Clinical and laboratory studies

Sustained improvement with prolonged topicaltretinoin (retinoic acid) for photoaged skinCharles N. Ellis, MD,a Jonathan S. Weiss, MD,a,* Ted A. Hamilton, MS,aJohn T. Headington, MD,a,b Alvin S. Zelickson, MD,c and John 1. Voorhees, MDaAnn Arbor, Michigan, and Minneapolis, Minnesota

We performed a 22-month trial of topical tretinoin (retinoic acid) in the treatment of pho­toaging. Thirty patients participated in a 4-month, randomized, blinded, vehicle-controlledstudythat has beenreported previously; 21patients continued tretinoin therapy onan open­labelbasis, participating in the studyfora totalof 10months, and 16patients continued for22 months. During the open-label study, the statistically significant improvement that hadoccurred infine andcoarse wrinkling andskin texture duringouroriginal study wassustained,despite reductions in dose or frequency of application of tretinoin. The number of discretelentigines decreased by 71% compared withthenumber before therapy.Histologic findingsincluded a statistically significant thickening ofthe epidermis. Side effects were limited toacutaneous retinoid reaction that diminished astherapyproceeded. (J AMACAD DERMATOL1990;23:629-37.)

WeI have demonstrated in a 4-month trial thattopical tretinoin (all-trans-retinoic acid, Retin-A)improves photoaged skin. Histologic' andultrastruc­tura12, 3 changes seen in forearm skin treated withtretinoin but not in skin treated with vehicle creamincluded compaction of stratum corneum, increasedgranular layer and epidermal thickness, increasednumbers of mitoses in keratinocytes, presence ofglycosaminoglycan-like substance in the compactedstratum corneum, increased numbers of anchoringfibrils at the dermoepidermaljunction, and improve­

ment of epidermal dysplastic changes. Herein wereport the results of an open-label trial, extend­ing tretinoin therapy for up to 22 months, in pa­tients who had completed our original 4-monthstudy.1

From the Dermatopharmacology Unit, Department ofDermatology,"and Department of Pathology," University of Michigan MedicalCenter, Ann Arbor, and the Department of Dermatology, Universityof Minnesota Medical School, Minneapolis,"

Supported by a grant from R. W. Johnson Pharmaceutical ResearchInstitute atOrtho Pharmaceutical Corp., Raritan, N.J., and by theBabcock Dermatologic Endowment, Ann Arbor, Mich.

Presented in part atthe Forty-sixth Annual Meeting of the AmericanAcademy ofDermatology, Washington, D.C., Dec. 3-8,1988.

Accepted for publication Jan. 5, 1990.Reprint requests: John J.Voorhees, MD, Department of Dermatology,

University ofMichigan Medical Center, Room 1910 Taubman Cen­ter, 1500East Medical Center Dr., Ann Arbor, MI 48109-0314.

"Dr, Weiss is now with Emory University School ofMedicine, Atlanta.16/1/19369

MATERIAL AND METHODS

Patients

The 30 patients who completed our original double­blind study were asked to continue in a 6-month openstudy; 21 agreed. After 6 months of therapy had beencompleted, the patients were asked to continue in thestudy for another year, and 16 agreed. Of the nine pa­tients who leftthestudyafter the initial4months, sixcitedeither the inconvenience of the protocol or that they didnotwantfurtherbiopsies andthreecited intermittent skinirritation. Allfive wholeftafter 10months citedinconve­nience or biopsies as the reason. No patient gavelackofefficacy asa reasonfor leaving. Allsegments ofthestudywere approved byThe University of Michigan MedicalCenterInstitutionalReview Board, andinformed consentwas obtained from all patients after the nature of thestudyand procedures hadbeen explained.

Treatment

Asin ouroriginal study, treatmentsites consisted ofthefaceand thedorsal aspectofthe forearms and hands. Pa­tients applied tretinoincream (Retin-A, Ortho Pharma­ceutical Corp., Raritan, N.J.) daily to theseareas.

