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Tretinoin emollient cream for photodamaged skin: Results of 48-week, multicenter, double-blind studies
THERAPY Tretinoin emollient cream for photodamaged skin: Results of 48-week, multicenter, double-blind studies Elise A. Olsen, MD, a H. Irving Katz, MD, b Norman Levine, MD, c Thomas P. Nigra, MD, d Peter E. Pochi, MD, e Ronald C. Savin, MD, f Jerome Shupack, MD,g Gerald D. Weinstein, MD, h Laura Lufrano, MD, i and Barbara H. Perry, PhD i Durham, North Carolina; Fridley,
Minnesota; Tucson, Arizona; Washington, D.C.; Boston, Massachusetts; New Haven, Connecticut; New York, New York; Irvine, California; and Raritan, New Jersey
Background: The ability of topical tretinoin to improve certain signs of skin photodamage has been shown previously.
Objective: Our purpose was to assess the effectiveness of tretinoin emollient cream in maintaining or further improving photodamaged skin during extended use.
Methods: Photodamaged subjects who completed 24 weeks of once-daily use of tretinoin emollient cream 0.05% (n = 149) or 0.01% (n = 149) continued to use the same strength formulation in a 24-week double-blind extension. Results: Maintenance of improvement or continued reduction in signs of photodamage was noted in both investigators' and subjects' evaluations of the 0.05% and 0.01% preparations; these results were confirmed by skin replica analyses. Cutaneous side effects were less common during the extension study than during the first 24 weeks of therapy. Conclusion: Both strengths of tretinoin emollient cream (0.05% and 0.01%) appeared safe and effective in the treatment of photodamaged skin during a 48-week treatment period. (J Am Acad Dermato! 1997;37:217-26.)
Aging of the skin, especially that induced or exacerbated by UV irradiation (photodamage or dermatoheliosis), may be regarded as an undesirable form of cell differentiation.l,2 Keratinocytes and fibroblasts of photodamaged skin have a shorter life span, respond less to mitogenic stimuli, and are more sensitive to growth inhibitors than those of sun-protected skin. 1 In addition, this skin is typified histologically by irregularly dispersed melanocytes, elastosis, and reductions and From the Dermatopharmacology Study Center, Duke University Medical Centera; Minnesota Study Center, Fridleyb; University of Arizona Health Sciences Center, Tucsone; Washington Hospital Centerd; Boston UniversityC; Savin Dermatology Center P.C., New Havenf; New York University Medical Centerg; University of California, Irvineh; and R. W. Johnson Pharmaceutical Research Institute, Raritan. i Supported by the R. W. Johnson Pharmaceutical Research Institute, Raritan, N.J. Reprint requests: Elise A. Olsen, MD, Director, Dermatopharmacol0gy Study Center, Duke University Medical Center, Box 3294, Durham, NC 27710, Copyright © 1997 by the American Academy of Dermatology, Inc. 0190-9622/97/$5.00 + 0 16/1/80145
alterations in collagen. 3,4 These changes are manifested clinically by fine and coarse wrinkling, roughness, dryness, laxity, sallowness, pigmentary mottling, telangiectasia, and, in some cases, preneoplastic and neoplastic changes. 2,4 The cosmetic alterations produced by photodamage can have adverse effects on subjects' self-perceptions and the way they appear to others. 2,5 The ability of topical retinoic acid, particularly the all-trans form (tretinoin), to reverse some changes of photoaging has been recognized for approximately 20 years. 6 Tretinoin-treated human skin shows an increased number and activity of fibroblasts, reduced melanocyte activity, and rapid formation of a zone of subepidermal connective tissue with new collagen, anchoring filaments, and fibrils. 3'7-9 In the earliest controlled trials of topical tretinoin therapy for photodamage, both clinical and histologic improvements were seen in facial skin treated with 0.05% or 0.1% tretinoin cream (RetinA). 8-12 However, this formulation, designed for the treatment of ache, has a base that tends to dry skin, an undesirable property for use on photodamaged
217
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T a b l e I. Investigators' evaluations o f i m p r o v e m e n t in p h o t o d a m a g e at 24 and 48 weeks of therapy with tretinoin emollient c r e a m 0.05% or 0.01% % Subjects Group 1: Tretinoin emollient cream 0.05% (n=126) Evaluations compared with baseline
Global evaluations* Excellent Good Fair Total improved Poor Mean score p Value (24 vs 48 wk)t
Group 2: Tretinoin emollient cream 0.01%
(n=133)
Week 24
Week 48
Week 24
Week 48
10 30 40 79 21 2.29
13 32 37 82 18 2.40
1 17 40 57 43 1.75
3 29 43 74 26 2.09
Overall severity of photodamage; Improved units I -3 1 -2 11 -1 59 Total 71 No change 27 +1 (Worse) 2 Mean change -0.85 from baseline§ (% change) (-22.1) p Value (24 vs 48 wk)ll
0.132
<0.001
1 8 19 46 74 25 1 -1.10
0 1 5 43 49 47 4 -0.53
(-28.6)
(-13.5)
<0.001
0 3 23 43 68 29 3 -0.94 (-24.0) <0.001
*Excellent (4) = much improved;good (3) = improved;fair (2) = slightlyimproved;poor (1) = no change or worse. tStatistical comparisonsare based on mean scores. $Severity of photodamageon a 10-point scale (0 = absent; 9 = most severe). §Mean baselines for subjects receivingtretinoin emollientcream 0.05% or tretinoin emollientCream0.01% were 3.84 and 3.94, respectively. 11Statistical comparisonsare based on mean changes from baseline.
skin. Thus an emollient base for tretinoin was developed and three concentrations of tretinoin emollient cream (0.001%, 0.01%, and 0.05%) were tested on facial skin in two large, 24-week, multicenter, double-blind trials. 13,14 Use of 0.05% tretinoin emollient cream (Renova/Retinova) in particular was associated with a significant reduction in free wrinkling, roughness, and mottled hyperpigmentation. Skin replica analysis 15 and histologic evaluation 16 conf i r m e d the tretinoin-associated improvement. The present study was a continuation o f these earlier trials to assess the 48-week efficacy of 0.05% and 0.01% tretinoin emollient c r e a m in the treatment of mildly to moderately p h o t o d a m a g e d facial skin. SUBJECTS
AND METHODS
Subjects
In the present study, 298 subjects who had completed 24 weeks of treatment with tretinoin emollient cream
(0.05% or 0.01%) in double-blind studies at eight centers 13'14 elected to continue in the present double-blind 24-week extension trial. Additional groups of subjects, who were initially randomly assigned to receive either tretinoin emollient cream 0.001% or vehicle for the first 24 weeks and who were then randomly assigned to receive tretinoin emollient cream 0.05% or 0.01% during the extension, are not presented here. Thus, although blinded as to dose, both subject and investigators were aware that all subjects were now receiving active drug. All enrolled subjects, 80% of whom were women, were white, were in generally good health, had a mean age of 42 years, and initially (week 0) had mild to moderate facial photodamage. Subjects with severe photodamage were excluded. Photodamage was globally rated (based primarily on fine and coarse wrinkling and hyperpigmentation) on a 10-point scale (0 = none, 1 to 3 = mild, 4 to 6 = moderate, and 7 to 9 = severe). Representative photographs for each arbitrary grade of photodamage were
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T a b l e I I . I m p r o v e m e n t f r o m baseline (week 0) in individual k e y signs of photodamage* after 24 and 48 w e e k s o f therapy with tretinoin emollient c r e a m 0.05% or 0.01% Group 1:
Group 2:
Tretinoin emollient cream 0.05 % (n--126) Week 24
Fine wrinkling Any improvement (% of subjects) > 2 Units improvement (% of subjects) Mean reduction in score (units) % Reduction in score p Value (wk 24 vs wk 48)t Roughness Any improvement (% of subjects) > 2 Units improvement (% of subjects) Mean reduction in score (units) % Reduction in score p Value (wk 24 vs wk 48)t Mottled hyperpigmentation Any improvement (% of subjects) > 2 Units improvement (% of subjects) Mean reduction in score (units) % Reduction in score p Value (wk 24 vs wk 48)t
68 24 0.97 26
Tretinoin emollient cream 0.01% (n=133)
Week 48
Week 24
73 37 1.23 33
51 12 0.59 16
< 0.001 51 16 0.60 25
65 24 0.92 25 < 0.001
57 25 0.83 35
43 12 0.49 20
< 0.001 63 38 1.17 33
Week 48
53 23 0.75 31 < 0.001
69 38 1.29 36
53 29 0.77 22
0.260
67 38 1.06 31 < 0.001
*Severity of photodamage on a 10-point scale (0 = absent; 9 = most severe). ~Statistical comparisons based on mean reductions in scores at weeks 24 and 48.
given to the investigators to facilitate uniformity of ratings. To be able to be evaluated, subjects must have used their assigned formulation for at least a total of 305 days (target 48 weeks minus no more than 31 days). To be included in the analysis of an individual measure of efficacy, subjects otherwise eligible for inclusion needed to have baseline, 24-week, and 48week values for that measure. To be valid for the evaluation of safety, subjects must have made at least one of the monthly clinic visits during the period of the present study, and information must have been recorded concerning cutaneous irritation or adverse events.
