a supplement to skin & allergy news · be known as “comedone busters.” kligman’s study...

Produced in affiliation with the 29th Annual Hawaii Dermatology Seminar

Maximizing Results in the Treatment ofAcne and Improving Facial Appearance

FACULTY

Lawrence J. Green, MDGeorge Washington University School of Medicine

Washington, D.C.

Emil A. Tanghetti, MDUniversity of California, DavisMedical DirectorCenter for Dermatology and Laser Surgery

Sacramento, Calif.

Diane Thiboutot, MDPennsylvania State University College of Medicine

Hershey, Pa.

Jeanine B. Downie, MD, FAADimage Dermatology P.C.Montclair, N.J.

Evidence-Based Results With Topical Retinoids for Acne

The Use of Topical Retinoids With Combination Therapies in the Management of Acne Vulgaris

How to Optimize Topical Retinoid/Oral Antibiotic Therapy in Acne

State-of-the-Art Therapies for Aging and Photoaging of the Skin

Skin & Allergy News®

A SUPPLEMENT TO

President, Elsevier/IMNGAlan J. Imhoff

Vice President,Medical Education & Business DevelopmentSylvia H. Reitman, MBA

Program Manager, Medical EducationSara M. Hagan

Clinical EditorGill Shears, PhD

National Account ManagerCheryl J. Gromann

Graphic DesignLehner & Whyte, Inc.

Production ManagerJudi Sheffer


The articles in this supplement are based onfaculty presentations. This supplement is pro-duced in affiliation with the Skin DiseaseEducation Foundation’s 29th Annual HawaiiDermatol-ogy Seminar, a continuing medicaleducation program held March 18-24, 2005, inMaui, Hawaii.

This educational supplement to SKIN &ALLERGY NEWS, designated by the AmericanAcademy of Dermatology (AAD) for AADCME credit, was supported by an unrestrictededucational grant from

It was produced by the medical educationdepartment of International Medical NewsGroup. Neither the Editor of SKIN & ALLERGYNEWS, the Editorial Advisory Board, nor thereporting staff reviewed or contributed to itscontent. The opinions expressed in this sup-plement are those of the faculty and do notnecessarily reflect the views of the supporteror of the Publisher.Copyright © 2005 Elsevier Inc. All rightsreserved. No part of this publication may bereproduced or transmitted in any form, by anymeans, without prior written permission ofthe Publisher. Elsevier Inc. will not assumeresponsibility for damages, loss, or claims ofany kind arising from or related to the infor-mation contained in this publication, includingany claims related to the products, drugs, orservices mentioned herein.

FACULTYLawrence J. Green, MDAssistant Clinical Professor of Dermatology

George Washington University School of Medicine

Washington, D.C.

Emil A. Tanghetti, MDClinical Professor DermatologyDepartment of DermatologyUniversity of California, DavisMedical DirectorCenter for Dermatology and Laser Surgery

Sacramento, Calif.

Maximizing Results in the Treatment

Evidence-Based Results With Topical Retinoids for Acne 4

The Use of Topical Retinoids WithCombination Therapies in theManagement of Acne Vulgaris 4

How to Optimize Topical Retinoid/Oral Antibiotic Therapy in Acne 6

State-of-the-Art Therapies for Aging and Photoaging of the Skin 8

CME Post-test and Evaluation 10

Diane Thiboutot, MDProfessor of DermatologyDepartment of DermatologyPennsylvania State University College of Medicine

Hershey, Pa.

Jeanine B. Downie, MD, FAADPresidentimage Dermatology P.C.Montclair, N.J.

4

6

8

11

15

CME RECOGNITIONThis SKIN & ALLERGY NEWS supplement is recog-

nized by the American Academy of Dermatology

for 1 hour of AAD Category 1 CME credit and

may be used toward the American Academy

of Dermatology’s Continuing Medical Education

Award.

This program was developed in accordance with the

Accreditation Council for Continuing Medical

Education guidelines.

Term of approval: September 2005-August 31, 2006

Estimated time to complete this educational activity:

1 hour.

TARGET AUDIENCEThis activity has been developed for dermatol-

ogists and other healthcare professionals involved in

the treatment of facial acne vulgaris or in facial

aesthetics.

EDUCATIONAL NEEDSMaximizing Results in the Treatment of Acne and

Improving Facial Appearance is a continuing medical

education activity for dermatologists. The goals of

this supplement are twofold. One goal is to update

dermatologists on the use of topical retinoids, both

as monotherapy and in combination therapy, in the

treatment of facial acne vulgaris.The other goal is to

discuss the beneficial effects of antioxidant and

topical retinoid therapy in reducing the effects of

skin aging.

LEARNING OBJECTIVESAfter reading this supplement, participants should

be able to:

• Compare and contrast the efficacy and tolerability

of different topical retinoids used in the treatment

of acne vulgaris.

• Evaluate the benefits of using an antibiotic and/or

benzoyl peroxide adjunctively with a topical

retinoid in the treatment of acne vulgaris.

• Describe how to optimize the use of topical

retinoid and oral antibiotic therapy in acne vul-

garis.

• Discuss how the effects of skin aging can be

reduced using state-of-the-art antioxidant and top-

ical retinoid products.

FACULTY AND UNAPPROVED USE DISCLOSURESFaculty/authors must disclose any significant finan-

cial interest or relationship with proprietary entities

that may have a direct relationship to the subject

matter. They must also disclose any discussion of

investigational or unlabeled uses of products.

