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Topical tretinoin (retinoic acid) treatment of hyperpigmented lesions associated with photoaging in Chinese and Japanese patients: A vehicle-controlled trial
Therapy Topical tretinoin (retinoic acid) treatment of hyperpigmented lesions associated with photoaging in Chinese and Japanese patients: A vehicle-controlled trial Christopher E. M. Griffiths, MD, MRCP, Michael T. Goldfarb, MD, Lawrence J. Finkel, MD, Vassia Roulia, MS, Michiko Bonawitz, MT, Ted A. Hamilton, MS, Charles N. Ellis, MD, and John J. Voorhees, MD Ann Arbor, Michigan Background: Hyperpigmented lesions are a predominant component of photoaging in Chinese and Japanese persons. Topical 0.1% tretinoin cream improves the hyperpigmentation associated with photoaging in Caucasian persons. Objective: Our purpose was to assess the efficacy of 0.1 % tretinoin cream treatment of hyperpigmented lesions associated with photoaging in Chinese and Japanese patients. Methods: Forty-five photoaged patients (23 Chinese, 22 Japanese) completed a double-blind, randomized study in which 21 applied 0.1 % tretinoin cream and 24 applied vehicle cream once daily to face and/or hands for 40 weeks. Patients' hyperpigmented lesions were evaluated clinical1y and by colorimetry throughout the study and by histologic analysis of skin biopsy specimens taken before therapy and at the end of treatment. Results: At the end of treatment, hyperpigrnented lesions of the face and hands were lighter or much lighter in 90% of patients receiving tretinoin compared with 33% receiving vehicle (p < 0.0001). Colorimetry demonstrated significant lightening oflesions after tretinoin compared with vehicle (p < 0.05). Histologic analysis of hyperpigmented lesions demonstrated a statistically significant 41 % decrease in epidermal pigmentation with tretinoin therapy as compared with a 37% increase in the vehicle group (p = 0.0004). No patient withdrew for adverse effects. Conclusion: By clinical, colorimetric, and histologic evaluation, 0.1 % tretinoin cream significantly lightens the hyperpigmentation of photoaging in Chinese and Japanese patients. (J AM ACAD DERMATOL 1994;30:76-84.)
Several studies have demonstrated that topical tretinoin (all-trans-retinoic acid) alleviates finewrinkling, roughness, and mottled hyperpigmentation associated with photoaging."! Until recently, these
From the Dermatopharmacology Unit, Department of Dermatology, University of Michigan Medical Center. Supported in part by a grant from the R. W. Johnson Pharmaceutical Research Institute, Raritan, N.J. (which had no part in the design or conduct of the study or in the analysis, interpretation, or reporting of the results) and the Babcock Dermatologic Endowment, Ann Arbor. Reprint requests: John J. Voorhees, MD, Department of Dermatology, University of Michigan Medical Center, Room 1910 A. Alfred Taubman Health Care Center, 1500 East Medical Center Dr., Ann Arbor, MI 48109-0314. Copyright © 1994 by the American Academy of Dermatology, Inc. 0190-9622/94 $1.00
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studies had been performed only in Caucasian persons because less pigmented skin manifests more photoaging than any other racial phenotype. However, all races are subject to photoaging, and amelioration is often sought by affected persons. Thus it is pertinent to study the efficacy of topical tretinoin in the treatment of photoaging in racial groups other than Caucasian. The most prominent feature of photoaged Chinese and Japanese skin is discrete hyperpigmented lesions, whereas wrinkling is usually a lesser problem.6, 7 To evaluate the ability of topical tretinoin 0.1% cream to lighten hyperpigmented lesions in photoaged Chinese and Japanese skin, we performed a double-blind, vehicle-controlled clinical trial.
Journal of the American Academy of Dermatology Volume 30, Number)
METHODS Study population Forty-seven healthy patients (24 Chinese, 23 Japanese) participated in this 10-month study. Pregnant or nursing women were excluded. None of the patients had received an experimental drug within 30 days before admission, had used topical retinoids for 6 months before initiation of treatment, or had any history of prior oral retinoid therapy. Patients with significant pigmentation unrelated to sun exposure were excluded. Twenty-three patients (15 women, 8 men; mean age 61 years, range 41 to 76 years) were treated with 0.1% tretinoin cream. However, two patients did not complete the study; one relocated after 8 weeks, and the other was lost to follow-up after 20 weeks. Twenty-four patients (16 women, 8 men; mean age 60 years, range 40 to 75 years) were treated with vehicle cream. Each patient had at least four hyperpigmented macules with the clinical characteristics of actinic lentigines on the face and/or hands . All participants gave signed informed consent to participate in the protocol, which had been approved by the institutional review board of the University of Michigan Medical Center.
Study design Patients were treated with 0.1% tretinoin cream (Retin-A, Ortho Pharmaceutical Corp., Raritan, N .J.) or color-matched vehicle cream. Randomized treatment assignments, with a block size of four, were made with the use of a computerized random number generator. Stratification by ethnic origin was performed to ensure an equal balance of treatment assignments for Chinese and Japanese patients. Patients and investigators were blinded as to which group each patient had been assigned. The sample size provides statistical power of 0.7 in detecting a difference in overall improvement of at least one halfunit between treatment groups at a type I error rate of 0.05 for a two-tailed hypothesis.
Treatment The patients were instructed to apply test cream to the face and/or back of their hands each evening for 40 weeks. Initially, they were instructed to apply a "peasized" amount and increase it gradually to tolerance. They were also instructed not to wash the treated areas or to apply other topical preparations to their skin for at least I hour after application of test cream. Patients were provided with a mild soap to wash the treatment areas 20 minutes before application of test creams, as well as a mild emollient to treat skin irritation or dryness. Patients who experienced severe irritation were instructed to abstain from the medication for at least 24 hours and resume it on disappearance of the irritation.
Griffiths et al. 77 Patients were advised to avoid excess exposure to sun, sunlamps, and wind and to minimize the use of cosmetics,washing, and harsh scrubbing of the skin. A sunscreen of sun protection factor 15 was provided to be applied each morning. Before each study visit, patients were instructed not to apply any topical preparations, including emollients, sunscreens, or cosmetics to the designated treatment areas.
Clinical evaluations Clinical evaluations were performed at beginning of study, after the second and fourth weeks oftreatment, and at monthly intervals thereafter, for a total of 40 weeks. A single investigator evaluated every patient at every visit. Overall severity score of macular hyperpigmented lesions was determined for face and each hand monthly throughout the study. Severity was assessed on a a to 9 scale: 0, no hyperpigmentation; 1-3, mild ; 4-6, moderate; and 7-9, severe; the ranges of numbers were used to indicate severity within each category. In addition, at week 40, an assessment of the global response was made comparing the change over the entire study in all macular hyperpigmen ted lesions of face and hands combined. Global response was rated on a - 3 to + 3 scale where -3 was much darker; -2, darker; -1, slightly darker; 0, no change; + 1, slightly lighter; +2, lighter; and +3, much lighter. Four "designated lesions" on the face and/or hands were selected before therapy to be observed throughout the study. Pigmentation of each designated lesion was rated at each visit on a 0 to 7 scale: 0, absent; 1, very light; 2, light; 3, slightly light; 4, medium; 5, slightly dark; 6, dark; and 7, very dark. The designated lesions were numbered on Polaroid photographs taken before therapy to aid in locating each throughout the study. In 20 of 21 patients in the tretinoin group, one or more of the designated lesions was on the face (total of 69 facial lesions), and in 9 of 21 patients, the designated lesions were on the hands (total of IS). In the vehicle group, all 24 patients had one or more designated lesions on the face (total of 82) and 10 patients had designated lesions on the hands (total of 14).