Skin Cream, and Sundown Sunblock (sun protection factor 15) were supplied to each subject. Substitution of similar products was permitted at the discretion of the investigators or at the request of the subjects. To evaluate compliance, the tubes of the study medication were weighed at each clinic visit, and the change from the previous study was determined. It was estimated that each application of the formulation to the entire face weighed approximately 500 mg. Subjects were asked about any missed applications or treatments of less than 50% of the face, and the reasons for these were recorded.
Drug administration and concomitant medications
Clinical assessment of efficacy
Subjects were instructed to wash their faces every evening and to apply the assigned formulation to the entire face 20 to 30 minutes later. No other topical medications were to be applied, and no other therapies, such as collagen injection, that could affect study results were permitted. No topical products, including study drug, were to be used in the 48 hours preceding the scheduled clinic assessments. All subjects were advised to minimize use of facial cosmetics, to avoid exposure to UV light, and to apply a sunscreen before unavoidable periods of sun exposure. Johnson's Baby Bar, Purpose Dry
Clinical evaluations by the investigators and selfassessments by the subjects were performed monthly. The investigators graded the overall severity of photodamage, as well as eight components thereof (coarse wrinkling, fine wrinkling, mottled hyperpigmentation, tactile roughness, yellowing, laxity, lentigines, and telangiectasia), on a scale of 0 to 9 (absent to most severe). At the end of the study, the investigators made a global evaluation of the response from week 0 to week 48 on a 4-point scale (excellent = much improved [4], good = improved [3], fair = slightly improved [2], or poor = no change or worse [1]). After 24 and 48 weeks
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Table III. I m p r o v e m e n t in subjects' self-assessments of skin*at weeks 24 and 48 of therapy with tretinoin emollient cream 0.05% or 0.01% Group 1: Tre6noin emolliient cream 0.05% (n = 126)* Week 24
Week 48
Much Somewhat Much Somewhat improved improved improved improved
% Subjects improved* Small wrinkles Pink/rosy tone Brown spots Texture Tightness Pore size Overall assessment Overall mean score p Value (24 vs 48 wk) §
13 14 14 25 13 10 25
Group 2: Tretiuoiu emollient cream 0.01% (n = 133)*
61 50 48 54 56 49 63 3.11
21 17 24 35 14 12 37
65 59 48 56 58 53 58
Week 24
Week 48
Much Somewhat Much Somewhat improved improved improved improved
7 8 8 14 5 3 10
3.31
44 47 42 50 45 35 60 2.74
16 13 13 19 11 5 28
57 53 48 54 53 43 62 3.17
< 0.001
< 0.001
*Subjects graded their skin as much improved (4), somewhat improved (3), the same (2), or worse (1). *Except for brown spots (n = 124) and tightness (n = 125). *Except for small wrinkles (n = 131). §Statistical comparisons based on the changes in the mean overall scores from week 24 to week 48.
of therapy, subjects graded changes from week 0 in six tactile and visual features (small wrinkles, pink/rosy tone, brown spots, texture, tightness, and pore size) and the overall appearance and feel of the skin on a 4-point scale (4 = much improved, 3 = somewhat improved, 2 = the same, or 1 = worse).
Objective measures of efficacy: Skin replica analysis To supplement the clinical assessment, silicone rubber replicas were made of a 1 cm diameter circular area of the right cheek and the right lateral periorbital ("crow's feet") area during the clinic visits at baseline, week 24, week 36, and week 48. Measures of skin topography (Ra and Rz 17) were analyzed by means of the Magiscan digital-image processing system. R a is defined as the area of deviation of the surface features above and below an average central line. R z is defined as the difference between the maximum and minimum heights in five equal segments of the surface profile. 18,19 The values for "north" (0 degrees) and "south" (180 degrees), which are obtained with the light perpendicular to the major skin lines, and those for "east" (90 degrees) and "west" (270 degrees), which are obtained with the light parallel to the major skin lines, were averaged to create "north-south" (NS) and "east-west" (EW) values. 15 In the "crow's feet" area, the NS values are predominantly influenced by coarse wrinkling, whereas the EW values chiefly assess fine wrinkles.
Histologic evaluation At baseline and after 24 and 48 weeks of therapy, 2 mm punch biopsy specimens were obtained from
the left lateral periorbital region. Specimens at 24 and 48 weeks were taken from sites immediately adjacent to the previous biopsy location. The lateral periorbital area was selected because of its sun exposure and the ease of hiding biopsy scars in wrinkles. Specimens were placed in Trump's fixative and processed centrally. Representative pieces of each specimen were embedded in paraffin and Epon medium, and 3 and 1 ~tm sections, respectively, were stained with Fontana-Masson for examination of melanin, toluidine blue for granular layer evaluations or Polysciences Multiple Stain for other evaluations. In addition, immunostaining was performed on paraffin sections for detection of a 75 kd glycoprotein expressed by normal melanocytes, nevi, and melanoma cells. Slides were assessed by a single investigator (except for keratinocytic and melanocytic atypia, which were evaluated by two investigators) in a blinded fashion with computerized image analysis and conventional light microscopy. Features evaluated included (1) stratum corneum morphology, (2) epidermal,thickness, (3) granular cell layers, (4) keratinocytic atypia, (5) melanocytic atypia, (6) melanin content, (7) melanocyte number, (8) epidermal mucin, (9) dermal mucin, (10) elastic tissue content, (11) papillary dermal thickness, a n d (12) perivascular inflammation. Additional details of histologic methods have been described elsewhere. 16,2°
Safety At each monthly clinic visit, six signs and symptoms of skin irritation were rated on a scale of 0 to 9 (absent to most severe). The investigators rated erythema, peeling, inflammation, and dryness. Subjects rated
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Table IV. Summary of _histologic changes at 24 and 48 weeks in tretinoin-treated skin 24 weeks Group 1: Group 2: Tretinoin emollient cream Tretinoin emollient c r e a m 0.05 % 0,01%
% Change from baseline Epidermal thickness 33* Granular cell layers 60t Melanin content -66 t Number of melanocytes 6 Dermal mucin 16t Elastic tissue content 6 Papillary dermal thickness -9 Perivascular inflammation 23 % Subjects Compact stratum comeum* 90 t Epidermal mucin§ 8 Keratinocytic grade 1 atypiaII 2 Melanocytic grade 1 atypiaII,~I 11
48 weeks Group 1: Group 2: Tretinoin emollient c r e a m Tretinoin emollient cream 0.05 % 0.01%
30t 38 t -48 t ND 26 t 0 -5 17
-6* 25 t -83 t -6 14" -18 t -18" -21"
-4 19t -75 t ND 24 t -19 t -13 -16
78 t 10 ND ND
51 t 22 t 3 9
47 t 24 t ND ND
Note: Number of subjects with evaluable data ranged from 101 to 118 in group 1 and from 104 to 121 in group 2, except for n = 86 in both groups for stratum corneum morphology and n = 90 for evaluation of melanocyte number in the 0.05% group. Adapted from Bhawan J, Palko M, Lee J, et al. J Geriatr Dermatol 1995;3:62-7. ND, Not determined
*p< 0.05. *p < 0.001 (baseline comparisons). tBaseline values were 16% in group 1 and 22% in group 2. §Baseline value was 4% to 5% in both groups. flAll other subjects had no atypia (0 on a 0-4 semiquantitative scale). At baseline, atypia was grade 0 = normal or grade 1 = rare atypia or dyskeratosis or slight increase in cell size or number of melanocytes. l o n e subject had grade 2 atypia at 24 weeks.
itching and burning/stinging. Any intercurrent medical events were recorded. Statistical methods Changes from baseline (week 0) or from week 24 to week 48 were analyzed separately for each treatment group. For some variables, changes were analyzed by means of a one-way ANOVA with the investigator as the independent variable. With this method, both the consistency of the changes across the participating medical centers and the significance of the pooled change were analyzed. For other variables, including investigators' global evaluations, subjects' self-assessments, stratum corneum morphology, epidermal and dermal mucin, and pervascular inflammation, an analysis for categorical data was performed with appropriate terms to assess investigator effects.21 All statistical tests were twosided, and p values of 0.05 or less were considered significant. In all analyses, whenever the significance level of the test for investigator difference was 0.10 or less, a second test of the overall mean change (a paired t test or its categorical model equivalent) was performed that provided a more conservative assessment of the significance of the overall mean change, using the pooled results from all the centers.