Dr Downie is a consultant to and owns stock in

Allergan, Inc. She discusses the unlabeled use of

Retin A for photodamage. Dr Green is a consultant

to Allergan. Dr Tanghetti has received funding for

clinical grants and is a consultant to Allergan and

Stiefel Laboratories, Inc. Dr Thiboutot has served as

an investigator in clinical trials sponsored by and is

on the Advisory Board at Allergan, Galderma S.A.,

and OrthoNeutrogena.

of Acne and Improving Facial Appearance

Maximizing Results in the Treatment of Acne and Improving Facial Appearance 3

4 Maximizing Results in the Treatment of Acne and Improving Facial Appearance

Evidence-Based Results With Topical Retinoids for Acne Lawrence J. Green, MD

The Evolution of Topical Retinoid Therapy

The potential usefulness ofretinoids for treating acne was rec-ognized more than 50 years ago.1 Asearly as the 1940s, oral vitamin Awas reported to improve acne,1 and,in the 1960s, Kligman et al reportedthe results of a clinical trial showingthat topical vitamin A acid(tretinoin) was effective in reducingthe overall lesion count and come-dones in particular.2 This landmarkstudy heralded the beginning of anera where topical retinoids came tobe known as “comedone busters.”Kligman’s study compared tretinoin(0.1% in an alcohol-based formula-tion) with other treatment optionsavailable at the time in patientswhose acne consisted predominantlyof comedonal lesions. The results ofthe study demonstrated that thistretinoin formulation achieved agreater reduction in overall lesioncount than either 5% benzoyl per-oxide or 5% sulphur/3% resorcinollotion (two topical treatments often

used at that time). Thus, this formu-lation of tretinoin was shown notonly to be efficacious but also tooffer superior efficacy against othertreatment options.

In the 1970s, tretinoin (once-daily0.05% cream) was shown to be efficacious against inflammatorylesions as well as comedones, and itbecame apparent that the clinicalutility of tretinoin was not limited tothe treatment of comedonal acne.3

More than 15 years later, in the late1990s, two novel topical retinoids—tazarotene and adapalene—were

“Tazarotene cream isbetter tolerated than is

tazarotene gel, adapalenegel is better tolerated than

is adapalene cream, andtretinoin microsponge isbetter tolerated than is

tretinoin cream.”

Figure 1. Reduction in comedone count after 12 weeks of topical retinoid therapy (all data from multicenter, double-blind,randomized, parallel-group trials).4-7

Figure 2. Reduction in inflammatory lesion count after 12 weeks of topical retinoid therapy (all data from multicenter,double-blind, randomized, parallel-group trials).4-7

approved by the US Food and DrugAdministration for the treatment ofacne. The receptor selectivity ofthese retinoids was hypothesized tohelp enhance tolerability relative totretinoin (which is not as receptorselective). A new microsponge for-mulation of tretinoin was also introduced in an attempt to mini-mize tolerability issues withtretinoin. The introduction of twonew retinoids and several new for-mulations widened the treatmentoptions available and necessitatedcomparative evaluations of efficacyand tolerability.

Efficacy comparisonsThe results from a series of

12-week multicenter, double-blind,randomized, parallel-group trialsinvolving more than 600 patients intotal have shown that tazaroteneoffers superior efficacy to that ofother retinoids regardless of whichformulation is used.Thus, tazarotene0.1% gel has been shown to offersuperior efficacy to that of adapa-

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Creams

P >–0.001

Gels

Change incomedonecount frombaseline

(%)

Taz 0.1%

Adap 0.1%

P >–0.001

Taz 0.1%

Adap 0.1%

P >–0.05

Taz 0.1%

Tret 0.025%

P >–0.05

Taz 0.1%

Tret micro 0.1%

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Creams Gels

Change ininflammatory

lesioncount frombaseline

(%)

Taz 0.1%

Adap 0.1%

P >–0.001

Taz 0.1%

Adap 0.1%

Taz 0.1%

Tret 0.025%

Taz 0.1%

Tret micro 0.1%

Taz=tazarotene; Adap=adapalene; Tret=tretinoin; Micro=microsponge Taz=tazarotene; Adap=adapalene; Tret=tretinoin;Micro=microsponge

lene 0.1% gel, tretinoin 0.025% gel, and tretinoin 0.1% microspongegel (Figures 1 and 2).4-6 Similarly,tazarotene 0.1% cream has beenshown to offer superior efficacy toadapalene 0.1% cream (Figure 1).7

Alternate-day applications oftazarotene 0.1% gel have also beenshown to be as effective as once-daily applications of adapalene0.1% gel.8 Furthermore, both alter-nate-day and once-daily applicationsof tazarotene 0.1% gel have been

demonstrated to be more cost-effec-tive treatment options than is once-daily adapalene 0.1% gel.4,9

Tolerability ComparisonsThe results of split-face studies

have demonstrated that tolerabilitymay be influenced by the concentra-tion of the retinoid, the sensitivity ofthe patient’s skin, the vehicle used inthe formulation, and the choice ofretinoid.10 As might be expected, tol-erability is optimal with lower-rather than higher-concentration formulations and in patients withnormal skin rather than sensitiveskin.The vehicle with the best toler-ability depends on which retinoid isbeing evaluated—tazarotene creamis better tolerated than is tazarotenegel, adapalene gel is better toleratedthan is adapalene cream, andtretinoin microsponge gel is bettertolerated than is tretinoin cream.

When retinoid creams were com-pared, the overall levels of erythemaand dryness were lower withtazarotene 0.1% cream than withadapalene 0.1% cream or tretinoin0.1% cream both on normal and onsensitive skin (Figures 3 and 4).10

These differences reached statisticalsignificance versus tretinoin 0.1%cream for both erythema (Figure 3)and dryness on normal skin and fordryness (but not erythema) on sensi-tive skin.

When retinoid gels were com-pared, the overall levels of erythemaand dryness were lower with adapa-lene 0.1% gel than with tazarotene0.1% gel or tretinoin 0.1% micro-sponge gel on both normal and sen-sitive skin.These differences reachedstatistical significance versustazarotene 0.1% gel for erythemaand dryness only on normal skin.

Future Trends in Topical Retinoid Therapy

Although the efficacy of topicalretinoid therapy in both inflam-matory and comedonal acne wasevident in the early years, initially itwas used primarily for comedonalacne and was often overlooked forinflammatory acne. Today, it is


“Tazarotene offers superior

efficacy to that of

other retinoids.”

