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&AGING; - The Dermatologist

Supplement to the May 2010& AGINGSUPPLEMENT PROCEEDINGS FROM THE 2010Based on selected presentations from theWinter Clinical Dermatology Conference — Hawaii ®held in Kohala Coast, HIJanuary 23–28, 2010Supplement supported by an unrestricted educational grantfrom Galderma Laboratories, L.P.


PARTICIPANTSMark V. Dahl, MDProfessor of Dermatology,College of MedicineMayo Clinic ArizonaScottsdale, AZJames Q. Del Rosso, DODermatology Residency DirectorValley Hospital Medical CenterLas Vegas, NVBarbara A. Gilchrest, MDProfessor and Chair-Emeritus,Department of DermatologyBoston University School of Medicineand Boston Medical CenterBoston, MAPearl E. Grimes, MDClinical Professor of DermatologyUniversity of California, Los AngelesLos Angeles, CALinda Stein Gold, MDDirector of DermatologyClinical ResearchHenry Ford HospitalDetroit, MIJerry Bagel, MDClinical Assistant Professorof DermatologyColumbia UniversityEast Windsor, NJCONTENTSADVANCES IN ROSACEA THERAPYMARK V. DAHL, MDPAGE 4ACNE VULGARIS STATUS REPORTJAMES Q. DEL ROSSO, DOPAGE 7PHOTODYNAMIC THERAPY ANDSELECTED OFF-LABEL USESBARBARA A. GILCHREST, MDPAGE 10MANAGEMENT OFPIGMENTARY DISORDERSPEARL E. GRIMES, MDPAGE 13TOPICAL THERAPIES FOR PSORIASISLINDA STEIN GOLD, MD; JERRY BAGEL, MD; ANDMARK LEBWOHL, MDPAGE 16Mark Lebwohl, MDSol and Clara Kest ProfessorChairman, Department of DermatologyThe Mount Sinai School of MedicineNew York, NY, LLC2010-560-170-BSUPPLEMENT PROCEEDINGS FROM THE 2010Based on selected presentations from the WinterClinical Dermatology Conference — Hawaii ® heldin Kohala Coast, Hawaii January 23–28, 2010Supplement supported by Galderma Laboratories, L.P.Articles in this supplement are basedon selected presentations from the2010 Winter Clinical DermatologyConference — Hawaii ®held January 23–28, 2010,in Kohala Coast, HI.STAFFEXECUTIVE EDITOR STEFANIE TULEYAMANAGING EDITOR ELLEN MEYERSPECIAL PROJECTS EDITOR STEPHANIE WASEKCREATIVE DIRECTOR VIC GEANOPULOSART DIRECTOR KAREN COPESTAKESPRODUCTION MANAGER MONICA MCLAUGHLINVICE PRESIDENT/GROUP PUBLISHER RICK EHRLICH83 GENERAL WARREN BLVD, SUITE 100, MALVERN, PA 19355(800) 237-7285 • (610) 560-0500 • FAX (610) 560-0501Supplement to Skin & Aging ■ May 2010 3


ADVANCES IN ROSACEA THERAPYMark V. Dahl, MDScottsdale, AZIn 2009, 26 experts published two papers relating to treatmentof rosacea. These papers are not guidelines for care byphysicians, but rather consensus opinions of state-of-the-arttreatment. Too often, patients find conflicting information onWeb sites and print magazines. By setting consensus opinion,the world of dermatology and skin care can coalesce aroundprinciples that guide successful outcomes.CONSENSUS ON DAILY CAREThe first publication addressed the broad spectrum of care,including history taking, lifestyle management, adjunctivecare, drug therapies, and light therapies, including use oflasers. 1 The second addressed options for treatment based onrosacea’s four subtypes — erythematotelangiectatic, papulopustular,phymatous and ocular. 2The consensus papers outlined daily treatment. The patientshould avoid trigger factors, gently cleanse the skin,and apply moisturizers to help maintain skin barrier function.The patient should wash the face gently with nonirritatingcleansers and avoid washcloths, abrasives andloofahs. After blotting the face dry, the patient shouldapply a moisturizer, usually one containing a sunscreen.Advise the patients to wait up to 30 minutes before applyingmoisturizer if stinging occurs, as stinging is morelikely if skin is wet.Rosacea patients must stop smoking. A recent multivariateanalysis compared questionnaire responses of 172 physiciandiagnosedrosacea patients to 145 “skin-healthy” controls. 3Rosacea patients were more likely to have smoked(OR=2.01, 95% CI=1.07-3.80; P