Patients had applied tretinoin cream to one forearmand vehicle to the other in our original 4-month study.Therefore in this extended trial allpatients had onefore­arm to which theyapplied tretinoin cream (T) for a totalof 10months (lOT) and 22months (22T) and one fore­arm towhich theyapplied vehiclecream(V)for4months(4V), followed bytretinoin creamin an open-label fash­ionfor6 months(4V+ 6T) and 18months (4V+ 18T).

In our original study,patients wererandomly assignedto applytretinoin or vehicle to the facefor 4 months (4T

629

630 Ellis et al.

Journal of theAmerican Academy of

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Table 1. Study design, abbreviations used, and numbers of patients completing each study phase

Originalstudy! (4 mol Open study I (6 mol Open study 2 (12 mol

Vehicle I 0.1'Yo Tretinoin 0.05% or 0.1% Tretinoin 0.05% or 0.1% Tretinoin

Random assignment; parallel groupsGroup 1: Face 4V

(n = 15)

Group 2: Face

All patients; bilateral comparisonOne forearm 4V

(n =30)Other forearm

4T(n = 15)

4T(n = 30)

4V+6T 4V + 18T(n =12) (n =8)

lOT 22T(n =9) (n =8)

4V+6T 4V + 18T(n =21) (n =16)

lOT 22T(n =21) (n =16)

For explanation of abbreviationssee text ("Material and Methods: Treatment").

or 4V). Those patients who received tretinoin during theoriginalstudy applied tretinoin cream to the face for a to­tal of 10 months (lOT) and 22 months (22T). Those pa­tients who applied vehicle cream to the face during thedouble-blind study received tretinoin to the face for a to­tal of 6 months (4V + 6T) and 18 months (4V + 18T)(Table I).

All patients used tretinoin 0.1%cream in our originalstudy. Depending on frequency and tolerance by patientsof previous side effects, we assigned nine patients in theinitial open-label phase lasting 6 months to continue us­ingtretinoin 0.1%creamdaily, nine to 0.05%cream daily,two to 0.1% cream on the arms and 0.05% cream on theface daily; one began with 0.05% cream but increased to0.1%cream 4 months later. During the second open-la­belphase lasting 12months, three patients continued with0.1%cream daily, eight used0.1%cream every other day,and five used 0.05% cream every other day.

Application of topical agents other than tretinoin wasrestricted, as in our original study. Patients were suppliedwith mildsoap and emollientcream (Purpose, Johnson &Johnson Products, Inc., New Brunswick, N.J.). Sun­screen (Sundown-SPF 15, Johnson & Johnson) was sup­plied for use in advance of prolonged sun exposure.Patients were instructed to use the same brands andquantities of cosmetics as they had before and during theoriginal study.

Clinical evaluations

Patients' faces and forearms were graded for indicatorsofphotoaging: (1) finewrinkling, (2) coarse wrinkling, (3)texture (tactile roughness), (4) telangiectasia, and fortreatment effects: (1) pinkness, (2) dermal edema. Thegrading scale for each parameter or treatment effectranged from 0 to 4 (0 =absent, 1 =mild, 2 =moderate,3 =moderately severe, 4 == severe). In addition, lenti­gineswere counted under normal lighting conditions. Allgrading for all visits of every patient was carried out by

the same investigator (J. S. W.) who, throughout thestudy, was unaware of the individual assignments oftretinoin or vehicle made in the original4-month study,although he was aware of the results of mean datapresented by us.'

Evaluations were made monthly for 6 months and ev­ery 2 months thereafter. Evaluations were performed atleast 14 hours after the patient applied the test cream toreduce or eliminate cosmetic improvements caused by thetemporary moisturizing effect of the cream.