Figure 3. Erythema with retinoid creams on normal skin. Area-under-the-curve analysesshowed that, overall, tazarotene cream was associated with the lowest levels of erythe-ma (and significantly lower levels than tretinoin cream, P >–0.01).10

Figure 4. Erythema with retinoid creams on sensitive skin. Area-under-the-curve analy-ses showed that tazarotene cream was associated with the lowest levels of erythemaalthough there were no significant between-group differences.10

Adapted with permission from the Journal of Drugs in Dermatology.


continued on Page 14

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Meanerythema

score

| | | | | | | | | | | | | | | | | | | | | | | | | | | | | |

Baseline 7 14 21 29

Days

Marked

Moderate

Slight

None

–– Tazarotene 0.1% cream (n=66)

–– Adapalene 0.1% cream (n=26)

–– Tretinoin 0.1% cream (n=26)

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4 ____________________________________________________________________

2 ____________________________________________________________________

0 ____________________________________________________________________

Meanerythema

score

| | | | | | | | | | | | | | | | | | | | | | | | | | | | | |

Baseline 7 14 21 29

Days

Marked

Moderate

Slight

None

–– Tazarotene 0.1% cream (n=19)

–– Adapalene 0.1% cream (n=20)

–– Tretinoin 0.1% cream (n=20)

The Use of Topical RetinoidsWith Combination Therapies in theManagement of Acne Vulgaris Emil A. Tanghetti, MD

Topical retinoids are highly effec-tive against both comedonal andinflammatory acne. They helpresolve comedonal acne by promot-ing normalization of follicularepithelial desquamation, whichencourages comedonal drainage andhelps prevent the development ofnew comedones. The efficacy of topical retinoids against inflammato-ry acne may be partly a conse-quence of this comedonal drainage(which helps create a less favorablefollicular microenvironment for Pro-pionibacterium acnes) and partly a consequence of inhibiting theexpression of toll-like receptors onmonocytes and macrophages (whichresults in reduced expression ofproinflammatory cytokines).1

Enhancing the Efficacy of Topical Retinoids

Although topical retinoids arehighly effective, it is conceivable thattheir efficacy could be enhanced stillfurther through the adjunctive useof other antiacne agents with com-plementary mechanisms of action(eg, antibiotics and benzoyl perox-ide, which also reduce the prolifera-tion of P. acnes). Although the primary mechanism of action ofantibiotic/benzoyl peroxide prod-ucts is antibacterial, this antibacteri-al action also reduces the release of comedogenic and inflammatoryproducts from P. acnes—which, inturn, lowers the potential for thedevelopment of comedones andinflammatory lesions. Benzoyl per-oxide, in particular, has been report-ed to have comedolytic activity,2-4

and clindamycin/benzoyl peroxidehas been shown to result in signifi-

cantly greater reductions in come-donal lesions (as well as inflammato-ry lesions) than has clindamycinalone.5

Adjunctive Use of anAntibiotic/Benzoyl PeroxideProduct With a Topical Retinoid

There are few studies in the litera-ture describing combination therapywith a retinoid and an antibiotic/benzoyl peroxide. One community-based study involving 440 patientswith mild to moderate acne vulgarisreported that the adjunctive use oferythromycin/benzoyl peroxide sig-

nificantly increased the reduction ininflammatory lesion count achiev-able with tazarotene 0.1% gel butdid not increase the reduction incomedone count.6 The adjunctiveuse of benzoyl peroxide alone orclindamycin alone did not enhancethe efficacy of tazarotene againsteither type of acne. Although thedata on inflammatory lesions fromthis trial should be reliable, it is pos-sible that the accuracy of the come-done counts could have been com-promised by the community settingof this trial—comedones are harderto count accurately than are inflam-matory lesions, and many of themore than 40 investigators involvedwere not routinely involved inassessing comedone counts in aresearch setting.

Recently, the results of anothertrial have demonstrated that theadjunctive use of clindamycin1%/benzoyl peroxide 5% gel (aready-to-dispense formulation con-taining two emollients) can signifi-cantly (P<–0.01) increase the reduc-

“Adjunctive use ofclindamycin/benzoyl

peroxide can significantlyincrease the reduction in

both inflammatory lesionsand comedones achievable

with tazarotene.”

Figure 1. Improvement in acne with tazarotene monotherapy.

Baseline Week 8 Week 12Photographs courtesy of Alan Shalita, MD.


tion in both inflammatory lesionsand comedones achievable withtazarotene 0.1% cream (Figures 1and 2).7 In this trial of 121 patientswith moderate to severe facial acne,once-daily applications of tazaro-tene (in the evening) plus clin-damycin/benzoyl peroxide (in themorning) resulted in significantlygreater anticomedonal efficacy—aswell as faster efficacy—than didtazarotene alone. The reduction incomedones was significantly greaterwith tazarotene plus clindamycin/benzoyl peroxide than withtazarotene alone as early as week 4,and the significant between-groupdifference continued through theend of the study. At week 12, thereduction in comedones was a meanof 60% with tazarotene alone and70% with tazarotene plus clin-damycin/benzoyl peroxide (Figure 3,P<–0.01).7 Furthermore, tolerabilitywas at least as good with the combi-nation therapy as with tazarotenealone (the incidences of peeling and dryness were both lower withcombination therapy than withmonotherapy, although statisticalsignificance was not achieved). Thispossible improvement in tolerabilitymay be due to the clindamycin/ben-zoyl peroxide specifically, or it maybe related to the emollient vehicle inwhich the product used in the studywas formulated. (The formulation

used contains the emollients glyc-erin and dimethicone.)

Although perhaps unexpected,possible improvements in tolerabili-ty have been reported previouslywhen topical retinoids are used incombination therapy rather than asmonotherapy. In the study with ery-thromycin/benzoyl peroxide men-tioned above, the incidences of peel-ing and dryness were not specifical-ly reported, but the incidence of dis-continuations due to adverse eventswas lower with tazarotene plus ery-thromycin/benzoyl peroxide thanwith tazarotene alone (6% vs 11%,respectively).6 The incidence of dis-continuations due to adverse events

was also lower with other combina-tions (tazarotene plus clindamycin[5%] or tazarotene plus benzoylperoxide [7%]) than with tazarotenealone. Less irritation has also beenreported when tretinoin is used inconjunction with benzoyl peroxidethan when used alone.8

SummaryA topical retinoid plus adjunctive

use of an antibiotic/benzoyl perox-ide product can be appropriate first-line therapy for both comedonal andinflammatory acne. Such therapytargets three of the four factorsknown to be involved in the patho-genesis of acne—abnormal desqua-mation of the follicular epithelium,inflammation, and proliferation of P. acnes—and therefore should offerexcellent efficacy. Furthermore, per-haps a little unexpectedly, tolerabili-ty may also be enhanced by combi-nation therapy. The results of thestudy with tazarotene and clin-damycin/benzoyl peroxide providefurther supportive evidence for the

Figure 3. Reduction in comedone count with tazarotene or tazarotene plus clindamycin/benzoyl peroxide.7

continued on Page 14

Figure 2. Improvement in acne with tazarotene plus clindamycin/benzoyl peroxide.