RESULTS
Clinical assessment Efficacy of treatment was evaluated in a total of 126 subjects treated with tretinoin emollient cream 0.05% (group 1) and in 133 subjects treated with the 0.01% concentration (group 2). The mean number of days of therapy for the subjects in group 1 was 337 (range, 314 to 362 days); the corresponding number in group 2 was 339 days (range, 323 to 366 days). Investigators' global evaluations of improvement of photodamaged skin compared with baseline were consistently higher for subjects in group 1 (0.05% formulation) than for subjects in group 2 (0.01% formulation) (Table I). However, only minimal increases were observed from weeks 24 to 48 in the percentage of subjects showing improvement in global scores (79% to 82%) or in the mean global evaluation scores (2.29 to 2.40) in group 1. The effect of continued treatment resulted in greater change in group 2 (0.01%) than in group 1; the percentage of subjects who showed improvement rose from 57% at week 24 to 74% at week 48, and the mean global evaluation score
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Table ¥. Incidence of common cutaneous adverse events among subjects who received up to 48 weeks of cumulative exposure to tretinoin emollient cream 0.05% or 0.01%* G r o u p 1: Tretinoin emollient cream 0.05 % First 24 weeks (n = 179)
Skin and subcutaneous tissue Peeling, dry skin Burning, stinging Erythema Irritation Pruritus Papules
Second 24 weeks (n = 147)
90% 65% 53% 42 % 25% 23% 12%
Group 2: Tretinoin emollient cream 0.01% First 24 weeks (n = 179)
74% 50% 29% 24 % 12% 16% 14%
73% 32% 29% 17% 14% 15% 11%
Second 24 weeks (n = 147)
61% 32% 18% 18% 7% 12% 10%
*Adverse events reported by 10% of subjects or more in any treatment group during the second 24 weeks.
increased from 1.75 to 2.09 (p < 0.001; Table I), The percentage of subjects in group 2 with an excellent rating by the investigator at 48 weeks still was not as high, however, as that of group 1 (3% vs 13%, respectively). The scores for the overall severity of photodamage in both groups showed progressive declines from baseline during the 48-week treatment period with consistently better (i.e., lower) scores for the 0.05% formulation (Fig. 1). The differences between the mean changes at week 24 and week 48 were statistically significant (p < 0.001) for both the 0.05% group (from -0.85 to -1.10) and the 0.01% group (from -0.53 to -0.94) (Table I). The percentage of subjects improving by two or more grades increased during weeks 24 to 48, from 13% to 28% in group 1 and from 6% to 26% in group 2. Scores for severity of fine wrinkling, roughness, and mottled hyperpigmentation indicated that improvement of photodamaged skin was maintained or enhanced (Table II). Additional reductions in fine wrinkling and roughness at 48 versus 24 weeks were obtained by both groups (p < 0.001) and in mottled hyperpigmentation by group 2 (p < 0.001).
Subjects' self-assessment The subjects' global ratings of 48-week therapy were consistent with the investigators' evaluations and indicated maintenance as well as some enhancement of the benefits obtained during the first 24 weeks (Table III). Overall, 94% of the subjects receiving the 0.05% preparation and 90% of those receiving the 0.01% concentration reported some improvement in their skin at 48 weeks compared with 88% and 70%, respectively, at week 24. Among the subjects receiving 0.05% tretinoin
emollient cream, 37% thought their skin was much improved at week 48 compared with 25% at week 24. The corresponding figures for subjects treated with 0.01% tretinoin were 28% and 10%, respectively. The difference in the mean overall scores at week 24 versus week 48 was statistically significant for both doses (p < 0.001). Subjects' assessments of the various individual signs of photodamage s h o w e d similar trends with increased percentages of subjects reporting much improvement (the highest score) at 48 weeks compared with 24 weeks.
Skin replica assessment R a and R z measurements declined further from baseline (week 0) in both groups during the present extension study, as compared with the first 24 weeks of therapy, reflecting continued improvement in skin topography (Fig. 2). With tretinoin emollient cream 0.05% treatment, improvement in R a and R z measurements was significantly greater at week 48 than at week 24 for cheek and "crow's feet" NS determinations (p < 0.05) and for all "crow's feet" EW determinations (p < 0.001). With 0.01% tretinoin emollient cream, significant improvement in "crow's feet" EW measurements (p < 0.05) and cheek NS measurements (p < 0.001) were obtained in comparisons week 48 versus week 24.
Histologic findings Histologic evaluations at 48 weeks in both groups showed reversal of the increase in stratum corneum compaction, epidermal thickness, and the number of granular cell layers observed after 24 weeks of treatment (Table IV). 2° In group 1, the percentages of patients with compact stratum
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. ..................................................................................................
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•~"
3.5
.................................................................................
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• 2.5
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I
I
[
I
I
I
I
I
I
I
I
4
8
12
16
20
24
28
32
36
40
44
48
Weeks of Therapy Fig. 1. Overall severity of photodamage (higher numbers indicate greater severity) during 48 weeks of therapy with tretinoin emollient cream 0.05% or 0.01%. Subjects were graded on a 10-point scale (0 = none, 1-3 = mild, 4-6 -- moderate, and 7-9 = severe photodamage).
corneum increased from 16% at baseline to 90% after 24 weeks and then decreased to 51% after 48 weeks of therapy. Also in group 1, percentage increases over baseline in epidermal thickness (33%) or number of granular cell layers (60%) after 24 weeks of therapy decreased to -6% (a decrease from baseline) and 25%, respectively, after 48 weeks. In contrast, melanin content continued to decrease from a 66% reduction at week 24 to 83% at week 48 in group 1 and from 48% to 75% in group 2. No evidence of an increase from baseline in keratinocyte or melanocyte atypia or in the number of melanocytes was obtained at either 24 weeks or 48 weeks with the 0.05% formulation (no determinations were made for these variables in the 0.01% group). Epidermal mucin, which showed no appreciable change from baseline at week 24, was significantly increased at week 48 in both groups (p < 0.001). Compared with baseline, groups 1 and 2 showed a reduction in elastic tissue content of 18% and 19%, respectively, at week 48 (p < 0.001). With the 0.05% formulation, papillary dermal thickness decreased significantly (by 18%) at week 48 compared with baseline, and perivascular inflammation, which had increased (by 23%) from baseline to week 24, decreased significantly (by 21%) at week 48 compared with baseline. The histologic results of this study are presented in detail elsewhere. 2°
Safety Group 1 (tretinoin emollient cream 0.05%) and group 2 (0.01%) had similar cumulative exposures (334 vs 337 days, respectively). Two subjects in group 1 and one in group 2 withdrew from the study because of skin irritation. For most subjects, however, skin irritation was generally mild during the extension study. During the present study, adverse events showed a decline in frequency with time in group 1 and a similar trend in group 2 (Table V). The frequency of adverse events was lower in group 2 than in group 1 at 48 weeks. No unexpected serious adverse events were reported during the study that could reasonably be associated with tretinoin emollient cream.
DISCUSSION Although the effect of retinoids on photodamaged skin was at one time ascribed by some observers to irritation, it has since become clear that topical tretinoin acts through more specific effects. Nonspecific irritants such as salicylic acid do not duplicate the action of retinoids, 7 n o r is there a correlation between the intensity of skin irritation during treatment and the extent of reduction in photodamage.4,*Many cells contain specific nuclear and cytoplasmic receptors for retinoic
Journal of the American Academy of Dermatology
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0.05% Tretinoin Emollient Cream Crow's Feet
5
Cheek
[] 24Weeks • 48Weeks
oS~
_ 24 ~ Weeks [ ] • 48Weeks
0-
-5
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-10
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p=O.O06*
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p=0.039"
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p=0.191 p<0.001"
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I
p=0.093
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I
R=-NS R,-EW
•
p=O.O02*
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~]NS
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R,~NS R=-'EW R=~NS I~-Ew
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0.01% Tretinoin Emollient Cream
im
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¢1
tO
p=0.31t p=0.284 p=0.680
p=0.861 p=0.018" p=0.006* p<0.001* p
I~='-NS R='EW R='-NS R=-'EW
R=-NS R=-'EW Rz-NS RjEW
Fig. 2. Results of facial skin replica analyses of "crow's feet" and cheek. Percent changes in means from baseline to end of 24 and 48 weeks of tretinoin emollient cream 0.05% or 0.01%. Asterisk, Statistically significant difference between means at 24 versus 48 weeks. acid, and ligand binding to these receptors appears to be ,linked to initiation of gene transcription important in cell proliferation and differentiation. 1,4 At the same time, growth control mechanisms appear to continue to operate in the presence of retinoids, inasmuch as evidence of uncontrolled hyperplasia has not been seen in histologic studies. 13,14,16,20 Despite these findings, the precise mechanism(s) of retinoid action in photodamaged skin remain to be elucidated. In the present study histologic evaluations with light microscopy of facial skin biopsy specimens obtained after 48 weeks of treatment with tretinoin *Thorne EG, Lufrano L, Boateng F, Sampson AR. Effects of tretinoin emollient cream on photodamaged skin: relationship between skin irritation and clinical improvement. Presented as part of a scientific exhibit at the 51st Annual Meeting of the American Academy of Dermatology, San Francisco, Calif., Dec. 5-10, 1992.