Skin biopsy specimens

One 4 rom full-thickness punch biopsy specimen wastaken from the proximal third of the dorsal aspect ofeachforearm before therapy (n = 28 patients), at the end ofour original 4-month study (n =28), after 10 months(n =21), and after 22 months (n = 16). Biopsy speci­mens were prepared for light microscopy and interpretedin a manner identical to that in our original study.' In asimilar fashion before therapy and after 4 and 10 months,2 mm punch biopsy specimens were obtained from sevenpatients. These specimens were placed in a cacodylate­buffered (pH 7.2) 2.5% glutaraldehyde solution, post­fixed in 1% osmium tetroxide, dehydrated in ethanol, andembedded (Spurr embedding medium). Thin sectionswere stained with uranyl acetate and lead citrate and ex­amined with an electron microscope (model EMU4,

RCA, Camden, N.J.). All specimens were taken within1 to 2 em of each other; care was taken to avoid scar tis­sue, keratoses, and lentigines. Throughout the study,specimens were provided to the microscopists (1. T. H.and A. S. Z.) in a coded fashion.

Statistical method

Data are reported as means ± 1 standard error of themean; all p values are two-sided. The analyses were per­formed with the use of the Michigan Interactive DataAnalysis System (MIDAS), a statistical software pack-

Volume 23Number 4, Part 1October 1990 Prolonged tretinoin for photoaging 631

DOUBLE-BLIND OPEN DOUBLE·BLIND OPEN1.0·,r--------,--------,

wo w2.5if~ciS c:s 2.0~lI)

~ ~ 1.5

~ ~ 1.0

~ lI) 0.5Ii:

A BL

BL

4 MOS.

4V+6T

** 10T

4V+1ST

* 22T

22 MOS.

4V+1ST 22T

N=8 N;;8

B

1.5

~ w 1.2if~en g 0.9

ffi~~ s0.6zGja::: CI) 0.3

D BL

4 MOS.

4V+1ST

22TN;;8

22 MOS.

4V+18T 22TN;;8 N=8

Fig. 1. Clinical parameters of the face over time. Large, open bars indicate mean; smallerbarsindicate standard error. Severity score scalesvary to aid in graphic representation. Val­ues for p in double-blind phase refer to comparisons of changes from baseline between V (ve­hicle) and T (tretinoin) groups. Values for p in open phase refer to comparisons to baseline.For explanation of V and T see Table I and text. BL. Baseline (pretherapy); N, number ofpatients evaluated in each treatment regimen at each time point; MOS, months of study du­ration (first 4 months were performed in double-blind design! whereas the remaining 18months were open-label). r, 0.05 <p <0.07; *, 0.01 <p -< 0.05; **,0.001 <» ~ 0.01; ***,0.0001 <p -< 0.001; ****,p s:0.0001.

age developed by the Statistical Research Laboratory atThe University of Michigan. The time points for presen­tation of the data were chosen to correspond with thecompletion of the various phases of the protocol.

Originalstudy(pretberapy to 4 montbs),These methodsare described in our original article.'

Open-label phases (4 to 22 months). At 10 and 22months, data for each treatment regimen were comparedwith the respective pretherapy values and analyzed withthe sign test (for efficacy data and discrete histologic pa­rameters) or the paired Student t test (for continuous his­tologic measurements). The Wilcoxon signed-rank testwas used to compare 4T with lOT data. The statistics arepresented for descriptive purposes; therefore no adjust­ment for the number of comparisons was made. Statisti­cal comparisons at each time-point include only those pa­tients who remained in the study and exclude data ofpa­tients who withdrew before then.

Representative nature of study patients

To ensure that the patients who completed the studywere representative of the original cohort of 30 patients,a comparison was made of the overall response after 4months oftretinoin therapy between the 16 patients who

went on to complete the study and the 14 who left beforecompletion. As in our original study, overall response wasdetermined on a scale of 1 to 5 (1 =much improved,2 =improved, 3 = slightly improved, 4 = no change,5 =worse). The results showed no detectable differencesin improvement (p = 1.0, Wilcoxon rank-sum test) forboth groups after 4T. Thus there was no evidence for theintroduction of a bias in our open-label trial related to thepatients' decision to continue in the study as a result oftheir clinical improvement or lack thereof.