Baseline Week 8 Week 12Photographs courtesy of Alan Shalita, MD.


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Medianchange in comedo

count (%)

0 4 8 12| | |

Week

–– Tazarotene 0.1% cream

–– Tazarotene 0.1% cream + clindamycin 1%/benzoyl peroxide 5% gel

-18%

-44%

-60%

-34%

*

-64%

†

*-70%

*P<–0.01; †P<–0.001 vs tazarotene alone.


“Tolerability may also be enhanced

by combination therapy.”

Topical retinoids are the mainstayof therapy for both inflammatoryand noninflammatory acne as theyhelp prevent the development ofmicrocomedones—the precursors of all other acne lesions. Their abili-ty to help normalize folliculardesquamation promotes comedolyt-ic activity and prevents follicularblockage. Recent research also sug-gests that topical retinoids havedirect immunomodulatory effectsthat may contribute to their activityagainst inflammatory lesions—forexample, stimulation of interleukin-5 release and inhibition of interfer-on-� release by superantigen-stimu-lated human peripheral bloodmononuclear cells1 and inhibition ofthe expression of toll-like receptor 2.2

Primary TherapyRecently published consensus rec-

ommendations on the managementof acne advocate the use of topicalretinoids as primary therapy in mostforms of acne, with adjunctiveantimicrobial therapy when inflam-matory acne lesions are present(Table 1).3 As topical retinoids andantimicrobials have different mecha-nisms of action, this provides agreater range of pathophysiologictargets than would be feasible witheither as monotherapy. It is knownthat topical retinoid plus oral anti-biotic therapy results in greater,and more rapid, reductions inPropionibacterium acnes counts andfree fatty acid levels than does eitheragent alone.4 As a result, such com-bination therapy is highly valuablein optimizing efficacy and the speedof clinical improvement. It may bethat the retinoid indirectly augments

the efficacy of the antibiotic as aresult of increasing vascular perme-ability, resulting in enhanced deliv-ery of the antibiotic to the inter-stitial fluid compartment of the dermis.4 The retinoid-induced in-crease in cell turnover of the follicular epithelium may also facili-tate greater transport of the antibiot-ic into the follicular canal.

Maintenance TherapyAlthough the advantages of using

oral antibiotics in early treatmentare evident, the prolonged use oforal antibiotics is undesirable forseveral reasons. First, many patientsprefer to minimize their exposure to

How to Optimize Topical Retinoid/OralAntibiotic Therapy in Acne Diane Thiboutot, MD

> Topical retinoids should be the primary treatment for most forms of acne vulgaris

> Use early (at the onset of therapy) for greatest and fastest results

> Combine with antimicrobial therapy when inflammatory lesions are present

> Clearing of both inflammatory lesions and comedones is faster and significantlygreater with combination therapy than with antibiotic therapy alone

> The antibiotic should be discontinued when inflammatory lesions resolve adequately

> Topical retinoids are an essential part of maintenance therapy

> Continue use of the topical retinoid to maintain remission when antibiotic therapy is discontinued

“Maintenance strategies for acne should

aim to minimize the long-term use of

antibiotics.”

oral medications in general and oralantibiotics in particular. Second,recent research raised concern whenit was suggested that long-termexposure to antibiotics may be asso-ciated with an increased risk ofbreast cancer.5 Third, the resistanceof P. acnes to antibiotics is a growingproblem (the overall incidence ofsuch resistance increased from 20%to 62% between 1978 and 1996),6

and the potential transfer of antibi-otic resistance to other bacteriaagainst which these drugs are used isa major concern. Resistant P. acnesare widely distributed not only onacne-prone skin but also in thenares.7 Because of this, it is likelythat these bacteria (and particularlythose in the nasal reservoir) are hardto eradicate with existing therapeu-tic regimens, and so our attentionmust be focused on prevention. Tohelp minimize the development of P. acnes resistance, the consensusgroup of experts has recommendedthat maintenance strategies for acne

Table 1. Key consensus recommendations for the management of acne.3


should aim to minimize the long-term use of antibiotics.3

Topical retinoids are the treatmentof choice for maintenance therapybecause of their ability to preventthe development of microcome-dones,8 and it is possible that topicalretinoid therapy alone may providesufficient efficacy for maintenancetherapy. To evaluate the clinicalpotential of such treatment, a studyhas been performed to compare theefficacy of three maintenance thera-pies (tazarotene alone, minocyclinealone, and tazarotene plus minocy-cline) in sustaining the clinicalimprovement attained after initialtazarotene plus minocycline therapy.In this study of 189 patients withmoderate to severe inflammatoryacne, all patients were initially treat-ed for 12 weeks with once-dailytazarotene 0.1% gel plus twice-dailyminocycline 100-mg capsules.9 Pa-tients who had achieved at least a75% global improvement at week12 were eligible to enter the double-blind, randomized, maintenancephase, in which they were assignedtreatment with tazarotene alone,minocycline alone, or tazaroteneplus minocycline for an additional12 weeks. The results of the studyshow that all three regimens werehighly effective maintenance thera-pies. There were no significantbetween-group differences in overalldisease severity at any timepointduring the maintenance phase(Figure 1) and between 80% and90% of patients in each group sus-tained at least 50% global improve-ment from baseline through the endof the 12-week maintenance phase.9

Figure 2 shows the excellent mainte-nance of clinical improvement that

“…an important option toconsider in patients who

might otherwise beprescribed oralisotretinoin.”