emollient c r e a m 19 showed some reversal of the increases in epidermal thickness, stratum corneum compaction, and the number of granular cell layers observed after 24 weeks of treatment with tretinoin emollient cream 0.05% or 0.01%. 16 With continued clinical improvement, the relation between photodamage repair and the initial structural changes or the subsequent accommodation of the skin is unclear. Melanin content continued to decrease from week 24 to week 48, consistent with improvement in dyspigmentation. Increases in epidermal and dermal mucin were observed that may be partially responsible for other continued clinical improvements. In electron microscopy studies from randomly selected subjects in the present study, ultrastructural changes were found after 48 weeks, but not after 24 weeks of treatment with tretinoin emollient cream 0.05%. 22,23 Improvement
Joumal of the AmericanAcademyof Dermatology Volume37, Number 2, Part 1 of the degree of keratinocyte degeneration or vacuolar alterations in the basal lamina was seen at week 48 compared with baseline, but not at week 24. Likewise, after 24 weeks of treatment with 0.05% cream, neither the degree of baseline disorganization of collagen in the papillary dermis nor the degenerated microfibrils in the dermoepidermal junction showed improvement. 23 After 48 weeks of treatment, however, the majority of subjects showed new, well-organized collagen fibers and normal-appearing microfibrils with no significant change in the number of anchoring fibrils during the course of treatment. These data may provide keys to the complex mechanisms by which topical tretinoin exerts its clinical improvement on photodamaged skin. A total of 619 subjects with mild to moderate facial photodamage were enrolled in the initial 24week trials that compared 0.001%, 0.01%, and 0.05% tretinoin emollient cream with vehicle. Seventy-eight percent of the subjects using 0.05% cream showed overall improvement based on the investigators' global evaluations, compared with less than half (44%) of those using the vehicle alone as well as a comprehensive skin-care and sun-avoidance program. 13,14 Fine wrinkling, mottled hyperpigmentation, and tactile roughness were the most responsive signs. Skin replica analysis confirmed that the higher two tretinoin concentrations were superior to the vehicle in decreasing roughness and fine wrinkling. 15 The positive effects of 0.01% tretinoin emollient cream were less pronounced, but side effects were also less than those of the 0.05% formulation. 13,14 Three questions remained unanswered at the conclusion of the first 24-week trials. (1) Will improvement be maintained or furthered with continued use of tretinoin emollient cream? (2) Will any of the subjects who did not respond within 24 weeks improve with continued use of tretinoin emollient cream? (3) Is there tolerance to the side effects of tretinoin emollient cream over time? As the present results show, the answer to all three questions is "yes." Of those subjects who used the 0.05% cream for 48 weeks, most showed maintenance or continued enhancement of improvement. Subjects receiving the 0.01% formulation improved more during the second than during the first 24 weeks of therapy but still did not achieve the levels of response observed with the 0.05% formulation over 48 weeks of treatment.
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In both treatment groups, some subjects showed no response after 24 weeks of therapy but did respond during the 24-week extension, indicating that positive effects may be slow or delayed in some subjects. Investigators' global evaluations, for example, showed that 65% of the subjects in the 0.05% group and 56% of those in the 0.01% group who failed to show any improvement during the first 24 weeks experienced a favorable response (a slight to excellent improvement) during the second 24 weeks. Furthermore, in terms of the investigators' assessments of severity of photodamage, 36% of the 0.05% group and 46% of the 0.01% group who showed no change in the initial 24 weeks showed improvement at week 48, whereas only 3% of the subjects in each group showed a decline. Adverse events declined in frequency from week 24 to week 48 of therapy, particularly in the 0.05% group. In comparison to the 0.05% group, fewer adverse events with the 0.01% formulation were observed at both 24 and 48 weeks. The willingness of 97% of subjects to continue in the present trial, the low dropout rate (8%), and the low rate of withdrawals attributable to adverse events (17%) attest to the tolerability of tretinoin emollient cream. The minor deviations from the treatment regimen that are reflected in the compliance figures and the infrequent reported use of other topical therapies are unlikely to have had a significant effect on the measures of efficacy and safety. Compliance data indicated, however, that the 0.05% formulation was more irritating than the 0.01% formulation as 89% of the subjects in group 2 versus approximately 73% of those in group 1 made 90% or more of the prescribed applications. Further trials are suggested by the present data. A lead-in period of very low-dose tretinoin emollient cream, for example, might mitigate some of the irritation associated with the initial use of the 0.05% formulation. In addition, the optimal regimen for maintenance of the beneficial effects remains to be determined. REFERENCES 1. Gilchrest BA, Yaar M. Ageing and photoageing of the skin: observationsat the cellular and molecularlevel. Br J Dermatol 1992;127(Suppl 41):25-30. 2. Taylor CR, Stern RS, Leyden JJ, Gilchrest BA. Photoaging/photodamage and photoprotection. J Am Acad Dermatol 1990;22:1-15. 3. Kligman LH, Duo CH, Kligman AM. Topical retinoic
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6. 7.
8. 9.
10. 11.
12. 13. 14.
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acid enhances the repair of ultraviolet-damaged dermal connective tissue. Connect Tissue Res 1984; 12:139-50. Green L J, McCormick A, Weinstein GD. Photoaging and the skin: the effects of tretinoin. Dermatol Clin 1993;11:97-105. Gupta MA, Schork NJ, Ellis CN. Psychosocial correlates of the treatment of photodamaged skin with topical retinoic acid: a prospective controlled study. J Am Acad Dermatol 1994;30:969-72. Leyden JJ. Tretinoin therapy in photoageing: historical perspective. Br J Dermatol 1990;122(Suppl 35):83-6. Kligman AM, Grove GL, Hirose R, Leyden JJ. Topical tretinoin for photoaged skin. J Am Acad Dermatol 1986;15:836-59. • Zelickson AS, Mottaz JH, Weiss JS, Ellis CN, Voorhees JJ. Topical tretinoin in photoaging: an ultrastructural study. J Cutan Aging Cosmet Dermatol 1988;1:41-7. Weiss JS, Ellis CN, Headington JT, Tincoff T, Hamilton TA, Voorhees JJ. Topical tretinoin improves photoaged skin: a double-blind vehicle-controlled study. JAMA 1988;259:527-32. Leyden JJ, Grove GL, Grove MJ, Thorne EG, Lufrano L. Treatment of photodamaged facial skin with topical tretinoin. J Am Acad Dermatol 1989;21:638-44. Ellis CN, Weiss JS, Hamilton TA, Headington JT, Zelickson AS, Voorhees JJ. Sustained improvement with prolonged topical tretinoin (retinoic acid) for photoaged skin. J Am Acad Dermatol 1990;23:629-7. Lever L, Kumar P, Marks R. Topical retinoic acid for treatment of solar damage. Br J Dermatol 1990;122:91-8. Weinstein GD, Nigra TP, Pochi PE, et al. Topical tretinoin for treatment of photodamaged skin: a multicenter study. Arch Dermatol 1991; 127:659-65. Olsen EA, Katz HI, Levine N, et al. Tretinoin emollient cream: a new therapy for photodamaged skin. J Am Acad Dermatol 1992;26:215-24
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15. Grove GL, Grove MJ, Leyden JJ, et al. Skin replica analysis of photodamaged skin after therapy with tretinoin emollient cream. J Am Acad Dermatol 1991;25:231-7. 16. Bhawan J, Gonzalez-Serva A, Nehal K, et al. Effects of tretinoin on photodamaged skin: a histologic study. Arch Dermatol 1991;127:666-72. 17. Grove GL. Dermatological applications of the Magiscan image analyzing computer. In: Marks R, Payne PA, editors. Bioengineering and the skin. New York: MTP Press; 1979. p. 173-81. 18. Grove GL, Grove MJ. Objective methods for assessing skin surface topography noninvasively. In: Leveque J-L, editor. Cutaneous investigation in health and disease. New York: Marcel Dekker; 1989. p. 1-32. 19. Grove GL, Grove MJ, Leyden JJ. Optical profilometry: an objective method for quantification of facial wrinkles. J Am Acad Dermatol 1989;21:631-7. 20. Bhawan J, Palko M, Lee J, et al. Reversible histologic effects of tretinoin on photodamaged skin. J Geriatr Dermatol 1995;3:62-7. 21. Grizzle JE, Starmer CF, Koch GG. Analysis of categorical data by linear models. Biometrics 1969;25:489-504. 22. Yamamoto O, Bhawan J, Hara J, Gilchrest BA. Keratinocyte degeneration in human facial skin: documentation of new ultrastructural markers for photodamage and their improvement during topical tretinoin therapy. Exp Dermatol 1995;4:9-19. 23. Yamamoto O, Bhawan J, Solares G, Tsay AW, Gilchrest BA. Ultrastructural effects of topical tretinoin on dermoepidermal junction and papillary dermis in photodarnaged skin: a controlled study. Exp Dermatol 1995;4:14654.