Colorimetry As an objective measure of designated lesion color and of normal skin, a colorimeter (Chroma Meter-CR 200, Minolta Camera Co. Ltd., Osaka, Japan) was used before therapy and at 12, 24, and 40 weeks. Colorimetric assessment of skin lightening or darkening is a measure of reflectance, designated by the L * value in the L*a *b* color system defined by the Commission International de l'Bclairage.v? The L * value has a theoretical range of 0 (pure black) to 100 (pure white), but the range in human skin is far narrower. Caucasian skin has a mean L * value
Journal of the American Academy of Dermatology January 1994
78 Griffiths et al.
% of Patients
4%
o Much
Lighter
o Lighter Slightly Lighter •
Unchanged
Tretlnoln (n=21)
Vehicle (n=24)
Fig. 1. Global response to 40 weeks of tretinoin therapy for hyperpigmented lesions of face and hands. As compared with vehicle, tretinoin caused significant lightening of hyperpigmented lesions (p = 0.0006).
of 65 to 69 for sun-protected skin and 58 to 60 for sun-exposed skin.!? For each designated lesion and for nonlesional skin, five colorimeter measuremen ts were performed in succession and the mean value used. Measurements were obtained by placing the colorimeter probe perpendicular to the skin; blanching was prevented by applying minimal pressure.
Cutaneous and adverse reactions The degrees of erythema, burning/stinging sensation, and dryness/peeling were evaluated at each visit on a 0 to 4 scale: 0, absence of symptoms; 1, mild; 2, moderate; 3, moderately severe; 4, severe symptoms.
Light-microscopic analysis Before therapy and after treatment, a full-thickness 2 mm punch biopsy specimen was taken from one of the four designated lesions and analyzed by light microscopy. The posttreatment specimen was taken from the same lesion but far enough away to avoid scar tissue. Specimens were placed in 10%neutral-buffered formalin, embedded in paraffin, and stained with hematoxylin and eosin. Specimens taken before and after therapy were available from 16 patients treated with 0.1% tretinoin cream and 17 patients treated with vehicle cream. The histopathologic diagnosis was determined (Table 1) and various features (Table II) were graded on a semiquantitative 0 to 4 scale, with half-unit increments (0 = absence of characteristics and 4 = maximum presence of characteristics). Epidermal thickness was measured in microns in five high-power fields. The dermatopathologist who analyzed these histologic sections (L. J. F.) was blinded as to which specimens were pretherapy or posttreatment and from which treatment group they had come.
Statistical analysis The chi-square test was used to compare global response at the end of 40 weeks compared with pretherapy between tretinoin- and vehicle-treated patients; within the Chinese and Japanese patient subgroups, Fisher's exact test was used. Changes in overall severity of the facial or hand lesions for each patient at specific time points relative to pretherapy values were compared with the twosample t test. Values for the designated lesions were averaged for face and hands separately; comparisons of the changes in clinical and colorimetric features after 40 weeksof treatment were performed for all patients and by histologic subgroups with the two sample t test. The strength of the relation between clinically discernible improvement and histologic changes in epidermal melanin or changes in colorimetric values was assessed with the Pearson product-moment correlation coefficient. All p values are two-sided. Summary statistics are expressed as means ± standard error. The data were analyzed with the Michigan Interactive Data Analysis System (MIDAS, a statistical software package developed by the Center for Statistical Consultation and Research at the University of Michigan).
Photographic analysis Color photographs of patients for documentation were taken by a professional medical photographer before treatment, and at 12,24, and 40 weeks of therapy. The same photographic laboratory was used for all film processing. Broad diffuse illumination was provided by four studio flash units anchored in fixed positions. A Kodak standard gray card (18% reflectance) was photographed with the patient in all photographic sessions. The gray card provided a control value for any shifts in image color or density caused by extraneous variables.
Journal of the American Academy of Dermatology Volume 30, Number I
Griffiths et of. 79
Fig. 2. Examples of good responses to tretinoin therapy in three patients. A, A 65-year-old Japanese man before treatment (Wk 0), after 24 weeks of treatment with 0.1% tretinoin (Wk 24), and after completion of 40-week course of tretinoin therapy (Wk 40). Hyperpigmented lesions had lightened at week 24 and some had disappeared at week 40. B, A 59-year-old Chinese woman before treatment (Wk 0), after 24 weeks of treatment with 0.1% tretinoin (Wk 24), and after completion of 40-week course of tretinoin therapy (Wk 40). Hyperpigmented lesions had lightened at week 24 and some had disappeared at week 40. C (frontal view) and D (side view), A 66-year-old Japanese man before treatment (Wk 0) and after completion of 40 weeks of 0.1 % tretinoin treatment. Many hyperpigmented lesions had disappeared by end of therapy.
RESULTS Global response
Change in overall severity of hyperpigmented lesions by region
After 40 weeks of treatment, patients treated with 0.1 % tretinoin cream had statistically significant improvement compared with the vehicle group (p = 0.0006; Figs. 1 and 2) . Of the 21 tretinoin-treated patients, 8 (38%) were much lighter, 11 (52%) were lighter, and 2 (10%) were slightly lighter. Of the 24 vehicle-treated patients, 1 (4%) was much lighter, 7 (29%) were lighter, 12 (50%) were slightly lighter, and 4 (17%) were unchanged.