RESULTS

Clinical results

During the open-label phases, the mean scores for

fine and coarse wrinkling and texture indicate thatthe improvement that occurred in our original,4-month study was sustained (Figs. 1,2, and 3). Finewrinkling and surface texture continued to show themost consistent improvement in the mean scores ofboth arms and face compared with those beforetherapy. As demonstrated by the changes in meansfrom 4V to 4V +6T and from 4T to lOT (Figs. 1and 2), most of the alterations in the clinical indica-

632 Ellis et al.

Journal of theAmerican Academy of

Dermatology

DOUBLE·BlIND OPEN DOUBLE·BLlND OPEN

4V+18T 22T

N=16

**** ****

10 MOS. 22 MOS.

4V+6T 10T

N==21

**** **** .......""'T"""........

B

1.8(I)~

1~1.5~ 1.2

~~0.9~~0.6

en 0.3

0.0 LL~:::-JLL~~llr:::E::r:::E:::L.J~~:.lJ

4V+18T 22T

4V+6T 10T

lJ)

~w~ ~3.0

~ t7) 2.4

~ ~1.8-a:a:w~ [j 1.2

~ lJ) 0.6[;

A

****

BL

V T

N=30

en w 2.4

~ ~2.0<cu.. en 1.6~~w CE 1.2Zw~ ai 0.8c, en 0.4

0.0 l.Gt:::r::;tJ-...r:::;ti-llL-=t~U..:J~1J

oFig. 2. Clinical parameters of the arms over time. For explanationof symbols, see Fig. 1.N. Number of patients evaluated at each time point; onearm received each treatment reg­imen indicated. Mean severityvaluesare identical for textureinthe openphases becausemostpatients had scores of O.

lJ)

:::E~w•. II: 2.0

~§1.6i ~1.2~wO~ £ij .8

!i lJ) 0.4

8 0.0.L-L---=-"_1.-J....---L .u.L..---L_J......I...---L_J-J

C

*p =0.03 compared with pretherapy; sign test. Only patients with dis­crete, counted lentigines are included.

Table II. Number of lentigines present onthe face

tors occurred during the first 6 to 10 months oftretinoin therapy.

There was greater pinkness of the skin comparedwith the pretherapy skin color at all evaluations af­ter tretinoin therapy had begun (Figs. I and 2). Inall patients with discrete, countable lentigines, thenumber of lentigines was reduced after 6 months ormore of tretinoin treatment (Table II); lightening ofcolor occurred in lentigines that did not disappear.Tretinoin had no positive or negative effect on

telangiectasia and it did not induce clinically detect­able dermal edema.

To determine whether extending therapy beyondthe 4 months of our original study is of clinical ben­efit despite the reduction in tretinoin concentrationused in the open phase, we compared the scores forthe photoaging indicators at 4T with those at lOT.On the arms after 10 months of tretinoin therapy,mean scores for fine wrinkling, texture, and coarsewrinkling were lower than the 4-month values(p == 0.0002,0.001, and 0.07, respectively). The im­provement that was noted after lOT was maintainedat 22T (i.e., there was no statistically significant dif­ference in the scores of photoaging between lOT and22T). The parallel design provided too few compar­isons to perform a similar analysis for data from theface.

Patients were not assigned randomly to the twoconcentrations oftretinoin (0.1% and 0.05%) used inthe open phases; therefore the effect ofconcentrationcannot be definitively assessed and an optimal treat­ment regimen cannot be determined from our data.Nevertheless, for descriptive purposes, we have ex­amined the mean scores for the nine patients who

oo24oo6

oo241a"7

After 6 to 10 rno After 18 to 22 rnotretinoin therapy* tretinoin therapy*

44372I

21

.53132363839

Total

Patient No.