Minnesota; Tucson, Arizona; Washington, D.C.; Boston, Massachusetts; New Haven, Connecticut; New York, New York; Irvine, California; and Raritan, New Jersey
Background: The ability of topical tretinoin to improve certain signs of skin photodamage has been shown previously.
Objective: Our purpose was to assess the effectiveness of tretinoin emollient cream in maintaining or further improving photodamaged skin during extended use.
Methods: Photodamaged subjects who completed 24 weeks of once-daily use of tretinoin emollient cream 0.05% (n = 149) or 0.01% (n = 149) continued to use the same strength formulation in a 24-week double-blind extension. Results: Maintenance of improvement or continued reduction in signs of photodamage was noted in both investigators' and subjects' evaluations of the 0.05% and 0.01% preparations; these results were confirmed by skin replica analyses. Cutaneous side effects were less common during the extension study than during the first 24 weeks of therapy. Conclusion: Both strengths of tretinoin emollient cream (0.05% and 0.01%) appeared safe and effective in the treatment of photodamaged skin during a 48-week treatment period. (J Am Acad Dermato! 1997;37:217-26.)
Aging of the skin, especially that induced or exacerbated by UV irradiation (photodamage or dermatoheliosis), may be regarded as an undesirable form of cell differentiation.l,2 Keratinocytes and fibroblasts of photodamaged skin have a shorter life span, respond less to mitogenic stimuli, and are more sensitive to growth inhibitors than those of sun-protected skin. 1 In addition, this skin is typified histologically by irregularly dispersed melanocytes, elastosis, and reductions and From the Dermatopharmacology Study Center, Duke University Medical Centera; Minnesota Study Center, Fridleyb; University of Arizona Health Sciences Center, Tucsone; Washington Hospital Centerd; Boston UniversityC; Savin Dermatology Center P.C., New Havenf; New York University Medical Centerg; University of California, Irvineh; and R. W. Johnson Pharmaceutical Research Institute, Raritan. i Supported by the R. W. Johnson Pharmaceutical Research Institute, Raritan, N.J. Reprint requests: Elise A. Olsen, MD, Director, Dermatopharmacol0gy Study Center, Duke University Medical Center, Box 3294, Durham, NC 27710, Copyright © 1997 by the American Academy of Dermatology, Inc. 0190-9622/97/$5.00 + 0 16/1/80145
alterations in collagen. 3,4 These changes are manifested clinically by fine and coarse wrinkling, roughness, dryness, laxity, sallowness, pigmentary mottling, telangiectasia, and, in some cases, preneoplastic and neoplastic changes. 2,4 The cosmetic alterations produced by photodamage can have adverse effects on subjects' self-perceptions and the way they appear to others. 2,5 The ability of topical retinoic acid, particularly the all-trans form (tretinoin), to reverse some changes of photoaging has been recognized for approximately 20 years. 6 Tretinoin-treated human skin shows an increased number and activity of fibroblasts, reduced melanocyte activity, and rapid formation of a zone of subepidermal connective tissue with new collagen, anchoring filaments, and fibrils. 3'7-9 In the earliest controlled trials of topical tretinoin therapy for photodamage, both clinical and histologic improvements were seen in facial skin treated with 0.05% or 0.1% tretinoin cream (RetinA). 8-12 However, this formulation, designed for the treatment of ache, has a base that tends to dry skin, an undesirable property for use on photodamaged
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T a b l e I. Investigators' evaluations o f i m p r o v e m e n t in p h o t o d a m a g e at 24 and 48 weeks of therapy with tretinoin emollient c r e a m 0.05% or 0.01% % Subjects Group 1: Tretinoin emollient cream 0.05% (n=126) Evaluations compared with baseline
Global evaluations* Excellent Good Fair Total improved Poor Mean score p Value (24 vs 48 wk)t
Group 2: Tretinoin emollient cream 0.01%
(n=133)
Week 24
Week 48
Week 24
Week 48
10 30 40 79 21 2.29
13 32 37 82 18 2.40
1 17 40 57 43 1.75
3 29 43 74 26 2.09
Overall severity of photodamage; Improved units I -3 1 -2 11 -1 59 Total 71 No change 27 +1 (Worse) 2 Mean change -0.85 from baseline§ (% change) (-22.1) p Value (24 vs 48 wk)ll
0.132
<0.001
1 8 19 46 74 25 1 -1.10
0 1 5 43 49 47 4 -0.53
(-28.6)
(-13.5)
<0.001
0 3 23 43 68 29 3 -0.94 (-24.0) <0.001
*Excellent (4) = much improved;good (3) = improved;fair (2) = slightlyimproved;poor (1) = no change or worse. tStatistical comparisonsare based on mean scores. $Severity of photodamageon a 10-point scale (0 = absent; 9 = most severe). §Mean baselines for subjects receivingtretinoin emollientcream 0.05% or tretinoin emollientCream0.01% were 3.84 and 3.94, respectively. 11Statistical comparisonsare based on mean changes from baseline.
skin. Thus an emollient base for tretinoin was developed and three concentrations of tretinoin emollient cream (0.001%, 0.01%, and 0.05%) were tested on facial skin in two large, 24-week, multicenter, double-blind trials. 13,14 Use of 0.05% tretinoin emollient cream (Renova/Retinova) in particular was associated with a significant reduction in free wrinkling, roughness, and mottled hyperpigmentation. Skin replica analysis 15 and histologic evaluation 16 conf i r m e d the tretinoin-associated improvement. The present study was a continuation o f these earlier trials to assess the 48-week efficacy of 0.05% and 0.01% tretinoin emollient c r e a m in the treatment of mildly to moderately p h o t o d a m a g e d facial skin. SUBJECTS
AND METHODS
Subjects
In the present study, 298 subjects who had completed 24 weeks of treatment with tretinoin emollient cream
(0.05% or 0.01%) in double-blind studies at eight centers 13'14 elected to continue in the present double-blind 24-week extension trial. Additional groups of subjects, who were initially randomly assigned to receive either tretinoin emollient cream 0.001% or vehicle for the first 24 weeks and who were then randomly assigned to receive tretinoin emollient cream 0.05% or 0.01% during the extension, are not presented here. Thus, although blinded as to dose, both subject and investigators were aware that all subjects were now receiving active drug. All enrolled subjects, 80% of whom were women, were white, were in generally good health, had a mean age of 42 years, and initially (week 0) had mild to moderate facial photodamage. Subjects with severe photodamage were excluded. Photodamage was globally rated (based primarily on fine and coarse wrinkling and hyperpigmentation) on a 10-point scale (0 = none, 1 to 3 = mild, 4 to 6 = moderate, and 7 to 9 = severe). Representative photographs for each arbitrary grade of photodamage were
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T a b l e I I . I m p r o v e m e n t f r o m baseline (week 0) in individual k e y signs of photodamage* after 24 and 48 w e e k s o f therapy with tretinoin emollient c r e a m 0.05% or 0.01% Group 1:
Group 2:
Tretinoin emollient cream 0.05 % (n--126) Week 24
Fine wrinkling Any improvement (% of subjects) > 2 Units improvement (% of subjects) Mean reduction in score (units) % Reduction in score p Value (wk 24 vs wk 48)t Roughness Any improvement (% of subjects) > 2 Units improvement (% of subjects) Mean reduction in score (units) % Reduction in score p Value (wk 24 vs wk 48)t Mottled hyperpigmentation Any improvement (% of subjects) > 2 Units improvement (% of subjects) Mean reduction in score (units) % Reduction in score p Value (wk 24 vs wk 48)t
68 24 0.97 26
Tretinoin emollient cream 0.01% (n=133)
Week 48
Week 24
73 37 1.23 33
51 12 0.59 16
< 0.001 51 16 0.60 25
65 24 0.92 25 < 0.001
57 25 0.83 35
43 12 0.49 20
< 0.001 63 38 1.17 33
Week 48
53 23 0.75 31 < 0.001
69 38 1.29 36
53 29 0.77 22
0.260
67 38 1.06 31 < 0.001
*Severity of photodamage on a 10-point scale (0 = absent; 9 = most severe). ~Statistical comparisons based on mean reductions in scores at weeks 24 and 48.
given to the investigators to facilitate uniformity of ratings. To be able to be evaluated, subjects must have used their assigned formulation for at least a total of 305 days (target 48 weeks minus no more than 31 days). To be included in the analysis of an individual measure of efficacy, subjects otherwise eligible for inclusion needed to have baseline, 24-week, and 48week values for that measure. To be valid for the evaluation of safety, subjects must have made at least one of the monthly clinic visits during the period of the present study, and information must have been recorded concerning cutaneous irritation or adverse events.