Face. Overall severity of hyperpigmented lesions in the tretinoin group was reduced from 5.5 ± 0.3 before therapy to 3.4 ± 0.2 at 40 weeks, a change of 2.1 ± 0.3, as compared with the vehicle group whose overall severity was reduced from 5.5 ± 0.3 to 4.7 ± 0.3, a change of 0.8 ± 0.2 (p = 0.0007, Fig. 3). Significant lightening in the tretinoin group was seen as early as 8 weeks of treatment (p = 0.004, Fig. 3). Hands. Hyperpigmented lesions in the tretinoin
80
Journal of the American Academy of Dermatology January 1994
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Weeks of Therapy Fig. 3. Change in overall severity of facial lesions with tretinoin (solid lines) or vehicle treatment (broken lines). Circles and error bars indicate mean ± standard error of each patient's reduction in overall severity score for the face from pretherapy to the week indicated. Statistically significant and clinically detectable lightening of facial lesions was evident after 8 weeks of tretinoin treatment and was maintained for the rest of the study. Asterisk denotes significant difference (p -< 0.004) between groups.
group lightened in overall severity from 2.8 ± 0.5 at pretherapy to 1.9 ± 0.3 at 40 weeks. Values in the vehicle-treated group were 2.5 ± 0.4 at baseline and 2.0 ± 0.3 at 40 weeks (p = 0.18 compared with tretinoin therapy). Change in designated lesions Face. There was significant lightening of the designated lesions of the face in the tretinoin-treated group from 4.1 ± 0.2 before therapy to 1.9 ± 0.2 after 40 weeks as compared with 4.3 ± 0.2 to 3.4 ± 0.2 in the vehicle-treated group (p < 0.0001). Significant lightening was first seen in the tretinointreated group after 8 weeks of treatment (p < 0.05). Of the 20 tretinoin-treated patients who had designated lesions of the face before therapy, 7 (35%) had complete clearing of one or more of the lesions; none of the lesions completely disappeared with vehicle treatment (p = 0.002, Fisher's exact test). Hands. The lightening of the designated lesionsof the hands in the tretinoin-treated group (4.4 ± 0.4 before therapy to 3.5 ± 0.3 at 40 weeks) was not statistically significantly different from the change in the vehicle-treated group (4.0 ± 0.3 to 3.2 ± 0.5; p = 0.8). None of the lesions on the hands in either treatment group completely disappeared. Effect of treatment on colorimetry values After 40 weeks of treatment, colorimetry demonstrated an increase (lightening) in the L * scale of the
tretinoin-treated lesions of 0.9 ± 0.5 units (from 55.7 ± 0.7t056.6 ± 0.8)comparedwithadecrease (darkening) of 0.7 ± 0.4 of the vehicle-treated lesions (from 56.5 ± 0.7 to 55.8 ± 0.8; p = 0.02). The average pretherapy L * value for nonlesional skin was 58.1 ± 1.0. Therefore after 40 weeks of tretinoin treatment the average L * value of lesional skin was 38% closer to normal color. There was a statistically significant correlation between clinical improvement and colorimetric values (r = 0.54; p = 0.0001; Fig. 4). Nonlesional facial skin demonstrated no statistical differences in the colorimeter readings between tretinoin and vehicle groups throughout the treatment course. Cutaneous reactions The only untoward event associated with therapy was a local cutaneous reaction characterized by erythema, scaling, and a burning sensation-the socalled "retinoid reaction." Erythema or scaling to at least a moderate degree (graded as >2) noted at more than one visit occurred in 21 of 23 patients (91%) who received tretinoin and in 4 of 24 (17%) in the vehicle group. Onset of the reaction usually occurred during the first month of treatment and peaked within 2 months. Subsequently, the retinoid reaction decreased in severity despite continued treatment. In seven tretinoin-treated patients, the reaction was severe enough to require temporary discontinuation of treatment for 1 to 3 days. None
Journal of the American Academy of Dermatology Volume 30, Number I
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Table I. Histologic diagnoses of designated pigmented lesions and mean clinical color change after 40 weeks of treatment 0.1 % Tretinoin Histologic diagnosis·
No.
All Actinic lentigo§ Nonlentiginous lesion Seborrheic keratosis] Benign keratosis'[, Solar elastosiS# Spongiotic dermatitis** Normal skintt
16 12
4 3 1 0 0 0
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2.1 ± 0.3 2.1 ± 0.3 2.0 ± 0.6 1.7 ± 0.7 3 NA NA NA
17 9 8 3 0 1 3
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0.8 ± 0.2 0.8 ± 0.3 0.8 ± 0.4 1.0 ± 1.2 NA
0.0009 0.007 0.11 NS NA
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NA, Not applicable; NS, no statistical significance. • A 2 mm punch biopsy specimen of a single lesion from each patient was obtained before therapy and classified by light microscopy. Only patients who completed the study are presented in this table; for pretherapy histologic diagnoses of all patients, see text. tColor values are the difference between pretherapy and week 40 and represent measurements only from the biopsied lesions. Lesions were rated clinically before therapy and after 40 weeks of therapy according to the followingscale: 0, absent (no pigment); I, very light; 2, light; 3, slightly light; 4, medium; 5, slightly dark; 6, dark; 7, very dark. Values are mean ± SE and made so that positive numbers indicate lightening. tFor comparison of the change between groups. §The histologic criteria were epidermal atrophy, heavily pigmented basal keratinocytes and melanocytes, club-shaped elongated rete ridges, and papillary dermal elastosis. [The histologic criteria were hyperkeratosis, marked acanthosis, and horn-cyst formation. 'Same as seborrheic keratosis without horn-cyst formation. #The histologic criterion was papillary dermal elastosis without sufficient findingsfor the diagnosis of actinic lentigo; solar elastosis was accompanied by epidermal hyperpigmentation. *·The histologic criteria were widening of the spaces between keratinocytes and a mild superficial lymphocytic perivascular infiltrate. ttNo abnormality was detected by light microscopy.
of the vehicle-treated patients discontinued therapy because of a cutaneous reaction.
Histologic findings Comparison of clinical color change by histologic diagnosis is shown in Table I. Both the actinic lentigines and the other pigmented lesions showed the
same degree of lightening after 40 weeks of tretinoin therapy (2.1 ± 0.3 and 2.0 ± 0.6, respectively). Because of the small number of nonlentiginous lesionsstudied, only actinic lentigines showed statistically significanttightening (p = 0.OO7)whentretinoin therapy was compared with vehicle. At posttreatment, there was a statistical1y signif-
Journal of the American Academy of Dermatology January 1994
82 Griffiths et al.
Table II. Pretherapy and posttreatment histologic features of biopsy specimens* Vehicle (n = 17)
0.1 % Tretinoin (n = 16) Histologic evaluation
Stratum corneum compaction Granular cell layer thickness Spongiosis Epidermal thickness (/-Lm):!: Epidermal pigmentation§ Clubbing Dermal perivascular inflammation Dermal pigmentation
Pretherapy
0.9 ± 0.4 ± 0.6 ± 58 ± 2.2 ± 1.9 ± 1.2 ± 0.8 ±
0.3 0.1 0.1 3 0.2 0.3 0.2 0.2
I Posttreatment I % Change 3.3 ± 2.8 ± 2.5 ± 88 ± 1.3 ± 0.9 ± 2.3 ± 0.9 ±
0.3 0.3 0.3 4 0.3 0.2 0.2 0.3
+257 +633 +326 +53 -41 -53 +95 +17
Pretherapy
1.0 ± 0.3 ± 0.9 ± 61 ± 1.9 ± 1.5 ± 1.4 ± 0.6 ±
0.2 0.1 0.3 3 0.2 0.3 0.2 0.2
IPosttreatment I % 0aJJge 1.4 ± 1.2 ± 0.9 ± 62 ± 2.6 ± 1.7 ± 1.5 ± 0.5 ±
0.2 0.1 0.2 5 0.2 0.3 0.3 0.2
+44 +264 +3 +2 +37 +13 +13 -14
p Valuet
0.0001 <0.0001 <0.0001 <0.0001 0.0004 0.01
om
0.43
*A 2 mm punch biopsy specimen of a single lesion from each patient was obtained before therapy and after 40 weeks of therapy. AIl variables (except epidermal thickness which was measured in microns) were assessed with a semiquantitative scale in which 0 indicated the absence of the characteristic and 4 the maximal degree of involvement. Values are mean ± SE and all percentages were determined before mean values were rounded. tFor comparison of changes between groups. tFor each specimen, measurements from top of the granular layer to epidermal basement membrane at five interrete sites were averaged. §Epidermal pigmentation refers to melanin distributed throughout the epidermis, that is, in both melanocytes and keratinocytes.