Volume 23Number 4, Part 1October 1990 Prolonged tretinoin for photoaging 633

Fig. 3. A, Before tretinoin therapy (after 4V). B, After 6 months of tretinoin treatment. C,After 18 months of tretinoin therapy. All photographs were taken with a Nikon F3 35 mmcamera with a Nikon 105 mm micro-Nikkor lensbracketed at F 11 to F16 using Kodachrome25 ASA professional film with side lighting, which was positioned in standard fashion bymeasurement to within 1 em. Blue background was changed to black after the first picture.Photographs were obtained only to document clinical changes and were not used for datacollection or analysis; all data were obtained from direct observations of patients.

634 Ellis et al.

Journal of theAmerican Academy of

Dermatology

Fig. 4. Representative photomicrographs of skin from forearms. A, Before therapy, dem­onstrating a woven stratum corneum with minimal cytologic atypia in epidermis normal inthickness for the forearm, and moderate elastosis in papillary dermis. B, After 4 months oftretinoin therapy, showing compaction of the stratum corneum, thicker epidermis withoutcytologicatypia, and slight elastosisin papillarydermis.C, After 10 months of tretinoin ther­apy, demonstrating findings similar to 4-month specimen, with thickness of the epidermisgreater than that before therapy but lessthan at 4 months, and slight dermal elastosis. D, Af­ter 22 months, similar to the IG-monthspecimenbut with moderate dermal elastosis. Vari­ability in dermal elastosis is due to individualvariation and not the result of therapy; therewere no consistent changes in the dermis that could be observed by light microscopy. (A, B,C, and D, Hematoxylin-eosin stain; X50.)

received tretinoin 0.05% daily and the 11 patientswho received tretinoin 0.1% daily in the initial openphase lasting 6 months. The differences in the meanscores for the photoaging parameters between thetwo groups were clinically insignificant (differencesof 0.02 to 0.30 units) at both 4V + 6T and lOT.There was no difference in adverse effects betweenthe two groups.

i\dverse effects

Episodic peeling, dryness, and erythema were theonly side effects detected during the 22 months ofthis study; these were relieved by reducing the fre­quency of tretinoin application or by avoiding appli­cation of the medication to the area of reaction fora few days. Only one patient used a topical cortico-

steroid once for 2 days during the open-label phases.The side effects were generally limited to the ante­cubital fossa and the neck; biopsy specimens werenot obtained from areas exhibiting side effects.

Histologic results

Before tretinoin therapy, the stratum corneumexhibited a woven pattern (Fig. 4) in 94% of forearmbiopsy specimens. After 4 months of tretinoin treat­ment, 89% of the samples of stratum corneumexhibited compaction, with a homogeneous appear­ance or a combination of woven and compacted cor­neocytes; only 11% showed a purely woven pattern.Similarly, after 6 to 10 months of tretinoin therapy,71% of all specimens demonstrated compaction ofthe stratum corneum. However, after 18 to 22

Volume 23Number 4, Part IOctober 1990 Prolonged tretinoin for photoaging 635

4V-'-1ST 22TN=8 N=8

4V+1ST 22TN=8 N=8

22 MOS.

OPEN

OPEN

10 MOS.

4V+6T lOT

N=12 N=9

********

4V+4V 4T 6T 10T

N=15 N=15 N=12 N=9

DOUBLE· BLIND

DOUBLE·BLlND

V T 4V 4TN=15 N=15 N=15 N=15

BL 4 MOS,

(J) 100·f3~ _80'u(/')i: ~ 60 -I- a: riiiEh4_-I u~ ~ 40 'a:­wo 20- v Ta::w N=15 N=15

BL 4 MOS. 10 MOS. 22 MOS.

Fig. 5. Histologic parameters in biopsy specimens fromforearms over time. For explanation of symbols see Fig.1. For explanation of N . see Fig. 2.

DISCUSSION

blasts had normal-appearing mitochondria and en­doplasmic reticulum.