Skin Cream, and Sundown Sunblock (sun protection factor 15) were supplied to each subject. Substitution of similar products was permitted at the discretion of the investigators or at the request of the subjects. To evaluate compliance, the tubes of the study medication were weighed at each clinic visit, and the change from the previous study was determined. It was estimated that each application of the formulation to the entire face weighed approximately 500 mg. Subjects were asked about any missed applications or treatments of less than 50% of the face, and the reasons for these were recorded.
Drug administration and concomitant medications
Clinical assessment of efficacy
Subjects were instructed to wash their faces every evening and to apply the assigned formulation to the entire face 20 to 30 minutes later. No other topical medications were to be applied, and no other therapies, such as collagen injection, that could affect study results were permitted. No topical products, including study drug, were to be used in the 48 hours preceding the scheduled clinic assessments. All subjects were advised to minimize use of facial cosmetics, to avoid exposure to UV light, and to apply a sunscreen before unavoidable periods of sun exposure. Johnson's Baby Bar, Purpose Dry
Clinical evaluations by the investigators and selfassessments by the subjects were performed monthly. The investigators graded the overall severity of photodamage, as well as eight components thereof (coarse wrinkling, fine wrinkling, mottled hyperpigmentation, tactile roughness, yellowing, laxity, lentigines, and telangiectasia), on a scale of 0 to 9 (absent to most severe). At the end of the study, the investigators made a global evaluation of the response from week 0 to week 48 on a 4-point scale (excellent = much improved [4], good = improved [3], fair = slightly improved [2], or poor = no change or worse [1]). After 24 and 48 weeks
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Table III. I m p r o v e m e n t in subjects' self-assessments of skin*at weeks 24 and 48 of therapy with tretinoin emollient cream 0.05% or 0.01% Group 1: Tre6noin emolliient cream 0.05% (n = 126)* Week 24
Week 48
Much Somewhat Much Somewhat improved improved improved improved
% Subjects improved* Small wrinkles Pink/rosy tone Brown spots Texture Tightness Pore size Overall assessment Overall mean score p Value (24 vs 48 wk) §
13 14 14 25 13 10 25
Group 2: Tretiuoiu emollient cream 0.01% (n = 133)*
61 50 48 54 56 49 63 3.11
21 17 24 35 14 12 37
65 59 48 56 58 53 58
Week 24
Week 48
Much Somewhat Much Somewhat improved improved improved improved
7 8 8 14 5 3 10
3.31
44 47 42 50 45 35 60 2.74
16 13 13 19 11 5 28
57 53 48 54 53 43 62 3.17
< 0.001
< 0.001
*Subjects graded their skin as much improved (4), somewhat improved (3), the same (2), or worse (1). *Except for brown spots (n = 124) and tightness (n = 125). *Except for small wrinkles (n = 131). §Statistical comparisons based on the changes in the mean overall scores from week 24 to week 48.
of therapy, subjects graded changes from week 0 in six tactile and visual features (small wrinkles, pink/rosy tone, brown spots, texture, tightness, and pore size) and the overall appearance and feel of the skin on a 4-point scale (4 = much improved, 3 = somewhat improved, 2 = the same, or 1 = worse).
Objective measures of efficacy: Skin replica analysis To supplement the clinical assessment, silicone rubber replicas were made of a 1 cm diameter circular area of the right cheek and the right lateral periorbital ("crow's feet") area during the clinic visits at baseline, week 24, week 36, and week 48. Measures of skin topography (Ra and Rz 17) were analyzed by means of the Magiscan digital-image processing system. R a is defined as the area of deviation of the surface features above and below an average central line. R z is defined as the difference between the maximum and minimum heights in five equal segments of the surface profile. 18,19 The values for "north" (0 degrees) and "south" (180 degrees), which are obtained with the light perpendicular to the major skin lines, and those for "east" (90 degrees) and "west" (270 degrees), which are obtained with the light parallel to the major skin lines, were averaged to create "north-south" (NS) and "east-west" (EW) values. 15 In the "crow's feet" area, the NS values are predominantly influenced by coarse wrinkling, whereas the EW values chiefly assess fine wrinkles.
Histologic evaluation At baseline and after 24 and 48 weeks of therapy, 2 mm punch biopsy specimens were obtained from
the left lateral periorbital region. Specimens at 24 and 48 weeks were taken from sites immediately adjacent to the previous biopsy location. The lateral periorbital area was selected because of its sun exposure and the ease of hiding biopsy scars in wrinkles. Specimens were placed in Trump's fixative and processed centrally. Representative pieces of each specimen were embedded in paraffin and Epon medium, and 3 and 1 ~tm sections, respectively, were stained with Fontana-Masson for examination of melanin, toluidine blue for granular layer evaluations or Polysciences Multiple Stain for other evaluations. In addition, immunostaining was performed on paraffin sections for detection of a 75 kd glycoprotein expressed by normal melanocytes, nevi, and melanoma cells. Slides were assessed by a single investigator (except for keratinocytic and melanocytic atypia, which were evaluated by two investigators) in a blinded fashion with computerized image analysis and conventional light microscopy. Features evaluated included (1) stratum corneum morphology, (2) epidermal,thickness, (3) granular cell layers, (4) keratinocytic atypia, (5) melanocytic atypia, (6) melanin content, (7) melanocyte number, (8) epidermal mucin, (9) dermal mucin, (10) elastic tissue content, (11) papillary dermal thickness, a n d (12) perivascular inflammation. Additional details of histologic methods have been described elsewhere. 16,2°
Safety At each monthly clinic visit, six signs and symptoms of skin irritation were rated on a scale of 0 to 9 (absent to most severe). The investigators rated erythema, peeling, inflammation, and dryness. Subjects rated
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Table IV. Summary of _histologic changes at 24 and 48 weeks in tretinoin-treated skin 24 weeks Group 1: Group 2: Tretinoin emollient cream Tretinoin emollient c r e a m 0.05 % 0,01%
% Change from baseline Epidermal thickness 33* Granular cell layers 60t Melanin content -66 t Number of melanocytes 6 Dermal mucin 16t Elastic tissue content 6 Papillary dermal thickness -9 Perivascular inflammation 23 % Subjects Compact stratum comeum* 90 t Epidermal mucin§ 8 Keratinocytic grade 1 atypiaII 2 Melanocytic grade 1 atypiaII,~I 11
48 weeks Group 1: Group 2: Tretinoin emollient c r e a m Tretinoin emollient cream 0.05 % 0.01%
30t 38 t -48 t ND 26 t 0 -5 17
-6* 25 t -83 t -6 14" -18 t -18" -21"
-4 19t -75 t ND 24 t -19 t -13 -16
78 t 10 ND ND
51 t 22 t 3 9
47 t 24 t ND ND
Note: Number of subjects with evaluable data ranged from 101 to 118 in group 1 and from 104 to 121 in group 2, except for n = 86 in both groups for stratum corneum morphology and n = 90 for evaluation of melanocyte number in the 0.05% group. Adapted from Bhawan J, Palko M, Lee J, et al. J Geriatr Dermatol 1995;3:62-7. ND, Not determined
*p< 0.05. *p < 0.001 (baseline comparisons). tBaseline values were 16% in group 1 and 22% in group 2. §Baseline value was 4% to 5% in both groups. flAll other subjects had no atypia (0 on a 0-4 semiquantitative scale). At baseline, atypia was grade 0 = normal or grade 1 = rare atypia or dyskeratosis or slight increase in cell size or number of melanocytes. l o n e subject had grade 2 atypia at 24 weeks.
itching and burning/stinging. Any intercurrent medical events were recorded. Statistical methods Changes from baseline (week 0) or from week 24 to week 48 were analyzed separately for each treatment group. For some variables, changes were analyzed by means of a one-way ANOVA with the investigator as the independent variable. With this method, both the consistency of the changes across the participating medical centers and the significance of the pooled change were analyzed. For other variables, including investigators' global evaluations, subjects' self-assessments, stratum corneum morphology, epidermal and dermal mucin, and pervascular inflammation, an analysis for categorical data was performed with appropriate terms to assess investigator effects.21 All statistical tests were twosided, and p values of 0.05 or less were considered significant. In all analyses, whenever the significance level of the test for investigator difference was 0.10 or less, a second test of the overall mean change (a paired t test or its categorical model equivalent) was performed that provided a more conservative assessment of the significance of the overall mean change, using the pooled results from all the centers.