icant increase in stratum corneum compaction, granular cell layer thickness, epidermal thickness, spongiosis, and dermal perivascular inflammation in tretinoin-treated as compared with vehicle-treated skin (Table II). There was a 41 % decrease in epidermal pigmentation in tretinoin-treated as compared with a 37% increase in vehicle-treated skin (p = 0.0004; Table II). There was a statistically significant correlation between decrease in histologic epidermal pigment and clinical lightening (r = 0.45; P = 0.008; Fig. 5). There was no significant change in dermal pigmentation during treatment with either tretinoin or vehicle. Comparison of Chinese and Japanese patients At the end of 40 weeks of treatment, Chinese and Japanese patients had comparable improvement in global response to tretinoin treatment. Of the 11 tretinoin-treated Chinese patients, 10 (91%) were lighter or much lighter compared with only 3 (25%) of the 12 vehicle-treated Chinese patients (p = 0.003). Similarly, 9 (90%) of the 10 tretinoin-treated Japanese patients were lighter or much lighter compared with 5 (42%) of the 12 vehicle-treated Japanese patients (p = 0.03). Biopsy samples before therapy were available for all enrolled patients and had the following diagnoses (see Table I for descriptions): Among the 24 Chinese patients, there were 18 actinic lentigines (75%), 4 seborrheic keratoses (17%), 1 spongiotic dermatitis (4%), and 1 benign keratosis (4%). Among the 23 Japanese patients,
there were 15 with actinic lentigines (65%), 4 with seborrheic keratoses (17%), 2 with spongiotic dermatitis (9%), 1 with solar elastosis (4%), and 1 (4%) that failed to reveal disease. DISCUSSION
Asians and Caucasians have different phenotypes of photoaging. Chinese and Japanese persons primarily have hyperpigmented lesions and only a small degree of wrinkling after years of sun exposure'v"; in contrast, Caucasians display both wrinkling and hyperpigmentation in response to photoaging.7, 11, 12 In concordance with these observations, the patients in this study had insufficient wrinkling to evaluate. Regardless, this study demonstrates that in Chinese and Japanese facial skin, hyperpigmented lesionsassociated with photoaging willlighten with topical tretinoin therapy in the same manner as previously noted in Caucasian skin.1-S Indeed, statistically significant results were noted within the first 8 weeks of therapy (Fig. 3). Goh" has reported his experience with a regimen incorporating topical tretinoin that lightened hyperpigmented lesions in East Asian patients in 3 to 12 months. The same positiveresults were not observedon the hands of our patients, which is surprising because lesionsof the face and hands respond equally wellto tretinoin therapy in Caucasians. S We suspect that the small number of lesions on our patients' hands was a factor in the lack of significance;a larger study
Journal of the American Academy of Dermatology Volume 30, Number 1
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on hand lesions should be performed before conclusions specific to the hands are made. With photoaging, Chinese and Japanese persons have hyperpigmented lesions that fall into the same histologic spectrum of diagnoses as noted in Caucasians.! We cannot judge clinically with certainty whether a hyperpigmented lesion is an actinic lentigo. Nevertheless, as previously observed in the Caucasian population.f topical tretinoin is effective for lightening hyperpigmented lesions clinically similar to actinic lentigines regardless of the histologic diagnosis. Vehicle-treated patients also demonstrated some improvement of their pigmented lesions during the study. This may be attributed to avoidance of sunlight and the use of sunscreens during a 40-week period. The mechanism of action of topical tretinoin in lightening hyperpigmented macules is unknown. However, tretinoin is known to inhibit induced melanogenesis in vitro.P This proposed mechanism of action is supported by the histologic decrease in epidermal pigmentation observed after tretinoin as compared with vehicle therapy. In Caucasians, actinic lentigines cleared by topical tretinoin neither relapse nor repigment after cessation of treatment. 5 The observation of nonrelapse is additional evidence that tretinoin-induced lightening occurs as a result of melanin reduction and not because epidermal melanin content is diluted in a tretinoin-thickened epidermis. The other histologic changes, including epidermal thickening, in Table II are typical findings of topical tretinoin treatment.l"
None of the patients permanently discontinued tretinoin therapy because of adverse reactions. Ninety-one percent of tretinoin-treated patients experienced the retinoid reaction of at least a moderate degree at more than one visit, but none of the patients experienced any other side effects. This side-effect profile is similar to that reported in Caucasians.f 13 One problem with the retinoid reaction is that it can give the investigator clues as to which patients are taking active drug. However, the severity of the reaction varied throughout the study in any given patient and became insignificant in most when tolerance developed. REFERENCES I. Kligman AM, Grove GL, Hirose R, et al. Topical tretinoin for photoaged skin. J AM ACAD DERMATOL 1986; 15:83659. 2. Weiss JS, EllisCN, Headington JT, et aL Topical tretinoin improves photodamaged skin: a double-blind vehicle-controlled study. JAMA 1988;259:527-32. 3. Weinstein GD, Nigra TP, Pochi PE, et al. Topical tretinoin for treatment of photodamaged skin: a multicenter study. Arch Dermatol 1991;127:659-65. 4. Olsen EA, Katz I, Levine N, et al. Tretinoin emollient cream: a new therapy for photodamaged skin. J AM ACAD DERMATOL 1992;26:215-24. 5. Rafal ES, Griffiths CEM, Ditre CM, et al. Topical tretinoin (retinoic acid) treatment for liver spots associated with photodamage. N Engl J Med 1992;326:368-74. 6. Goh SH. The treatment of visible signs of senescence: the Asian experience. Br J Dermatol1990;122(suppI35):105-9. 7. Griffiths CEM, Wang TS, Hamilton T A, et aL A photonumeric scalefor the assessment of cutaneous photodamage. Arch Dermatol 1992;128:347-51. 8. Serup J, Agner T. Colorimetric quantification of erythema: a comparison of two colorimeters (Lange Micro Color and
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MinoIta Chroma Meter CR-200) with a clinical scoring scheme and laser-doppler flowmetry. Clio Exp Dermatol 1990;15:267-72. 9. Levine H, Sheftel 8N, Eytan T, et al. Induction of skin tanning by subcutaneous administration of a potent synthetic melanotropin. JAMA 1991;266:2730-6. 10. Andreassi L, Casini L, Simoni S, et al. Measurement of cutaneous colour and assessment of skin type. Photodermatol Photoimmunol Photomed 1990;7:10-4.