Figure 2A. Improvement in acne with tazarotene plus minocycline therapy (from baseline to week 12) and sustained improvement with tazarotene monotherapymaintenance therapy (from week 12 to week 24).9

Figure 1. Mean overall disease severity score.9

Baseline Week 12 Week 24Tazarotene + minocycline Tazarotene monotherapy

for weeks 12-24

Figure 2B. Improvement in acne with tazarotene plus minocycline therapy (from baseline to week 12) and sustained improvement with tazarotene monotherapymaintenance therapy (from week 12 to week 24).

Baseline Week 12 Week 24Tazarotene + minocycline Tazarotene monotherapy

for weeks 12-24

Meanoveralldiseaseseverity

score

–– Tazarotene –– Minocycline –– Tazarotene + minocycline

No signficant between-group differences in maintenance phase

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0 4 8 12 16 20 24

Severe

Moderate

Mild

None

Week

Treatment phase Maintenance phase


Photographs courtesy of James Leyden, MD.

Photographs courtesy of Alan Shalita, MD.

can be achieved with tazarotenemonotherapy.9

The results of this study suggestthat, after good clinical improve-ment in acne has been attained withinitial tazarotene plus minocyclinetherapy, tazarotene alone offers suf-ficient efficacy for ongoing mainte-nance therapy. (In everyday clinicalpractice, a gradual tapering of theantibiotic would likely offer thesmoothest transition between initialand maintenance treatments.)Clinically, the results have twoimportant implications. First, byhelping avoid long-term exposure toantibiotics, the use of tazarotenemonotherapy as maintenance thera-py should help minimize the de-velopment of antibiotic-resistant P. acnes. Second, the high degree ofefficacy demonstrated against mod-erate to severe inflammatory acne inboth the initial and the maintenancephases suggests that the approachdescribed here is an importantoption to consider in patients whomight otherwise be prescribed oralisotretinoin.

References1.Wauben-Penris PJ, Cerneus DP, van den

Hoven WE, et al. Immunomodulatoryeffects of tretinoin in combinationwith clindamycin. J Eur AcadDermatol Venereol. 1998;11 (suppl1):S2-S7; discussion S28-S29.

2.Vega B. Toll-like receptor-2: a novelmechanism of action of adapalene inthe treatment of inflammatory acnelesions. Poster #84 presented at: 61stAnnual Meeting of the AmericanAcademy of Dermatology; March 21-26, 2003; San Francisco, Calif.

3. Gollnick H, Cunliffe W, Berson D, etal. Management of acne: A reportfrom a Global Alliance to ImproveOutcomes in Acne. J Am AcadDermatol. 2003;49(1 suppl):S1-S37.

4. Kligman AM, Mills OH, McGinley KJ,Leyden JJ. Acne therapy withtretinoin in combination with antibi-otics. Acta Derm Venereol Suppl(Stockh). 1975;74:111-115.

5.Velicer CM, Heckbert SR, Lampe JW,Potter JD, Robertson CA, Taplin SH.Antibiotic use in relation to the risk ofbreast cancer. JAMA. 2004;291:827-835.

6. Cooper AJ. Systematic review ofPropionibacterium acnes resistance tosystemic antibiotics. Med J Aust.1998;169:259-261.

7. Coates P,Vyakrnam S, Eady EA, JonesCE, Cove JH, Cunliffe WJ. Prevalenceof antibiotic-resistant propionibacte-ria on the skin of acne patients: 10-year surveillance data and snapshotdistribution study. Br J Dermatol.2002;146:840-848.

8. Dréno B, Bettoli V, Ochsendorf F,Layton A, Mobacken H, Degreef H.European recommendations on theuse of oral antibiotics for acne. Eur JDermatol. 2004;14:391-399.

9. Leyden J,Thiboutot D, Shalita A, et al.Comparison of tazarotene andminocycline maintenance therapies inacne vulgaris. Poster presented at:63rd Annual Meeting of the AmericanAcademy of Dermatology; February18-22, 2005; New Orleans, La.


“Topical retinoids are thetreatment of choice formaintenance therapy.”

State-of-the-Art Therapies for Aging and Photoaging of the Skin Jeanine B. Downie, MD, FAAD

Skin aging can occur as a result ofboth genetics and environmentalfactors. Free radicals are thought toplay a role in the aging process, andtheir production in their body canbe accelerated by many factors,including exposure to the sun, ciga-rette smoke, and stress. To minimizeaging of the skin, it is important toprotect it from these stressors. Interms of skin care regimens, thismeans that the use of sunscreensand topical antioxidants is essential.A range of effective sunscreens havebeen available for many years, butresearch in the field of antioxidantsis still progressing rapidly.

The need for a standardizedmethod to compare various effectsof antioxidants

Although antioxidants havedemonstrated antioxidative andphotoprotective properties in vari-ous in vitro and in vivo studies, astandardized method to characterizeand compare the complex propertiesand effects of different topicalantioxidants has been lacking. Thetopical antioxidants that are current-ly most popular are very heteroge-neous in structure and origin, and astandardized protocol to comparethem therefore needs to consist of avariety of evaluations to gain thebroadest possible perspective ontheir effects. A protocol has beendeveloped whereby the results offive in vitro or in vivo evaluationsare combined to give an overallscore reflecting the capacity of anantioxidant to protect against oxida-tive stress.1 The five evaluationsassess the following: human sunburncell count after ultraviolet (UV)radiation, free radical scavenging

activity, primary products of lipidoxidation, secondary products oflipid oxidation, and byproducts ofUV radiation in nuclei of humankeratinocytes. The overall scoreobtained from the results of theseevaluations is termed the Environ-mental Protection Factor—in linewith the terminology for SunProtection Factor and ImmuneProtection Factor.2

Comparing Idebenone With OtherTopical Antioxidants

Recent research indicates thatidebenone is a particularly potentand effective antioxidant. It is a syn-thetic analog of naturally occurringcoenzyme Q10 but has a consider-ably lower molecular weight (338versus 863), which may helpenhance its penetration into the skinafter topical application. In addition,unlike coenzyme Q10, idebenoneprotects against free radical for-mation and cell damage in condi-tions of hypoxic (low oxygen) cellu-lar stress.3

Idebenone is relatively new todermatology, and the standardizedprotocol just described has enabledit to be compared objectively withother popular topical antioxidants,

including L-ascorbic acid, DL-�tocopherol, kinetin, DL-� lipoicacid, and ubiquinone.

