and dermaspectrometry, but the differences between the
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A
B
C
D
Fig 2. Changes associated with tazarotene and vehicle treatment (patient 108). A, Photomicrograph of a 4-mm punch biopsy specimen taken at week 0 (baseline) showing epidermal thickness and part of dermis before vehicle treatment. B, Photomicrograph of punch biopsy specimen taken at week 0 (baseline) showing epidermal thickness and part of dermis before tazarotene treatment. C, Photomicrograph of biopsy specimen after 12 weeks of treatment with vehicle, showing minimal epidermal thickening. D, Photomicrograph of biopsy specimen after 12 weeks of treatment with tazarotene, showing significant epidermal thickening.
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Table V. Conductance measurements
Skin hydration Tazarotene 0.1% gel Vehicle Hygroscopicity Tazarotene 0.1% gel Vehicle Water holding capacity Tazarotene 0.1% gel Vehicle Desorption rate constant Tazarotene 0.1% gel Vehicle
Week 0 (baseline value) (µS)
Week 12 (final value) (µS)
24.9 ± 12.7 19.9 ± 10.1
39.9 ± 18.9* 35.8 ± 22.4*
732 ± 232 711 ± 201
1074 ± 409*† 792 ± 368
232 ± 143 204 ± 123
353 ± 164*† 215 ± 129
2.29 ± 0.49 2.42 ± 0.43
2.16 ± 0.40 2.23 ± 0.59
*Statistically significant change compared with baseline. †Statistically significant difference between treatment groups.
treatment groups were not statistically significant (Table IV). The apparent melanin content of skin as determined by dermaspectrometry was reduced to some degree with both treatments, but again the differences between treatment groups were not significant. No statistically significant differences in the desquamation index were observed after 12 weeks of tazarotene or vehicle treatment. Skin blood flow was significantly increased after 12 weeks by tazarotene treatment (P = .02), but the difference between the treatment groups was not significant. TEWL showed a significant increase with tazarotene treatment compared with vehicle treatment (P = .03) after 12 weeks. Conductance measurements Measurements of skin conductance showed several statistically significant differences between treatments at weeks 0 and 12 (Table V). First, tazarotene caused a significant increase in hygroscopicity at week 12 compared with vehicle (P = .01) and compared with baseline (P = .02). Tazarotene-treated skin also showed a significant increase in water-holding capacity at week 12 compared with vehicle (P = .01) and compared with baseline (P = .03). There were no significant differences in skin hydration between the two treatment groups, though both groups showed an increase over time, compared with baseline (P = .003 and P = .04, respectively). Histologic observations The punch biopsy specimens taken at week 12 were evaluated histologically in a blinded fashion by the investigator (A. M. K.) who provided descriptive summaries of the changes associated with treatment
for each patient. A positive response included the following constellation of epidermal changes: • Acanthosis, an increased number of cell layers comprising the viable epidermis, resulting in a thicker epidermis • Hyperplastic keratinocytes, indicating higher metabolic activity and more rapid epidermal proliferation • Correction of atypia, with keratinocytes more uniform in size, shape, and staining properties • Correction of polarity, with more orderly differentiation as cells move upward • Widened intercellular spaces, due to accumulation of hyaluronic acid • Sparser and less heavily pigmented melanin granules, which should contribute to a bleaching of hyperpigmented spots • A thinner and more compact stratum corneum as a result of exfoliation of horny cells • A granular layer, 2 to 4 cells in thickness and with prominent, larger, more numerous granules When all these changes were present to a marked degree, the investigator scored the changes as +++. Moderate changes were scored as ++; slight changes were scored as +. It needs to be added here that the investigator could in essence break the study blind based on these histologic evaluations. Of the 10 subjects in the study, 3 scored +++ responses, 4 scored ++, and 1 scored + with tazarotene. One subject dropped out of the study, and another showed no change. Vehicle-treated sites showed no discernible effects. Other histologic evaluations The Fontana stain showed a moderate to marked depigmenting effect with decreased pigmentation on the tazarotene-treated sites in 6 of 8 subjects. Vehicle-treated sites showed no discernible effects. The Luna and Hale stains did not expose differences in elastosis or deposition of GAGs, respectively, between the treatment groups. Safety data All subjects experienced local side effects on the tazarotene-treated sites, ranging from mild to moderate erythema; typical of retinoid-induced dermatitis. Because of this fact, the investigator could in essence break the study blind. No subjects dropped out of the study because of adverse events. All adverse events resolved within 2 weeks after discontinuing treatment. No serious adverse events were observed.
DISCUSSION This pilot study is the first to evaluate the effects of tazarotene on photodamaged skin. The changes
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observed were consistent with the known effects of topical retinoids, namely decreases in skin roughness and reductions in fine wrinkling (reflected mainly by measurements on silicone replicas). Enhanced architecture, including the correction of epidermal atrophy and atypia, was observed as well. Five of the 7 measurements calculated by image analysis of the silicone replicas showed a significant change in the tazarotene-treated group (compared with baseline), whereas in the vehicle group no significance in any of the measurements was found. This parallels the skin replica analysis studies of photodamaged skin after application of tretinoin emollient cream reported by Grove et al.17 The increase in TEWL is an effect typical of topically applied retinoids and is thought to be associated with a perturbation of the stratum corneum water barrier function.18,19 It is also possible that the increase in TEWL could be related to the increased skin blood flow in tazarotene-treated skin. The lack of between-group significance for some of the parameters in the tazarotene versus vehicle pilot study is probably due to the small sample size (n = 10), as well as the short treatment time frame. Most tretinoin photodamage studies were conducted for 6 months to 1 year, with some studies continuing for 4 years.17,20,21 Because tretinoin studies show increasing improvement as treatment continues from month 3 to month 6, continued improvement with tazarotene in studies with a duration of more than 12 weeks might be expected.7 A recently completed 24-week study examining the effects of tazarotene cream on photodamaged skin showed a significant reduction in the severity of several clinical signs of photodamage with tazarotene, compared with vehicle.