Our results indicate that clinical improvementwas sustained when topical tretinoin therapy wasapplied for up to 22 months, even when the dosageor frequency of application of tretinoin was reduced.Although patients treated with the vehicle creamalone for 4 months in our original study had no dis­cernible improvement, I therapeutic benefit occurredafter they began tretinoin applications (Figs . 1 and2). In addition, with prolonged tretinoin treatment,71% of discrete lentigines (so-called liver or agespots) disappeared (Table II). Our results providefurther support for drug-induced improvement ofphotoaged skin, including wrinkles, and are consis­tent with other clinical studies.>?

We acknowledge three sources of potential bias inthis study, arising from (1) the retinoid react ion ex­perienced bysome patients, (2) the unblinded natureof the open-label segment, and (3) patient attrition.The first occurred in the double-blind phase and hasbeen discussed in detail. 1

We decided that it would not be feasible to pro­long the double-blind and vehicle-controlled designof our original study. Therefore, as with all opentrials, our results may be biased, presumably yield-

months of tretinoin therapy, the stratum corneumreverted to the pretherapy condition in many pa­tients; 69%of specimens demonstrated a wovenpat­tern.

The number ofcells in the granular layer doubled,on average, from pretherapy to the end of the study(Fig. 5). The mean epidermal thickness increased bymore than one third over the pretherapy value at alltime points during tretinoin therapy (Fig. 5). Thenumber of mitotic figures in seven adjacent high­power fields peaked early during tretinoin therapyand decreased to near pretherapy levels by the endof the study. The number of specimens with two ormore mitoses were as follows: zero at pretherapy;zero at 4V versus nine at 4T (p =0.01); three at4V + 6T and three at lOT (p < 0.05 for each com­pared with pretherapy); and one at both 4V + 18Tand 22T (p = no significance).

During tretinoin therapy, there was an increase inan alcian blue-positive substance in the epidermisand stratum corneum, although this material be­came less apparent after prolonged treatment. Noqualitative or quantitative changes in dermal colla­gen were detected .

Ultrastructural results

In the pretherapy specimens the stratum corneumwas thick (approximately 40 cells from the granularlayer to the free surface). Intracellular structuralproteins of the keratinocytes were dense and irreg­ular. Melanin was also readily apparent through­out the stratum corneum and in the epidermis, espe­cially in the lower portions capping the nuclei of ke­ratinocytes. At the dermoepidermal junction, an­choring fibrils were sparse. Collagen in the papillarydermis had a smudged appearance and was alignedhaphazardly; nearby fibroblasts contained enlargedmitochondria and distorted endoplasmic reticu­lum.

The samples obtained after 4 months- and 10months of therapy were similar. In the stratum cor­neum, there were approximately 25% fewer cell lay­ers, and the cells were thinner and more electron­dense. A finegranular material, similar to that foundin the epidermis after oral retinoid therapy andthought to be mucoid ," was seen between cells.Structural proteins in keratinocytes were thinnerand more orderly. Melanin appeared less frequentlythroughout the keratinocyte layers and was essen­tially absent from the stratum corneum. Anchoringfibrils were more numerous (Fig. 6).3Collagen witha normal-appearing structure and orientation waspresent in the papillary dermis and nearby fibro-

636 Ellis et al.Journal of the

American Academy ofDermatology

Fig. 6. Representative electron micrographs of skin from forearms. A, Before therapy; fewanchoring fibrils (AF) are seen along dermoepidermal junction (BL, basal lamina). B, After4 months of topical tretinoin therapy; anchoring fibrils (arrows) are more easily seen com­pared with those before therapy; collagen with normal appearance and orientation runs alongbottom of figure. C, After 10 months of therapy, findings are similar to those after 4 months;anchoring fibrils are easily seen (arrows). (A, B, and C, X46,OOO.)