The results of the human sunburncell assay showed that, among theseantioxidants, idebenone had thegreatest ability to reduce the devel-opment of sunburn cells after expo-sure to UV radiation—it resulted ina 38% lower sunburn cell countthan in skin not treated with anantioxidant, compared with 30%,20%, 11%, 9%, and 0% with toco-pherol, kinetin, ubiquinone, lipoicacid, and ascorbic acid, respectively.1

In terms of free radical scavengingactivity, idebenone, ascorbic acid,and tocopherol showed the greatestactivity (a concentration of 10nmol/L was required for an antioxi-dant effect compared with 100nmol/L with ubiquinone and >–1000nmol/L with kinetin and lipoic acid).

The greatest protection againstlipid oxidation products was provid-ed by kinetin and idebenone for pri-mary oxidation products (lipidhydroperoxides reduced by 80% to100% compared with 15% to 50%with the other antioxidants) and bylipoic acid and idebenone for sec-ondary oxidation products (malon-dialdehyde equivalents reduced by52% to 55% compared with 24% to47% with the other antioxidants).Finally, the greatest inhibition ofphotoproduct generation in thenuclei of human keratinocytes wasprovided by idebenone (45%), fol-lowed by ascorbic acid and kinetin(36%), tocopherol (34%), ubiqui-none (4%), and lipoic acid (0%).

Calculation of the EnvironmentalProtection Factor showed thatidebenone had the greatest antioxi-

“A standardized method to characterize

and compare the complexproperties and effects of

different topicalantioxidants has been lacking.”


dant activity overall, followed bytocopherol, kinetin, ubiquinone,ascorbic acid, and lipoic acid (Table 1).

Clinical Evaluation of IdebenoneA clinical evaluation of 1%

idebenone in 21 female subjectswith moderate photoaging showedthat it also offers efficacy in reducingdyspigmentation and wrinkling.3After twice-daily facial applicationsfor 6 weeks, electrical conductancewas used to assess skin hydration,and an expert grader assessed globalimprovement, fine lines and wrin-kles, and skin roughness and dry-ness. At week 6, skin hydration wasincreased by 37%, and there was a33% improvement in the globalassessment of the skin’s feel andappearance. Furthermore, there wasa 29% reduction in the appearance

Figure 1. Improvement in fine wrinkling before and after twice-daily applications of idebenone 1% for 6 weeks.

Figure 2. Improvement in dyspigmentation before and aftertwice-daily applications of idebenone 1% for 6 weeks.

Table 1. Environmental Protection Factor (EPF) calculated for idebenone, tocopherol, kinetin, ubiquinone, ascorbic acid, and lipoic acid.1

For each of the five tests in the standardized protocol for assessing antioxidant activity, the agent showing the greatest activity wasawarded the maximum score of 20 points. The other agents were awarded a percentage of this maximum score depending on the per-centage of their activity in that test relative to the highest-ranking agent.

of fine lines and wrinkles and a 26%reduction in skin roughness and dry-ness. As a result, idebenone is theonly antioxidant proven to help prevent sun damage to skin cells and to reduce fine lines and wrin-

kles. Photographic documentationdemonstrates visible improvementsin fine wrinkling (Figure 1) and dys-pigmentation (Figure 2)—the abilityof idebenone to improve dyspigmen-tation may relate to the fact that itsstructure is similar to that of hydro-

quinone. Idebenone was well toler-ated with no irritation or adverseeffects reported.

Topical Retinoids in the Treatment of Photodamage

Topical retinoids have alsodemonstrated efficacy in reducingseveral manifestations of photodam-age, including mottled hyperpigmen-tation, lentigines, irregular depig-mentation, fine wrinkling, coarsewrinkling, elastosis, and tactileroughness.4-6 The US Food and DrugAdministration has approved the0.1% formulation of tazarotenecream and 0.02% and 0.05% for-mulations of tretinoin for the ame-lioration of certain signs of photo-damage. In a 6-month study of 173adults with fine wrinkling and mot-tled hyperpigmentation that com-

Evaluation Idebenone Tocopherol Kinetin Ubiquinone Ascorbic Acid Lipoic Acid

Sunburn cell assay 20 16 11 6 0 5

Free radical scavenging activity 20 20 10 15 20 5

Primary oxidative products 16 10 20 5 3 4

Secondary oxidative products 19 17 10 12 12 20

Ultraviolet B–irradiated keratinocytes 20 17 17 17 17 7

Total score (EPF) 95 80 68 55 52 41

Baseline

Week 6

Baseline

Week 6


Reprinted with permission from the Journal of Cosmetic Dermatology.3 Reprinted with permission from the Journal of Cosmetic Dermatology.3

“Idebenone is the onlyantioxidant proven to help

prevent sun damage to skincells and to reduce fine

lines and wrinkles.”

pared tazarotene 0.1% cream withtretinoin 0.05% emollient cream, allsignificant between-group differ-ences in efficacy measures were infavor of tazarotene.7 Tazarotenetreatment was associated with a sig-nificantly higher percentage ofpatients achieving at least a one-grade improvement in mottledhyperpigmentation (at weeks 12 and16) and fine wrinkling (at week 24)(Figure 3).7 (A one-grade improve-ment represents a change betweengrades of none, minimal, mild, mod-erate, and severe.)

Minimizing Aging of the SkinMinimizing aging of the skin

requires a combination of measures,including sun protection to minimizeUV exposure, antioxidants to pro-

Figure 3. Percentage of subjects showing an improvement in fine wrinkling of at leastone grade (on a scale of none, minimal, mild, moderate, or severe) during treatment withtazarotene 0.1% cream or tretinoin 0.05% emollient cream.7

tect against oxidative stress, and top-ical retinoid therapy to ameliorateexisting signs of photodamage.Sunscreens and potent antioxidantscan provide excellent protectionagainst further aging of the skin, andtopical retinoids offer efficacyagainst existing signs of photo-damage. Optimal results can beachieved by choosing the most effective product within each ofthese classes. Idebenone is a logicalchoice for antioxidant therapy as it is more potent than other com-monly used antioxidants (ascorbicacid, tocopherol, kinetin, lipoic acid,

“Minimizing aging of theskin requires sun protection

to minimize UV exposure,antioxidants to protect

against oxidative stress, andtopical retinoid therapy toameliorate existing signs of

photodamage.”