RESULTS
Clinical assessment Efficacy of treatment was evaluated in a total of 126 subjects treated with tretinoin emollient cream 0.05% (group 1) and in 133 subjects treated with the 0.01% concentration (group 2). The mean number of days of therapy for the subjects in group 1 was 337 (range, 314 to 362 days); the corresponding number in group 2 was 339 days (range, 323 to 366 days). Investigators' global evaluations of improvement of photodamaged skin compared with baseline were consistently higher for subjects in group 1 (0.05% formulation) than for subjects in group 2 (0.01% formulation) (Table I). However, only minimal increases were observed from weeks 24 to 48 in the percentage of subjects showing improvement in global scores (79% to 82%) or in the mean global evaluation scores (2.29 to 2.40) in group 1. The effect of continued treatment resulted in greater change in group 2 (0.01%) than in group 1; the percentage of subjects who showed improvement rose from 57% at week 24 to 74% at week 48, and the mean global evaluation score
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Table ¥. Incidence of common cutaneous adverse events among subjects who received up to 48 weeks of cumulative exposure to tretinoin emollient cream 0.05% or 0.01%* G r o u p 1: Tretinoin emollient cream 0.05 % First 24 weeks (n = 179)
Skin and subcutaneous tissue Peeling, dry skin Burning, stinging Erythema Irritation Pruritus Papules
Second 24 weeks (n = 147)
90% 65% 53% 42 % 25% 23% 12%
Group 2: Tretinoin emollient cream 0.01% First 24 weeks (n = 179)
74% 50% 29% 24 % 12% 16% 14%
73% 32% 29% 17% 14% 15% 11%
Second 24 weeks (n = 147)
61% 32% 18% 18% 7% 12% 10%
*Adverse events reported by 10% of subjects or more in any treatment group during the second 24 weeks.
increased from 1.75 to 2.09 (p < 0.001; Table I), The percentage of subjects in group 2 with an excellent rating by the investigator at 48 weeks still was not as high, however, as that of group 1 (3% vs 13%, respectively). The scores for the overall severity of photodamage in both groups showed progressive declines from baseline during the 48-week treatment period with consistently better (i.e., lower) scores for the 0.05% formulation (Fig. 1). The differences between the mean changes at week 24 and week 48 were statistically significant (p < 0.001) for both the 0.05% group (from -0.85 to -1.10) and the 0.01% group (from -0.53 to -0.94) (Table I). The percentage of subjects improving by two or more grades increased during weeks 24 to 48, from 13% to 28% in group 1 and from 6% to 26% in group 2. Scores for severity of fine wrinkling, roughness, and mottled hyperpigmentation indicated that improvement of photodamaged skin was maintained or enhanced (Table II). Additional reductions in fine wrinkling and roughness at 48 versus 24 weeks were obtained by both groups (p < 0.001) and in mottled hyperpigmentation by group 2 (p < 0.001).
Subjects' self-assessment The subjects' global ratings of 48-week therapy were consistent with the investigators' evaluations and indicated maintenance as well as some enhancement of the benefits obtained during the first 24 weeks (Table III). Overall, 94% of the subjects receiving the 0.05% preparation and 90% of those receiving the 0.01% concentration reported some improvement in their skin at 48 weeks compared with 88% and 70%, respectively, at week 24. Among the subjects receiving 0.05% tretinoin
emollient cream, 37% thought their skin was much improved at week 48 compared with 25% at week 24. The corresponding figures for subjects treated with 0.01% tretinoin were 28% and 10%, respectively. The difference in the mean overall scores at week 24 versus week 48 was statistically significant for both doses (p < 0.001). Subjects' assessments of the various individual signs of photodamage s h o w e d similar trends with increased percentages of subjects reporting much improvement (the highest score) at 48 weeks compared with 24 weeks.
Skin replica assessment R a and R z measurements declined further from baseline (week 0) in both groups during the present extension study, as compared with the first 24 weeks of therapy, reflecting continued improvement in skin topography (Fig. 2). With tretinoin emollient cream 0.05% treatment, improvement in R a and R z measurements was significantly greater at week 48 than at week 24 for cheek and "crow's feet" NS determinations (p < 0.05) and for all "crow's feet" EW determinations (p < 0.001). With 0.01% tretinoin emollient cream, significant improvement in "crow's feet" EW measurements (p < 0.05) and cheek NS measurements (p < 0.001) were obtained in comparisons week 48 versus week 24.
Histologic findings Histologic evaluations at 48 weeks in both groups showed reversal of the increase in stratum corneum compaction, epidermal thickness, and the number of granular cell layers observed after 24 weeks of treatment (Table IV). 2° In group 1, the percentages of patients with compact stratum
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corneum increased from 16% at baseline to 90% after 24 weeks and then decreased to 51% after 48 weeks of therapy. Also in group 1, percentage increases over baseline in epidermal thickness (33%) or number of granular cell layers (60%) after 24 weeks of therapy decreased to -6% (a decrease from baseline) and 25%, respectively, after 48 weeks. In contrast, melanin content continued to decrease from a 66% reduction at week 24 to 83% at week 48 in group 1 and from 48% to 75% in group 2. No evidence of an increase from baseline in keratinocyte or melanocyte atypia or in the number of melanocytes was obtained at either 24 weeks or 48 weeks with the 0.05% formulation (no determinations were made for these variables in the 0.01% group). Epidermal mucin, which showed no appreciable change from baseline at week 24, was significantly increased at week 48 in both groups (p < 0.001). Compared with baseline, groups 1 and 2 showed a reduction in elastic tissue content of 18% and 19%, respectively, at week 48 (p < 0.001). With the 0.05% formulation, papillary dermal thickness decreased significantly (by 18%) at week 48 compared with baseline, and perivascular inflammation, which had increased (by 23%) from baseline to week 24, decreased significantly (by 21%) at week 48 compared with baseline. The histologic results of this study are presented in detail elsewhere. 2°
Safety Group 1 (tretinoin emollient cream 0.05%) and group 2 (0.01%) had similar cumulative exposures (334 vs 337 days, respectively). Two subjects in group 1 and one in group 2 withdrew from the study because of skin irritation. For most subjects, however, skin irritation was generally mild during the extension study. During the present study, adverse events showed a decline in frequency with time in group 1 and a similar trend in group 2 (Table V). The frequency of adverse events was lower in group 2 than in group 1 at 48 weeks. No unexpected serious adverse events were reported during the study that could reasonably be associated with tretinoin emollient cream.
DISCUSSION Although the effect of retinoids on photodamaged skin was at one time ascribed by some observers to irritation, it has since become clear that topical tretinoin acts through more specific effects. Nonspecific irritants such as salicylic acid do not duplicate the action of retinoids, 7 n o r is there a correlation between the intensity of skin irritation during treatment and the extent of reduction in photodamage.4,*Many cells contain specific nuclear and cytoplasmic receptors for retinoic
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August 1997
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0.05% Tretinoin Emollient Cream Crow's Feet
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Fig. 2. Results of facial skin replica analyses of "crow's feet" and cheek. Percent changes in means from baseline to end of 24 and 48 weeks of tretinoin emollient cream 0.05% or 0.01%. Asterisk, Statistically significant difference between means at 24 versus 48 weeks. acid, and ligand binding to these receptors appears to be ,linked to initiation of gene transcription important in cell proliferation and differentiation. 1,4 At the same time, growth control mechanisms appear to continue to operate in the presence of retinoids, inasmuch as evidence of uncontrolled hyperplasia has not been seen in histologic studies. 13,14,16,20 Despite these findings, the precise mechanism(s) of retinoid action in photodamaged skin remain to be elucidated. In the present study histologic evaluations with light microscopy of facial skin biopsy specimens obtained after 48 weeks of treatment with tretinoin *Thorne EG, Lufrano L, Boateng F, Sampson AR. Effects of tretinoin emollient cream on photodamaged skin: relationship between skin irritation and clinical improvement. Presented as part of a scientific exhibit at the 51st Annual Meeting of the American Academy of Dermatology, San Francisco, Calif., Dec. 5-10, 1992.