Journal of the American Academy of Dermatology January 1994
11. Kligman AM. Early destructive effects of sunlight on human skin. JAMA 1969;210:2377-80. 12. Gilchrest BA. Dermatoheliosis (sun-induced aging). In: Gilchrest BA, ed. Skin and aging Processes. Boca Raton, Fla: CRC Press, 1984:517-28. 13. Orlow 8J, Chakraborty AK, Pawelek JM. Retinoic acid is a potent inhibitor of inducible pigmentation in murine and hamster melanoma cell lines. J Invest Dermatol 1990; 94:461-4.
Several studies have demonstrated that topical tretinoin (all-trans-retinoic acid) alleviates finewrinkling, roughness, and mottled hyperpigmentation associated with photoaging."! Until recently, these
From the Dermatopharmacology Unit, Department of Dermatology, University of Michigan Medical Center. Supported in part by a grant from the R. W. Johnson Pharmaceutical Research Institute, Raritan, N.J. (which had no part in the design or conduct of the study or in the analysis, interpretation, or reporting of the results) and the Babcock Dermatologic Endowment, Ann Arbor. Reprint requests: John J. Voorhees, MD, Department of Dermatology, University of Michigan Medical Center, Room 1910 A. Alfred Taubman Health Care Center, 1500 East Medical Center Dr., Ann Arbor, MI 48109-0314. Copyright © 1994 by the American Academy of Dermatology, Inc. 0190-9622/94 $1.00
76
+ .10 16/1/50267
studies had been performed only in Caucasian persons because less pigmented skin manifests more photoaging than any other racial phenotype. However, all races are subject to photoaging, and amelioration is often sought by affected persons. Thus it is pertinent to study the efficacy of topical tretinoin in the treatment of photoaging in racial groups other than Caucasian. The most prominent feature of photoaged Chinese and Japanese skin is discrete hyperpigmented lesions, whereas wrinkling is usually a lesser problem.6, 7 To evaluate the ability of topical tretinoin 0.1% cream to lighten hyperpigmented lesions in photoaged Chinese and Japanese skin, we performed a double-blind, vehicle-controlled clinical trial.
Journal of the American Academy of Dermatology Volume 30, Number)
METHODS Study population Forty-seven healthy patients (24 Chinese, 23 Japanese) participated in this 10-month study. Pregnant or nursing women were excluded. None of the patients had received an experimental drug within 30 days before admission, had used topical retinoids for 6 months before initiation of treatment, or had any history of prior oral retinoid therapy. Patients with significant pigmentation unrelated to sun exposure were excluded. Twenty-three patients (15 women, 8 men; mean age 61 years, range 41 to 76 years) were treated with 0.1% tretinoin cream. However, two patients did not complete the study; one relocated after 8 weeks, and the other was lost to follow-up after 20 weeks. Twenty-four patients (16 women, 8 men; mean age 60 years, range 40 to 75 years) were treated with vehicle cream. Each patient had at least four hyperpigmented macules with the clinical characteristics of actinic lentigines on the face and/or hands . All participants gave signed informed consent to participate in the protocol, which had been approved by the institutional review board of the University of Michigan Medical Center.
Study design Patients were treated with 0.1% tretinoin cream (Retin-A, Ortho Pharmaceutical Corp., Raritan, N .J.) or color-matched vehicle cream. Randomized treatment assignments, with a block size of four, were made with the use of a computerized random number generator. Stratification by ethnic origin was performed to ensure an equal balance of treatment assignments for Chinese and Japanese patients. Patients and investigators were blinded as to which group each patient had been assigned. The sample size provides statistical power of 0.7 in detecting a difference in overall improvement of at least one halfunit between treatment groups at a type I error rate of 0.05 for a two-tailed hypothesis.
Treatment The patients were instructed to apply test cream to the face and/or back of their hands each evening for 40 weeks. Initially, they were instructed to apply a "peasized" amount and increase it gradually to tolerance. They were also instructed not to wash the treated areas or to apply other topical preparations to their skin for at least I hour after application of test cream. Patients were provided with a mild soap to wash the treatment areas 20 minutes before application of test creams, as well as a mild emollient to treat skin irritation or dryness. Patients who experienced severe irritation were instructed to abstain from the medication for at least 24 hours and resume it on disappearance of the irritation.
Griffiths et al. 77 Patients were advised to avoid excess exposure to sun, sunlamps, and wind and to minimize the use of cosmetics,washing, and harsh scrubbing of the skin. A sunscreen of sun protection factor 15 was provided to be applied each morning. Before each study visit, patients were instructed not to apply any topical preparations, including emollients, sunscreens, or cosmetics to the designated treatment areas.
Clinical evaluations Clinical evaluations were performed at beginning of study, after the second and fourth weeks oftreatment, and at monthly intervals thereafter, for a total of 40 weeks. A single investigator evaluated every patient at every visit. Overall severity score of macular hyperpigmented lesions was determined for face and each hand monthly throughout the study. Severity was assessed on a a to 9 scale: 0, no hyperpigmentation; 1-3, mild ; 4-6, moderate; and 7-9, severe; the ranges of numbers were used to indicate severity within each category. In addition, at week 40, an assessment of the global response was made comparing the change over the entire study in all macular hyperpigmen ted lesions of face and hands combined. Global response was rated on a - 3 to + 3 scale where -3 was much darker; -2, darker; -1, slightly darker; 0, no change; + 1, slightly lighter; +2, lighter; and +3, much lighter. Four "designated lesions" on the face and/or hands were selected before therapy to be observed throughout the study. Pigmentation of each designated lesion was rated at each visit on a 0 to 7 scale: 0, absent; 1, very light; 2, light; 3, slightly light; 4, medium; 5, slightly dark; 6, dark; and 7, very dark. The designated lesions were numbered on Polaroid photographs taken before therapy to aid in locating each throughout the study. In 20 of 21 patients in the tretinoin group, one or more of the designated lesions was on the face (total of 69 facial lesions), and in 9 of 21 patients, the designated lesions were on the hands (total of IS). In the vehicle group, all 24 patients had one or more designated lesions on the face (total of 82) and 10 patients had designated lesions on the hands (total of 14).