ing an overly favorable view of tretinoin activity.However, many of our patients had severe enoughphotodamage that the effects of extended tretinointherapy could be documented by photography (Fig.3) and show that our results cannot be due to eval­uator bias alone. In addition, the microscopic andultrastructural findings from coded specimens con­firmed that retinoid-induced effects occurred in theskin. Such effects, which occurred in our study andalso occur with oral retinoid therapy, include prolif­eration of epidermal cells," thickened granular celllayer.? presence of a mucoid substance in theepidermis's 10-12 that may be hyaluronate synthe­sized by keratinocytes, 13 and normalization of basallayer tonofilaments, 14, IS

With regard to the introduction of a bias by pa­tient attrition, we were concerned that only the re­sponsivepatients may have remained in the study forits full duration whereas those with more modest re­sults left, thereby imparting a positive bias to our re-

sults, However, a comparison ofthe overall responseof the 16 patients who remained versus the 14 whodeparted early revealed that both groups respondedequally well to tretinoin.

As indicated in Figs. 1 and 2 and Table II, mostclinical changes induced by tretinoin therapy wereachieved by the sixth to tenth month of treatment.Certain aspects of this study may have influencedthe time at which most of the benefit was recognized,including the discrete ordinal scales we used, and thereduction in both tretinoin concentration and fre­quency of application that most of our patients em­ployed. Although the study was not designed to de­termine a precise maintenance regimen, our dataindicate that the lower 0.05% concentration oralternate-day applications of tretinoin are effectivein sustaining the improvements in photoaged skingenerated by daily application of tretinoin 0.1%cream.

The increased pinkness of the skin that develops

Volume 23Number 4, Part IOctober 1990

during tretinoin application (Figs. I and 2) generallyenhances appearance. Pinkness of the skin is causedby oral retinoid therapy as wel116 and thus cannot bedue solely to a putative contact irritation induced bytretinoin. Indeed, evidence of inflammation waslacking in biopsy specimens even of pink skin.

The only problems encountered by our patientswere dryness of the skin and a so-called dermatitischaracterized by erythema and flaking of the stra­tum corneum. These reactions occur in response tooral or topical retinoid therapy'< 17and do not rep­resent an allergic contact or irritant dermatitis. 18Asin our original work, we carefully avoided areas ofretinoid reaction when patients' skin was evaluatedor subjected to biopsy. As therapy proceeded in theopen-label phases, the incidence and degree of thereaction declined and in most patients disappeared;however, clinical benefit was maintained. The dis­cordant time courses suggest that desirable retinoidactivity, not side effects,'? yields improvement ofphotoaged skin.

The reduction in the cutaneous side effects thatoccur with continued use of tretinoin may be relatedto changes in the stratum corneum. Although thecharacter of this layer was altered early in therapy,later it reverted toward normal in most patients. Thecause of this tachyphylactic response to tretinoin inthe stratum corneum, despite the increase in epider­mal thickness that remained constant throughoutthe study, is unknown. However, the return of thestratum corneum to a woven pattern may result ina more physiologic skin barrier; if so, diminishedpeeling and dryness and normal corneal resistance toultraviolet irradiation and transepidermal water losscould result.

As yet we have no formally gathered data regard­ing the prolongation of the effects of tretinoin aftertherapy has been stopped. However, our limitedclinical experience suggests that improvement per­sists for at least 2 months after therapy, followed bya gradual, partial regression. These findings do notsupport the concept that edema contributes to theimproved appearance of our patients' skin 19 becauseedema would be expected to subside within a fewdays after treatment is stopped.

Our patients' skin had undergone both chrono­logie aging and photodamage before therapy. Be­cause these conditions cannot be easily separated, wedo not yet know whether tretinoin therapy improvesboth of them. Nevertheless, our histologic andultrastructural findings indicate that tretinoin ther­apy causes more than esthetic improvement; it alsoinduces anatomic changes in the epidermis and

Prolonged tretinoin for photoaging 637

papillary dermis, in all likelihood without regard towhether the skin has been changed by time or sun.