emollient c r e a m 19 showed some reversal of the increases in epidermal thickness, stratum corneum compaction, and the number of granular cell layers observed after 24 weeks of treatment with tretinoin emollient cream 0.05% or 0.01%. 16 With continued clinical improvement, the relation between photodamage repair and the initial structural changes or the subsequent accommodation of the skin is unclear. Melanin content continued to decrease from week 24 to week 48, consistent with improvement in dyspigmentation. Increases in epidermal and dermal mucin were observed that may be partially responsible for other continued clinical improvements. In electron microscopy studies from randomly selected subjects in the present study, ultrastructural changes were found after 48 weeks, but not after 24 weeks of treatment with tretinoin emollient cream 0.05%. 22,23 Improvement
Joumal of the AmericanAcademyof Dermatology Volume37, Number 2, Part 1 of the degree of keratinocyte degeneration or vacuolar alterations in the basal lamina was seen at week 48 compared with baseline, but not at week 24. Likewise, after 24 weeks of treatment with 0.05% cream, neither the degree of baseline disorganization of collagen in the papillary dermis nor the degenerated microfibrils in the dermoepidermal junction showed improvement. 23 After 48 weeks of treatment, however, the majority of subjects showed new, well-organized collagen fibers and normal-appearing microfibrils with no significant change in the number of anchoring fibrils during the course of treatment. These data may provide keys to the complex mechanisms by which topical tretinoin exerts its clinical improvement on photodamaged skin. A total of 619 subjects with mild to moderate facial photodamage were enrolled in the initial 24week trials that compared 0.001%, 0.01%, and 0.05% tretinoin emollient cream with vehicle. Seventy-eight percent of the subjects using 0.05% cream showed overall improvement based on the investigators' global evaluations, compared with less than half (44%) of those using the vehicle alone as well as a comprehensive skin-care and sun-avoidance program. 13,14 Fine wrinkling, mottled hyperpigmentation, and tactile roughness were the most responsive signs. Skin replica analysis confirmed that the higher two tretinoin concentrations were superior to the vehicle in decreasing roughness and fine wrinkling. 15 The positive effects of 0.01% tretinoin emollient cream were less pronounced, but side effects were also less than those of the 0.05% formulation. 13,14 Three questions remained unanswered at the conclusion of the first 24-week trials. (1) Will improvement be maintained or furthered with continued use of tretinoin emollient cream? (2) Will any of the subjects who did not respond within 24 weeks improve with continued use of tretinoin emollient cream? (3) Is there tolerance to the side effects of tretinoin emollient cream over time? As the present results show, the answer to all three questions is "yes." Of those subjects who used the 0.05% cream for 48 weeks, most showed maintenance or continued enhancement of improvement. Subjects receiving the 0.01% formulation improved more during the second than during the first 24 weeks of therapy but still did not achieve the levels of response observed with the 0.05% formulation over 48 weeks of treatment.
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In both treatment groups, some subjects showed no response after 24 weeks of therapy but did respond during the 24-week extension, indicating that positive effects may be slow or delayed in some subjects. Investigators' global evaluations, for example, showed that 65% of the subjects in the 0.05% group and 56% of those in the 0.01% group who failed to show any improvement during the first 24 weeks experienced a favorable response (a slight to excellent improvement) during the second 24 weeks. Furthermore, in terms of the investigators' assessments of severity of photodamage, 36% of the 0.05% group and 46% of the 0.01% group who showed no change in the initial 24 weeks showed improvement at week 48, whereas only 3% of the subjects in each group showed a decline. Adverse events declined in frequency from week 24 to week 48 of therapy, particularly in the 0.05% group. In comparison to the 0.05% group, fewer adverse events with the 0.01% formulation were observed at both 24 and 48 weeks. The willingness of 97% of subjects to continue in the present trial, the low dropout rate (8%), and the low rate of withdrawals attributable to adverse events (17%) attest to the tolerability of tretinoin emollient cream. The minor deviations from the treatment regimen that are reflected in the compliance figures and the infrequent reported use of other topical therapies are unlikely to have had a significant effect on the measures of efficacy and safety. Compliance data indicated, however, that the 0.05% formulation was more irritating than the 0.01% formulation as 89% of the subjects in group 2 versus approximately 73% of those in group 1 made 90% or more of the prescribed applications. Further trials are suggested by the present data. A lead-in period of very low-dose tretinoin emollient cream, for example, might mitigate some of the irritation associated with the initial use of the 0.05% formulation. In addition, the optimal regimen for maintenance of the beneficial effects remains to be determined. REFERENCES 1. Gilchrest BA, Yaar M. Ageing and photoageing of the skin: observationsat the cellular and molecularlevel. Br J Dermatol 1992;127(Suppl 41):25-30. 2. Taylor CR, Stern RS, Leyden JJ, Gilchrest BA. Photoaging/photodamage and photoprotection. J Am Acad Dermatol 1990;22:1-15. 3. Kligman LH, Duo CH, Kligman AM. Topical retinoic
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acid enhances the repair of ultraviolet-damaged dermal connective tissue. Connect Tissue Res 1984; 12:139-50. Green L J, McCormick A, Weinstein GD. Photoaging and the skin: the effects of tretinoin. Dermatol Clin 1993;11:97-105. Gupta MA, Schork NJ, Ellis CN. Psychosocial correlates of the treatment of photodamaged skin with topical retinoic acid: a prospective controlled study. J Am Acad Dermatol 1994;30:969-72. Leyden JJ. Tretinoin therapy in photoageing: historical perspective. Br J Dermatol 1990;122(Suppl 35):83-6. Kligman AM, Grove GL, Hirose R, Leyden JJ. Topical tretinoin for photoaged skin. J Am Acad Dermatol 1986;15:836-59. • Zelickson AS, Mottaz JH, Weiss JS, Ellis CN, Voorhees JJ. Topical tretinoin in photoaging: an ultrastructural study. J Cutan Aging Cosmet Dermatol 1988;1:41-7. Weiss JS, Ellis CN, Headington JT, Tincoff T, Hamilton TA, Voorhees JJ. Topical tretinoin improves photoaged skin: a double-blind vehicle-controlled study. JAMA 1988;259:527-32. Leyden JJ, Grove GL, Grove MJ, Thorne EG, Lufrano L. Treatment of photodamaged facial skin with topical tretinoin. J Am Acad Dermatol 1989;21:638-44. Ellis CN, Weiss JS, Hamilton TA, Headington JT, Zelickson AS, Voorhees JJ. Sustained improvement with prolonged topical tretinoin (retinoic acid) for photoaged skin. J Am Acad Dermatol 1990;23:629-7. Lever L, Kumar P, Marks R. Topical retinoic acid for treatment of solar damage. Br J Dermatol 1990;122:91-8. Weinstein GD, Nigra TP, Pochi PE, et al. Topical tretinoin for treatment of photodamaged skin: a multicenter study. Arch Dermatol 1991; 127:659-65. Olsen EA, Katz HI, Levine N, et al. Tretinoin emollient cream: a new therapy for photodamaged skin. J Am Acad Dermatol 1992;26:215-24
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15. Grove GL, Grove MJ, Leyden JJ, et al. Skin replica analysis of photodamaged skin after therapy with tretinoin emollient cream. J Am Acad Dermatol 1991;25:231-7. 16. Bhawan J, Gonzalez-Serva A, Nehal K, et al. Effects of tretinoin on photodamaged skin: a histologic study. Arch Dermatol 1991;127:666-72. 17. Grove GL. Dermatological applications of the Magiscan image analyzing computer. In: Marks R, Payne PA, editors. Bioengineering and the skin. New York: MTP Press; 1979. p. 173-81. 18. Grove GL, Grove MJ. Objective methods for assessing skin surface topography noninvasively. In: Leveque J-L, editor. Cutaneous investigation in health and disease. New York: Marcel Dekker; 1989. p. 1-32. 19. Grove GL, Grove MJ, Leyden JJ. Optical profilometry: an objective method for quantification of facial wrinkles. J Am Acad Dermatol 1989;21:631-7. 20. Bhawan J, Palko M, Lee J, et al. Reversible histologic effects of tretinoin on photodamaged skin. J Geriatr Dermatol 1995;3:62-7. 21. Grizzle JE, Starmer CF, Koch GG. Analysis of categorical data by linear models. Biometrics 1969;25:489-504. 22. Yamamoto O, Bhawan J, Hara J, Gilchrest BA. Keratinocyte degeneration in human facial skin: documentation of new ultrastructural markers for photodamage and their improvement during topical tretinoin therapy. Exp Dermatol 1995;4:9-19. 23. Yamamoto O, Bhawan J, Solares G, Tsay AW, Gilchrest BA. Ultrastructural effects of topical tretinoin on dermoepidermal junction and papillary dermis in photodarnaged skin: a controlled study. Exp Dermatol 1995;4:14654.