Colorimetry As an objective measure of designated lesion color and of normal skin, a colorimeter (Chroma Meter-CR 200, Minolta Camera Co. Ltd., Osaka, Japan) was used before therapy and at 12, 24, and 40 weeks. Colorimetric assessment of skin lightening or darkening is a measure of reflectance, designated by the L * value in the L*a *b* color system defined by the Commission International de l'Bclairage.v? The L * value has a theoretical range of 0 (pure black) to 100 (pure white), but the range in human skin is far narrower. Caucasian skin has a mean L * value
Journal of the American Academy of Dermatology January 1994
78 Griffiths et al.
% of Patients
4%
o Much
Lighter
o Lighter Slightly Lighter •
Unchanged
Tretlnoln (n=21)
Vehicle (n=24)
Fig. 1. Global response to 40 weeks of tretinoin therapy for hyperpigmented lesions of face and hands. As compared with vehicle, tretinoin caused significant lightening of hyperpigmented lesions (p = 0.0006).
of 65 to 69 for sun-protected skin and 58 to 60 for sun-exposed skin.!? For each designated lesion and for nonlesional skin, five colorimeter measuremen ts were performed in succession and the mean value used. Measurements were obtained by placing the colorimeter probe perpendicular to the skin; blanching was prevented by applying minimal pressure.
Cutaneous and adverse reactions The degrees of erythema, burning/stinging sensation, and dryness/peeling were evaluated at each visit on a 0 to 4 scale: 0, absence of symptoms; 1, mild; 2, moderate; 3, moderately severe; 4, severe symptoms.
Light-microscopic analysis Before therapy and after treatment, a full-thickness 2 mm punch biopsy specimen was taken from one of the four designated lesions and analyzed by light microscopy. The posttreatment specimen was taken from the same lesion but far enough away to avoid scar tissue. Specimens were placed in 10%neutral-buffered formalin, embedded in paraffin, and stained with hematoxylin and eosin. Specimens taken before and after therapy were available from 16 patients treated with 0.1% tretinoin cream and 17 patients treated with vehicle cream. The histopathologic diagnosis was determined (Table 1) and various features (Table II) were graded on a semiquantitative 0 to 4 scale, with half-unit increments (0 = absence of characteristics and 4 = maximum presence of characteristics). Epidermal thickness was measured in microns in five high-power fields. The dermatopathologist who analyzed these histologic sections (L. J. F.) was blinded as to which specimens were pretherapy or posttreatment and from which treatment group they had come.
Statistical analysis The chi-square test was used to compare global response at the end of 40 weeks compared with pretherapy between tretinoin- and vehicle-treated patients; within the Chinese and Japanese patient subgroups, Fisher's exact test was used. Changes in overall severity of the facial or hand lesions for each patient at specific time points relative to pretherapy values were compared with the twosample t test. Values for the designated lesions were averaged for face and hands separately; comparisons of the changes in clinical and colorimetric features after 40 weeksof treatment were performed for all patients and by histologic subgroups with the two sample t test. The strength of the relation between clinically discernible improvement and histologic changes in epidermal melanin or changes in colorimetric values was assessed with the Pearson product-moment correlation coefficient. All p values are two-sided. Summary statistics are expressed as means ± standard error. The data were analyzed with the Michigan Interactive Data Analysis System (MIDAS, a statistical software package developed by the Center for Statistical Consultation and Research at the University of Michigan).
Photographic analysis Color photographs of patients for documentation were taken by a professional medical photographer before treatment, and at 12,24, and 40 weeks of therapy. The same photographic laboratory was used for all film processing. Broad diffuse illumination was provided by four studio flash units anchored in fixed positions. A Kodak standard gray card (18% reflectance) was photographed with the patient in all photographic sessions. The gray card provided a control value for any shifts in image color or density caused by extraneous variables.
Journal of the American Academy of Dermatology Volume 30, Number I
Griffiths et of. 79
Fig. 2. Examples of good responses to tretinoin therapy in three patients. A, A 65-year-old Japanese man before treatment (Wk 0), after 24 weeks of treatment with 0.1% tretinoin (Wk 24), and after completion of 40-week course of tretinoin therapy (Wk 40). Hyperpigmented lesions had lightened at week 24 and some had disappeared at week 40. B, A 59-year-old Chinese woman before treatment (Wk 0), after 24 weeks of treatment with 0.1% tretinoin (Wk 24), and after completion of 40-week course of tretinoin therapy (Wk 40). Hyperpigmented lesions had lightened at week 24 and some had disappeared at week 40. C (frontal view) and D (side view), A 66-year-old Japanese man before treatment (Wk 0) and after completion of 40 weeks of 0.1 % tretinoin treatment. Many hyperpigmented lesions had disappeared by end of therapy.
RESULTS Global response
Change in overall severity of hyperpigmented lesions by region
After 40 weeks of treatment, patients treated with 0.1 % tretinoin cream had statistically significant improvement compared with the vehicle group (p = 0.0006; Figs. 1 and 2) . Of the 21 tretinoin-treated patients, 8 (38%) were much lighter, 11 (52%) were lighter, and 2 (10%) were slightly lighter. Of the 24 vehicle-treated patients, 1 (4%) was much lighter, 7 (29%) were lighter, 12 (50%) were slightly lighter, and 4 (17%) were unchanged.
Face. Overall severity of hyperpigmented lesions in the tretinoin group was reduced from 5.5 ± 0.3 before therapy to 3.4 ± 0.2 at 40 weeks, a change of 2.1 ± 0.3, as compared with the vehicle group whose overall severity was reduced from 5.5 ± 0.3 to 4.7 ± 0.3, a change of 0.8 ± 0.2 (p = 0.0007, Fig. 3). Significant lightening in the tretinoin group was seen as early as 8 weeks of treatment (p = 0.004, Fig. 3). Hands. Hyperpigmented lesions in the tretinoin
80
Journal of the American Academy of Dermatology January 1994
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Weeks of Therapy Fig. 3. Change in overall severity of facial lesions with tretinoin (solid lines) or vehicle treatment (broken lines). Circles and error bars indicate mean ± standard error of each patient's reduction in overall severity score for the face from pretherapy to the week indicated. Statistically significant and clinically detectable lightening of facial lesions was evident after 8 weeks of tretinoin treatment and was maintained for the rest of the study. Asterisk denotes significant difference (p -< 0.004) between groups.