CONCLUSIONS In this small pilot study, tazarotene 0.1% gel was associated with improvement in some of the signs of photodamage, such as reduced skin roughness and fine wrinkling, after treatment for a period of 12 weeks. Beneficial histologic changes also occurred in the epidermis and stratum corneum. Further studies are needed to assess tazarotene’s efficacy and tolerability in longer-term studies. REFERENCES 1. Gilchrest BA. Skin aging and photoaging: an overview. J Am Acad Dermatol 1989;21:610-3. 2. Lavker RM. Cutaneous aging: chronologic versus photoaging. In: Gilchrest BA, editor. Photodamage. Malden (MA): Blackwell Science; 1995. p. 123-35.
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3. Kligman AM, Grove GL, Hirose R, Leyden JJ. Topical tretinoin for photoaged skin. J Am Acad Dermatol 1986;15:836-59. 4. Braverman IM, Fonferko E. Studies in cutaneous aging: I. The elastic fiber network. J Invest Dermatol 1982;78:434-43. 5. Fisher G, Datta SC, Talwar HS, Wang ZQ, Varani J, Kang S, et al. Molecular basis of sun-induced premature skin ageing and retinoid antagonism. Nature 1996;379:335-9. 6. Kang S, Fisher GJ,Voorhees JJ. Photoaging and topical tretinoin. Arch Dermatol 1997;133:1280-4. 7. Weinstein GD, Nigra TP, Pochi PE, Savin RC, Allan A, Benik K, et al. Topical tretinoin for treatment of photodamaged skin. Arch Dermatol 1991;127:659-65. 8. Chandraratna RAS. Tazarotene-first of a new generation of receptor-selective retinoids. Br J Dermatol 1996;135:18-25. 9. Nagpal S, Patel S, Jacobe H, DiSepio D, Ghosn C, Malhotra M, et al. Tazarotene-induced gene 2 (TIG2), a novel retinoid-responsive gene in skin. J Invest Dermatol 1997;109:91-5. 10. Levin AA, Sturzenbecker LJ, Kazmer S, Bosakowski T, Huselton C, Allenby G, et al. 9-Cis retinoic acid stereoisomer binds and activates the nuclear receptor RXRα . Nature 1992;355:359-61. 11. Fisher GJ, Talwar HS, Xiao JH, Datta SC, Reddy AP, Gaub MP, et al. Immunological identification and functional quantitation of retinoic acid and retinoid X receptor proteins in human skin. J Biol Chem 1994;269:20629-35. 12. Takiwaki H, Serup J. Measurement of color parameters of psoriatic plaques by narrow-band reflectance spectrophotometry and tristimulus colorimetry. Skin Pharmacol 1994;7:145-50. 13. Pinnagoda J, Tupker RA, Agner T, Serup J. Guidelines for transepidermal water loss (TEWL) measurement. Contact Dermatitis 1990;22:164-78. 14. Tagami H, Kanamaru Y, Inoue K, Suehisa S, Inoue F, Iwatsuki K, et al. Water sorption-desorption test of the skin in vivo for functional assessment of the stratum corneum. J Invest Dermatol 1982;78:425-8. 15. Serup J, Winther A, Blichmann C. A simple method for the study of scale pattern and effects of a moisturizer-quantitative and quantitative evaluation by D-Squame® tape compared with parameters of epidermal hydration. Clin Exp Dermatol 1989;14:277-82. 16. Schatz H, Altmeyer PJ, Kligman AM. Dry skin and scaling evaluated by D-Squames and image analysis. In: Serup J, Jemec GBE, editors. Handbook of non-invasive methods and the skin. Boca Raton (FL): CRC Press; 1995. p. 154-5. 17. Grove GL, Grove MJ, Leyden JJ, Lufrano L, Schwab B, Perry BH, et al. Skin replica analysis of photodamaged skin after therapy with tretinoin emollient cream. J Am Acad Dermatol 1991;25: 231-7. 18. Tagami H, Tadaki T, Obata M, Koyama J. Functional assessment of the stratum corneum under the influence of oral retinoid (etretinate) in guinea-pigs and humans: comparison with topical retinoic acid treatment. Br J Dermatol 1992;127:470-5. 19. Effendy I, Kwangsukstith C, Lee LY, Maibach HI. Functional changes in human stratum corneum induced by topical glycolic acid: comparison with all-trans retinoic acid. Acta Derm Venereol 1995;75:455-8. 20. Olsen EA, Katz HI, Levine N, Nigra TP, Pochi PE, Savin RC, et al. Tretinoin emollient cream for photodamaged skin: results of 48-week, multicenter, double-blind studies. J Am Acad Dermatol 1997;37:217-26. 21. Bhawan J, Olsen E, Lufrano L,Thorne EG, Schwab B, Gilchrest BA. Histologic evaluation of the long term effects of tretinoin on photodamaged skin. J Dermatol Sci 1996;11:177-82.