REFERENCES

1. Weiss JS, Ellis C~, Headington JT, et al. Topical tretinoinimprovesphotoagcd skin. A double-blind vehicle-controlledstudy. JAMA 1988;259:527-32,

2. Zelickson AS, Mottaz JH, Weiss JS, et al. Topical tretin­oin in photoaging: an ultrastructural study. J Cutan AgingCosmet DermatoI1989;1:41-7.

3. Woodley DT, Zelickson AS, Briggaman RA, et al. Treat­ment of photoaged skin with topical tretinoin increases epi­dermal-dermal anchoring fibrils: a preliminary report.JAMA (In press.)

4. Ellis CN, Gold RC, Grekin RC, et al. Etretinate therapystimulates deposition ofmucus-like material in epidermis ofpatients with psoriasis. J AM ACAD DERMATOL 1982;6:699-704. .

5. Cordero A Jr. La vitamina A acida en la piel senil. Actu­alizaciones Terapeuticas Dermatol6gicas 1983;6:49-54.

6. Kligman AM, Grove GL, Hirose R, et al. Topical tretinoinfor photoaged skin. J AM ACAD DERMATOL 1986;15:836­59.

7. Leyden 11, Grove GL, Grove MJ, et al. Treatment of pho­todamaged facial skin with topical tretinoin. J AM ACADDERMATOL 1989;21:638-44.

8. Gillenberg A, Immel C, Orfanos CEo Retinoid-EiflufJ aufdie Zellkinetik gesunder menschlicher Epidermis. ArchDermatol Res 1980;269:331-5.

9. Jablonska S, Wolska H, Dabrowski J, et al. Aromaticretinoids in psoriasis: clinical, histological, histochemical,electron microscopical and immunological investigations.In: Orfanos CE, Braun-Falco 0, Farber EM, et aI., eds.Retinoids: advances in basic research and therapy. Berlin:Springer-Verlag, 1981:165-73.

10. Orfanos CE, Runne U. Tissue changes in psoriatic plaquesafter oral administration of retinoid. Dermatologica 1978;157(suppll):19-25.

11. Kanerva LO, Johansson E, Niemi K-M, et al. Epiderrno­dysplasia verruciformis. Clinical and light- and electron­microscopic observations during etretinate therapy. ArchDermatol Res 1985;278:153-60.

12. Elias PM. Epidermal effects of retinoids: supramolecularobservations and clinical implications. J AM ACAD DER­MATOL 1986;15:797-809.

13. Tammi R, Ripellino JA, Margolis RU, eta!. Hyaluronateaccumulation in human epidermis treated with tretinoin inskin organ culture. J Invest Dermatol 1989;92:326-32.

14. Lauharanta J, Niemi K-M, Lassus A. Treatment ofDarier's disease with an oral aromatic retinoid (Ro 10­9359): a clinical and light and electron microscopic study.Arch Derm Venereol (Stockh) 1981;61:535-42.

15. Schultz-Ehrenburg U, Orfanos CEoLight and electron mi­croscopicchanges of human epidermis under oral retinoidtreatment. In: Orfanos CE, Braun-Falco 0, Farber EM, etal., eds. Retinoids: advances in basic research and therapy.Berlin: Springer-Verlag, 1981:85-92.

16. Ellis CN, Voorhees JJ. Etretinate therapy. J AM ACADDERMATOL 1987;16:267-91.

17. Silverman AK, Ellis CN, Voorhees JJ. HypervitaminosisA syndrome: a paradigm of retinoid side effects. J AMACAD DERMATOL 1987;16:1027-39.

18. Esmann J, Griffiths CEM, Talwar HS, et al. Biochemicaland immunological characterization of the "retinoid reac­tion" in normal human skin [Abstract]. Clin Res 1989;37:349A.

19. Ellis CN, Weiss JS, Hamilton TA, et al. Topical retinoicacid for photoaged skin: in reply. JAMA 1988;259:3271-4.