group lightened in overall severity from 2.8 ± 0.5 at pretherapy to 1.9 ± 0.3 at 40 weeks. Values in the vehicle-treated group were 2.5 ± 0.4 at baseline and 2.0 ± 0.3 at 40 weeks (p = 0.18 compared with tretinoin therapy). Change in designated lesions Face. There was significant lightening of the designated lesions of the face in the tretinoin-treated group from 4.1 ± 0.2 before therapy to 1.9 ± 0.2 after 40 weeks as compared with 4.3 ± 0.2 to 3.4 ± 0.2 in the vehicle-treated group (p < 0.0001). Significant lightening was first seen in the tretinointreated group after 8 weeks of treatment (p < 0.05). Of the 20 tretinoin-treated patients who had designated lesions of the face before therapy, 7 (35%) had complete clearing of one or more of the lesions; none of the lesions completely disappeared with vehicle treatment (p = 0.002, Fisher's exact test). Hands. The lightening of the designated lesionsof the hands in the tretinoin-treated group (4.4 ± 0.4 before therapy to 3.5 ± 0.3 at 40 weeks) was not statistically significantly different from the change in the vehicle-treated group (4.0 ± 0.3 to 3.2 ± 0.5; p = 0.8). None of the lesions on the hands in either treatment group completely disappeared. Effect of treatment on colorimetry values After 40 weeks of treatment, colorimetry demonstrated an increase (lightening) in the L * scale of the
tretinoin-treated lesions of 0.9 ± 0.5 units (from 55.7 ± 0.7t056.6 ± 0.8)comparedwithadecrease (darkening) of 0.7 ± 0.4 of the vehicle-treated lesions (from 56.5 ± 0.7 to 55.8 ± 0.8; p = 0.02). The average pretherapy L * value for nonlesional skin was 58.1 ± 1.0. Therefore after 40 weeks of tretinoin treatment the average L * value of lesional skin was 38% closer to normal color. There was a statistically significant correlation between clinical improvement and colorimetric values (r = 0.54; p = 0.0001; Fig. 4). Nonlesional facial skin demonstrated no statistical differences in the colorimeter readings between tretinoin and vehicle groups throughout the treatment course. Cutaneous reactions The only untoward event associated with therapy was a local cutaneous reaction characterized by erythema, scaling, and a burning sensation-the socalled "retinoid reaction." Erythema or scaling to at least a moderate degree (graded as >2) noted at more than one visit occurred in 21 of 23 patients (91%) who received tretinoin and in 4 of 24 (17%) in the vehicle group. Onset of the reaction usually occurred during the first month of treatment and peaked within 2 months. Subsequently, the retinoid reaction decreased in severity despite continued treatment. In seven tretinoin-treated patients, the reaction was severe enough to require temporary discontinuation of treatment for 1 to 3 days. None
Journal of the American Academy of Dermatology Volume 30, Number I
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Table I. Histologic diagnoses of designated pigmented lesions and mean clinical color change after 40 weeks of treatment 0.1 % Tretinoin Histologic diagnosis·
No.
All Actinic lentigo§ Nonlentiginous lesion Seborrheic keratosis] Benign keratosis'[, Solar elastosiS# Spongiotic dermatitis** Normal skintt
16 12
4 3 1 0 0 0
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2.1 ± 0.3 2.1 ± 0.3 2.0 ± 0.6 1.7 ± 0.7 3 NA NA NA
17 9 8 3 0 1 3
1
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Color changet
p Valuet
0.8 ± 0.2 0.8 ± 0.3 0.8 ± 0.4 1.0 ± 1.2 NA
0.0009 0.007 0.11 NS NA
1
NA NA NA
0.7 ± 0.3 0
NA, Not applicable; NS, no statistical significance. • A 2 mm punch biopsy specimen of a single lesion from each patient was obtained before therapy and classified by light microscopy. Only patients who completed the study are presented in this table; for pretherapy histologic diagnoses of all patients, see text. tColor values are the difference between pretherapy and week 40 and represent measurements only from the biopsied lesions. Lesions were rated clinically before therapy and after 40 weeks of therapy according to the followingscale: 0, absent (no pigment); I, very light; 2, light; 3, slightly light; 4, medium; 5, slightly dark; 6, dark; 7, very dark. Values are mean ± SE and made so that positive numbers indicate lightening. tFor comparison of the change between groups. §The histologic criteria were epidermal atrophy, heavily pigmented basal keratinocytes and melanocytes, club-shaped elongated rete ridges, and papillary dermal elastosis. [The histologic criteria were hyperkeratosis, marked acanthosis, and horn-cyst formation. 'Same as seborrheic keratosis without horn-cyst formation. #The histologic criterion was papillary dermal elastosis without sufficient findingsfor the diagnosis of actinic lentigo; solar elastosis was accompanied by epidermal hyperpigmentation. *·The histologic criteria were widening of the spaces between keratinocytes and a mild superficial lymphocytic perivascular infiltrate. ttNo abnormality was detected by light microscopy.
of the vehicle-treated patients discontinued therapy because of a cutaneous reaction.
Histologic findings Comparison of clinical color change by histologic diagnosis is shown in Table I. Both the actinic lentigines and the other pigmented lesions showed the
same degree of lightening after 40 weeks of tretinoin therapy (2.1 ± 0.3 and 2.0 ± 0.6, respectively). Because of the small number of nonlentiginous lesionsstudied, only actinic lentigines showed statistically significanttightening (p = 0.OO7)whentretinoin therapy was compared with vehicle. At posttreatment, there was a statistical1y signif-
Journal of the American Academy of Dermatology January 1994
82 Griffiths et al.
Table II. Pretherapy and posttreatment histologic features of biopsy specimens* Vehicle (n = 17)
0.1 % Tretinoin (n = 16) Histologic evaluation
Stratum corneum compaction Granular cell layer thickness Spongiosis Epidermal thickness (/-Lm):!: Epidermal pigmentation§ Clubbing Dermal perivascular inflammation Dermal pigmentation
Pretherapy
0.9 ± 0.4 ± 0.6 ± 58 ± 2.2 ± 1.9 ± 1.2 ± 0.8 ±
0.3 0.1 0.1 3 0.2 0.3 0.2 0.2
I Posttreatment I % Change 3.3 ± 2.8 ± 2.5 ± 88 ± 1.3 ± 0.9 ± 2.3 ± 0.9 ±
0.3 0.3 0.3 4 0.3 0.2 0.2 0.3
+257 +633 +326 +53 -41 -53 +95 +17
Pretherapy
1.0 ± 0.3 ± 0.9 ± 61 ± 1.9 ± 1.5 ± 1.4 ± 0.6 ±
0.2 0.1 0.3 3 0.2 0.3 0.2 0.2
IPosttreatment I % 0aJJge 1.4 ± 1.2 ± 0.9 ± 62 ± 2.6 ± 1.7 ± 1.5 ± 0.5 ±
0.2 0.1 0.2 5 0.2 0.3 0.3 0.2
+44 +264 +3 +2 +37 +13 +13 -14
p Valuet
0.0001 <0.0001 <0.0001 <0.0001 0.0004 0.01
om
0.43
*A 2 mm punch biopsy specimen of a single lesion from each patient was obtained before therapy and after 40 weeks of therapy. AIl variables (except epidermal thickness which was measured in microns) were assessed with a semiquantitative scale in which 0 indicated the absence of the characteristic and 4 the maximal degree of involvement. Values are mean ± SE and all percentages were determined before mean values were rounded. tFor comparison of changes between groups. tFor each specimen, measurements from top of the granular layer to epidermal basement membrane at five interrete sites were averaged. §Epidermal pigmentation refers to melanin distributed throughout the epidermis, that is, in both melanocytes and keratinocytes.