Subjectswith

improve-ment of

at least 1grade (%)

–– Tazarotene 0.1% cream –– Tretinoin 0.05% emollient cream

100 ____________________________________________________________________

80 ____________________________________________________________________

60 ____________________________________________________________________

40 ____________________________________________________________________

20 ____________________________________________________________________

0 ____________________________________________________________________| | | | | | |

0 4 8 12 16 20 24

Week

*P<–0.01vs tazarotene emollient.

Scale usedNoneMinimalMildModerateSevere

*


Adapted with permission from the Journal of Cosmetic and Laser Therapy.

“Idebenone is a particularly potent andeffective antioxidant.”

and ubiquinone) and is the onlyantioxidant proven to both help pre-vent sun damage to skin cells andreduce fine lines and wrinkles.Tazarotene cream is a logical choicefor topical retinoid therapy as it ismore effective than the only otherretinoid indicated for the treatmentof photodamage (tretinoin emollientcream).

References1. McDaniel DH, Neudecker BA,

DiNardo JC, Lewis JA II, Maibach,HI. Idebenone: A new antioxidant –Part I. Relative assessment of oxida-tive stress protection capacity com-pared to commonly known antioxi-dants. J Cosmet Dermatol.2005;4:10-17.

2.Young AR. Methods used to evaluatethe immune protection factor of asunscreen: Advantages and disadvan-tages of different in vivo techniques.Cutis. 2004;74(5 suppl):19-23.

3. McDaniel DH, Lewis JA II, DiNardoJC, Neudecker BA, Maibach HI.Idebenone: A new antioxidant – PartII. Clinical efficacy assessment in pho-todamaged skin at 0.5% and 1.0%dose concentrations. J CosmetDermatol. 2005 In press.

4. Phillips TJ, Gottlieb AB, Leyden JJ, etal. Efficacy of 0.1% tazarotene creamfor the treatment of photodamage: A12-month multicenter, randomizedtrial. Arch Dermatol. 2002;138:1486-1493.

5. Olsen EA, Katz HI, Levine N, et al.Tretinoin emollient cream: A newtherapy for photodamaged skin. J AmAcad Dermatol. 1992;26:215-224.

6. Nyirady J, Bergfeld W, Ellis C, et al.Tretinoin cream 0.02% for the treat-ment of photodamaged facial skin: Areview of 2 double-blind clinical stud-ies. Cutis. 2001;68:135-142.

7. Lowe N, Gifford M, Tanghetti E, et al.Tazarotene 0.1% cream versustretinoin 0.05% emollient cream inthe treatment of photodamaged facialskin: A multicenter, double-blind, ran-domized, parallel-group study. JCosmet Laser Ther. 2004;6:79-85.

recent consensus guidelines on treat-ing acne,2 which advocated the useof a topical retinoid plus an antibiot-ic/benzoyl peroxide product as afirst-line therapy for comedonalacne. Study data support the use of clindamycin/benzoyl peroxide(although apparently not ery-thromycin/benzoyl peroxide) toenhance the anticomedonal efficacyof topical retinoid therapy.

References1.Vega B. Toll-like receptor-2: A novel

mechanism of action of adapalene inthe treatment of inflammatory acnelesions. Poster presented at: 61stAnnual Meeting of the AmericanAcademy of Dermatology; March 21-26, 2003; San Francisco, Calif.

2. Gollnick H, Cunliffe W, Berson D, et

al. Management of acne: A reportfrom a Global Alliance to ImproveOutcomes in Acne. J Am AcadDermatol. 2003;49(1 suppl):S1-S37.

3.Warner GT, Plosker GL. Clinda-mycin/benzoyl peroxide gel: A reviewof its use in the management of acne.Am J Clin Dermatol. 2002;3:349-360.

4.Taylor GA, Shalita AR. Benzoyl per-oxide-based combination therapiesfor acne vulgaris. Am J Clin Derma-tol. 2004;5:261-265.

5. Lookingbill DP, Chalker DK,Lindholm JS, et al. Treatment of acnewith a combination clindamycin/ben-zoyl peroxide gel compared with clin-damycin gel, benzoyl peroxide gel andvehicle gel: Combined results of twodouble-blind investigations. J AmAcad Dermatol. 1997;37:590-595.

6. Draelos ZD, Tanghetti EA, and theTazarotene Combination Leads to

Efficacious Acne Results (CLEAR)Trial Study Group. Optimizing the useof tazarotene for the treatment offacial acne vulgaris through combina-tion therapy. Cutis. 2002;69(2suppl):20-29.

7.Tanghetti E, Abramovits W, SolomonB, Loven K, Shalita A.Tazarotene ver-sus tazarotene plus clindamycin/ben-zoyl peroxide in the treatment of acnevulgaris: A multicenter, double-blind,randomized, parallel-group trial.Poster presented at: 63rd AnnualMeeting of the American Academy ofDermatology; February 18-22, 2005;New Orleans, La.

8. Hurwitz S.The combined effect of vit-amin A acid and benzoyl peroxide inthe treatment of acne. Cutis.1976;17:585-590.

The Use of Topical Retinoids With Combination Therapies continued from Page 7

understood that topical retinoids actby helping prevent the developmentof microcomedones (the precursorsof all acne lesions) and, as a result,are the cornerstone of therapy forboth comedonal and inflammatoryacne. It is this key ability to preventthe development of microcome-dones that is also continuing to drivethe evolution of topical retinoidtherapy today. Given the ability toprevent both comedonal and inflam-matory acne, topical retinoid thera-py is the treatment of choice notonly for initial therapy but also formaintenance therapy. Currentresearch is demonstrating that, atleast with tazarotene, maintenancetherapy can achieve good resultseven in patients with moderate tosevere inflammatory acne.11

References1. Straumfjord JV.Vitamin A: Its effects

on acne. Northwest Med. 1943;42:219-225.