icant increase in stratum corneum compaction, granular cell layer thickness, epidermal thickness, spongiosis, and dermal perivascular inflammation in tretinoin-treated as compared with vehicle-treated skin (Table II). There was a 41 % decrease in epidermal pigmentation in tretinoin-treated as compared with a 37% increase in vehicle-treated skin (p = 0.0004; Table II). There was a statistically significant correlation between decrease in histologic epidermal pigment and clinical lightening (r = 0.45; P = 0.008; Fig. 5). There was no significant change in dermal pigmentation during treatment with either tretinoin or vehicle. Comparison of Chinese and Japanese patients At the end of 40 weeks of treatment, Chinese and Japanese patients had comparable improvement in global response to tretinoin treatment. Of the 11 tretinoin-treated Chinese patients, 10 (91%) were lighter or much lighter compared with only 3 (25%) of the 12 vehicle-treated Chinese patients (p = 0.003). Similarly, 9 (90%) of the 10 tretinoin-treated Japanese patients were lighter or much lighter compared with 5 (42%) of the 12 vehicle-treated Japanese patients (p = 0.03). Biopsy samples before therapy were available for all enrolled patients and had the following diagnoses (see Table I for descriptions): Among the 24 Chinese patients, there were 18 actinic lentigines (75%), 4 seborrheic keratoses (17%), 1 spongiotic dermatitis (4%), and 1 benign keratosis (4%). Among the 23 Japanese patients,
there were 15 with actinic lentigines (65%), 4 with seborrheic keratoses (17%), 2 with spongiotic dermatitis (9%), 1 with solar elastosis (4%), and 1 (4%) that failed to reveal disease. DISCUSSION
Asians and Caucasians have different phenotypes of photoaging. Chinese and Japanese persons primarily have hyperpigmented lesions and only a small degree of wrinkling after years of sun exposure'v"; in contrast, Caucasians display both wrinkling and hyperpigmentation in response to photoaging.7, 11, 12 In concordance with these observations, the patients in this study had insufficient wrinkling to evaluate. Regardless, this study demonstrates that in Chinese and Japanese facial skin, hyperpigmented lesionsassociated with photoaging willlighten with topical tretinoin therapy in the same manner as previously noted in Caucasian skin.1-S Indeed, statistically significant results were noted within the first 8 weeks of therapy (Fig. 3). Goh" has reported his experience with a regimen incorporating topical tretinoin that lightened hyperpigmented lesions in East Asian patients in 3 to 12 months. The same positiveresults were not observedon the hands of our patients, which is surprising because lesionsof the face and hands respond equally wellto tretinoin therapy in Caucasians. S We suspect that the small number of lesions on our patients' hands was a factor in the lack of significance;a larger study
Journal of the American Academy of Dermatology Volume 30, Number 1
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Fig. 5. Relation between histologic change in degree of epidermal pigmentation and clinically apparent color changes after 40 weeks' treatment with tretinoin (n = 16) or vehicle (n = 17). Best linear fit is represented by the line; r = 0.45, p = 0.008.
on hand lesions should be performed before conclusions specific to the hands are made. With photoaging, Chinese and Japanese persons have hyperpigmented lesions that fall into the same histologic spectrum of diagnoses as noted in Caucasians.! We cannot judge clinically with certainty whether a hyperpigmented lesion is an actinic lentigo. Nevertheless, as previously observed in the Caucasian population.f topical tretinoin is effective for lightening hyperpigmented lesions clinically similar to actinic lentigines regardless of the histologic diagnosis. Vehicle-treated patients also demonstrated some improvement of their pigmented lesions during the study. This may be attributed to avoidance of sunlight and the use of sunscreens during a 40-week period. The mechanism of action of topical tretinoin in lightening hyperpigmented macules is unknown. However, tretinoin is known to inhibit induced melanogenesis in vitro.P This proposed mechanism of action is supported by the histologic decrease in epidermal pigmentation observed after tretinoin as compared with vehicle therapy. In Caucasians, actinic lentigines cleared by topical tretinoin neither relapse nor repigment after cessation of treatment. 5 The observation of nonrelapse is additional evidence that tretinoin-induced lightening occurs as a result of melanin reduction and not because epidermal melanin content is diluted in a tretinoin-thickened epidermis. The other histologic changes, including epidermal thickening, in Table II are typical findings of topical tretinoin treatment.l"
None of the patients permanently discontinued tretinoin therapy because of adverse reactions. Ninety-one percent of tretinoin-treated patients experienced the retinoid reaction of at least a moderate degree at more than one visit, but none of the patients experienced any other side effects. This side-effect profile is similar to that reported in Caucasians.f 13 One problem with the retinoid reaction is that it can give the investigator clues as to which patients are taking active drug. However, the severity of the reaction varied throughout the study in any given patient and became insignificant in most when tolerance developed. REFERENCES I. Kligman AM, Grove GL, Hirose R, et al. Topical tretinoin for photoaged skin. J AM ACAD DERMATOL 1986; 15:83659. 2. Weiss JS, EllisCN, Headington JT, et aL Topical tretinoin improves photodamaged skin: a double-blind vehicle-controlled study. JAMA 1988;259:527-32. 3. Weinstein GD, Nigra TP, Pochi PE, et al. Topical tretinoin for treatment of photodamaged skin: a multicenter study. Arch Dermatol 1991;127:659-65. 4. Olsen EA, Katz I, Levine N, et al. Tretinoin emollient cream: a new therapy for photodamaged skin. J AM ACAD DERMATOL 1992;26:215-24. 5. Rafal ES, Griffiths CEM, Ditre CM, et al. Topical tretinoin (retinoic acid) treatment for liver spots associated with photodamage. N Engl J Med 1992;326:368-74. 6. Goh SH. The treatment of visible signs of senescence: the Asian experience. Br J Dermatol1990;122(suppI35):105-9. 7. Griffiths CEM, Wang TS, Hamilton T A, et aL A photonumeric scalefor the assessment of cutaneous photodamage. Arch Dermatol 1992;128:347-51. 8. Serup J, Agner T. Colorimetric quantification of erythema: a comparison of two colorimeters (Lange Micro Color and
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MinoIta Chroma Meter CR-200) with a clinical scoring scheme and laser-doppler flowmetry. Clio Exp Dermatol 1990;15:267-72. 9. Levine H, Sheftel 8N, Eytan T, et al. Induction of skin tanning by subcutaneous administration of a potent synthetic melanotropin. JAMA 1991;266:2730-6. 10. Andreassi L, Casini L, Simoni S, et al. Measurement of cutaneous colour and assessment of skin type. Photodermatol Photoimmunol Photomed 1990;7:10-4.
Journal of the American Academy of Dermatology January 1994
11. Kligman AM. Early destructive effects of sunlight on human skin. JAMA 1969;210:2377-80. 12. Gilchrest BA. Dermatoheliosis (sun-induced aging). In: Gilchrest BA, ed. Skin and aging Processes. Boca Raton, Fla: CRC Press, 1984:517-28. 13. Orlow 8J, Chakraborty AK, Pawelek JM. Retinoic acid is a potent inhibitor of inducible pigmentation in murine and hamster melanoma cell lines. J Invest Dermatol 1990; 94:461-4.