2. Kligman AM, Fulton JE Jr, Plewig G.Topical vitamin A acid in acne vul-

Tazarotene cream versus adapalenecream in the treatment of facial acnevulgaris: A multicenter, double-blind, randomized, parallel-groupstudy. J Drugs Dermatol. 2005;4:153-158.

8. Leyden J, Lowe N, Kakita L, DraelosZ. Comparison of treatment of acnevulgaris with alternate-day applica-tions of tazarotene 0.1% gel andonce-daily applications of adapalene0.1% gel: A randomized trial.Cutis.2001;67(6 suppl):10-16.

9. Lowe NJ, Lee J, Shamban A, BourgetT, Moore D.Tazarotene 0.1% gel is acost-effective treatment for facialacne vulgaris. Poster presented at:Academy 2000 Meeting of theAmerican Academy of Dermatology;August 2-6, 2000; Nashville, Tenn.

10. Leyden J, Grove G, Zerweck C.Facial tolerability of topical retinoidtherapy. J Drugs Dermatol. 2004;3:641-651.

11.Thiboutot D. How to optimize topi-cal retinoid/oral antibiotic therapy inacne. Skin & Allergy News 2005<<this supplement – citation detailsto be added once known>>

Evidence-Based Results With Topical Retinoids for Acne continued from Page 5

garis.Arch Dermatol. 1969;99:469-476.

3. Belknap BS. Treatment of acne with5% benzoyl peroxide gel or 0.05%retinoic acid cream. Cutis. 1979;23:856-859.

4.Webster GF, Guenther L, Poulin YP,Solomon BA, Loven K, Lee J.A mul-ticenter, double-blind, randomizedcomparison study of the efficacy andtolerability of once-daily tazarotene0.1% gel and adapalene 0.1% gelfor the treatment of facial acne vul-garis. Cutis. 2002;69(2 suppl):4-11.

5.Webster GF, Berson D, Stein LF,Fivenson DP, Tanghetti EA, Ling M.Efficacy and tolerability of once-daily tazarotene 0.1% gel versusonce-daily tretinoin 0.025% gel inthe treatment of facial acne vulgaris:A randomized trial. Cutis. 2001;67(6suppl):4-9.

6. Leyden JJ, Tanghetti EA, Miller B,Ling M, Berson D, Lee J. Once-dailytazarotene 0.1% gel versus once-daily tretinoin 0.1% microspongegel for the treatment of facial acnevulgaris: A double-blind randomizedtrial. Cutis. 2002;69(2 suppl):12-19.

7. Shalita A, Miller B, Menter A,Abramovits W, Loven K, Kakita L.


Instructions: For each question or incomplete statement, one answer or completion is correct. Circle the most appropriate response.Seven correct responses are required for credit.

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CME Activity Evaluation1. Were you able to meet the objectives of this CME activity?

YES NO (circle one)If no, please note which objectives you were not able to meet:

2.Will the information presented in this issue be useful in your practicesetting?YES NO (circle one)Comments:

3. Did you find the information presented in this publication to be objec-tive, balanced, and free of commercial bias?

YES NO (circle one)Comments:

1. Which of the following medications has shown superior efficacyagainst all the others?a. Tazarotene 0.1% gelb. Adapalene 0.1% gelc. Tretinoin 0.025% geld. Tretinoin 0.1% microsponge gel

2. What is the clinical significance of the ability of topicalretinoids to prevent the development of microcomedones? a. Optimizes efficacy against comedones aloneb. Optimizes efficacy against inflammatory lesions alonec. Optimizes efficacy against both comedones and inflammato-

ry lesionsd. Optimizes tolerability

3. The results of split-face studies show which of the followingstatements about the tolerability of topical retinoids to be true?a. Adapalene cream is better tolerated than is adapalene gel.b. Tazarotene cream is better tolerated than is tazarotene gel.c. Tretinoin gel is better tolerated than tretinoin microsponge

gel.d. All of the above

4. Based on the clinical data presented, which of the following isthe most rational choice to be used adjunctively with a topicalretinoid as first-line treatment for comedonal acne? a. Clindamycinb. Minocyclinec. Clindamycin/benzoyl peroxided. Erythromycin/benzoyl peroxide

5. The adjunctive use of an appropriate topical antibacterial thera-py with tazarotene can result in which of the following clinicalbenefits relative to tazarotene monotherapy? a. Enhanced efficacy, no effect on speed of efficacyb. Enhanced efficacy, deterioration in tolerabilityc. Enhanced efficacy, enhanced speed of efficacy, enhanced

tolerabilityd. Enhanced efficacy, enhanced speed of efficacy, deterioration

in tolerability

6. The results of the tazarotene/minocycline trial show that, withall three of the maintenance regimens, the percentage ofpatients sustaining at least a 50% global improvement frombaseline after 12 weeks of initial therapy and 12 weeks ofmaintenance therapy was:a. 60% to 70% c. 80% to 90%b. 70% to 80% d. 90% to 100%

7. Which of the following may be valid reasons to use topicalretinoid monotherapy as maintenance treatment for moderateto severe inflammatory acne?a. Desire to minimize adverse effects associated with oral

antibioticsb. Desire to minimize the development of P. acnes resistance to

antibioticsc. Desire to avoid oral isotretinoind. All of the above

8. In a standardized protocol for assessing antioxidant activity,which of the following was found to have the greatestEnvironmental Protection Factor?a. Ascorbic acid c. Kinetinb. Idebenone d. Tocopherol

9. Which antioxidant has been proven not only to help preventsun damage to skin cells but also to reduce fine lines and wrin-kles?a. Kinetin c. Idebenoneb. Ascorbic acid d. None of the above

10. During 24 weeks of treatment, tazarotene 0.1% cream hasshown significantly superior efficacy to tretinoin 0.05% emol-lient cream for which of the following manifestations of photo-damage?a. Mottled hyperpigmentation aloneb. Fine wrinkling alonec. Both mottled hyperpigmentation and fine wrinklingd. Neither mottled hyperpigmentation nor fine wrinkling


Copyright © 2005 Elsevier Inc.

Maximizing Results in the Treatment of Acne and Improving Facial Appearance

CME Posttest and Evaluation


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