Winter Clinical Dermatology Conference ProceedingsAttendees of the 2010 Winter Clinical Dermatology Conference — Hawaii ® in Kohala Coast learned critical conceptsabout emerging and established dermatology therapies.probably of about equal efficacy, based on published studies. 5,6Once-daily applications are enough; there is no additional efficacyin twice daily applications.For more severe patients, I often start with a topical agentand either tetracycline or doxycycline. I still like tetracycline.In a study of 113 patients, topical metronidazole gel and systemictetracycline 500 mg twice daily dropped the meancount of papules and pustules from 17 to three over 12 weeks.One-hundred-four patients had fewer papules and pustules,82 had less erythema, and a surprising 67 of the 113 (59%)patients were able to eliminate all papules and pustules atsome point during those 3 months. 7Tetracycline and its cousins have anti-inflammatory properties.For example, tetracyclines inhibit formation of metalloproteinases8, 9 and 13 that degrade the dermal matrix.I still hold that rosacea has a microbial origin, butwhether it does or not, subantimicrobial doses of doxycyclineto seem to arrest papulopustular rosacea. A prescriptionpill contains 30 mg of immediate-release doxycyclineand 10 mg of slow-release doxycycline beads (Oracea). Ingestionof one pill once daily can treat rosacea and maintainremission. The drug can be used as monotherapy even inobese patients, and photosensitivity is uncommon and wasnot reported at all in the Phase III clinical trials. The frequencyof adverse effects has been similar to placebo andgenerally mild or probably unrelated.I find submicrobial-dose doxycycline especially usefulfor treating patients who fear antibiotics will predisposethem to superinfections with villainous bacteria or yeasts.Studies show that using this product does not affect populationsof ordinary, non-pathogenic comensal bacteriafrom the oral cavity, skin, intestinal track or vagina.Other elements of papulopustular rosacea also respond tooral doxycycline or tetracycline. These include rosacea cellulitisand rosacea dermatitis. Rosacea cellulitis (also called“plaque rosacea”) consists of boggy inflammatory red plaquesextending well beyond individual follicles. Often papules andpustules can also be seen within them.Rosacea dermatitis is different. This facial redness is morediffuse, milder, and accompanied by an overlying fine “dry”scale. Some experts think this is coexisting irritant or seborrheicdermatitis. I don’t. Seborrheic dermatitis favors theeyebrows, glabella and nasolabial folds, whereas rosacea dermatitisfavors the cheeks. However, like seborrheic dermatitis,rosacea dermatitis responds to antimicrobial agents suchas tetracycline and topical metronidazole. For examplewithin 2 weeks, metronidazole gel improved erythema,desquamation,and skin “irritation” among 25 women withmild to moderate rosacea. 8Reduction of rosacea dermatitis may also explain whysome facial redness responds to topical metronidazole, azelaicacid or sulfacetamide/sulfur preparations. As the inflammationof the dermatitis wanes, the rednessattributable to it wanes, too. Studies of papulopustularrosacea routinely show reduction of mean erythema scoresalong with reduction of papules and pustules. In thesestudies, reduction of erythema scores are secondary endpoints.We need studies of patients with “pure” erythematotelangiectaticrosacea (with and without dryness) withredness as a primary endpoint in order to understand howSupplement to Skin & Aging ■ May 2010 5


W. Christopher (Kit) Duncan, MD, (second from left) wonthe pigmented lesions quiz at the 2010 Winter ClinicalDermatology Conference — Hawaii ® .much of this response is real. Some of the response may bea global optical impression that redness is less when redpapules and pustules are nearly gone.THE DEMODEX CONTROVERSYDemodex folliculitis remains controversial as a special subtype.Some believe it’s coincidentally associated, because infestedrosacea patients tend to have large pores and sebaceousphenotype. Whether causal of papules and pustules or not,Demodex mites are very prevalent in follicles of rosacea patients.As I observe situations, I increasingly believe Demodexmites do cause papules and pustules in at least some patients.Topical crotamiton or sulfur may be useful treatments forpapulopustular rosacea and for helping eliminate at least Demodexfolliculorum.Demodex also contributes to stinging in some patients, resultingis a cosmetic intolerance syndrome. Everything thesepatients put on their faces seems to sting and burn. As a consequence,they stop washing the skin and applying moisturizersand topical antirosacea agents. This is a mistake. Thedensity of Demodex mites increases, products of bacteria accumulate,skin fatty acids increase and stinging worsens.In addition, the skin can start scaling, especially at follicles. Hereagain rosacea dermatitis develops. The patient and the physicianmay interpret this stinging, scaling and increased redness as irritantdermatitis or as asteatotic dry skin, and support the patient’serroneous notion that facial cleansing is deleterious.In fact, facial cleaning is the treatment of choice to interruptthis vicious circle of stinging, which stops normal cleansing,which increases facial and follicular toxins andconcentrations of Demodex mites, which lead to more rednessand dryness and to ongoing stinging and burning sensations.Though it might seem counter-intuitive to apply sulfur to irritatedskin, this route works over the long term, perhaps bykilling Demodex mites.Barrier repair by simple moisturization is also importantfor treating this syndrome. Del Rosso studied facial stinging,burning, tingling and itching among 78 rosacea patientts. 9 Patientscleansed and applied azelaic acid to their entire facetwice daily. Then they applied moisturizer to only half of theface twice daily. Sensory scores decreased for both sides of theface over the course of the 7-day study, but CSS scores decreasedsignificantly more on the side of the face also beingtreated with moisturizer. Of note, a moisturizer containingniacinamide was tested among rosacea patients and found toreduce erythema, papules and pustules. 10For stinging patients with cosmetic intolerance syndrome,I’m content to recommend use of any moisturizer a patientcan tolerate including petrolatum or hydrophilic petrolatum.Or, if the patient believes he or she can only use a certainproduct, I check the ingredients and often encourage the patientto use it at least once or twice daily, perhaps having apharmacy add some hydrocortisone 1% and/or sulfur 2% toit if rosacea dermatitis or demodiciosis is also present.In summary, a rosacea patient whose skin stings, burns oritches may have a skin barrier problem, dermatitis or demodiciosisthat can variably respond to regular cleansing and moisturizationplus oral doxycycline and a topical agent such asmetronidazole, azelaic acid, or sulfacetamide/sulfur.Once remission is obtained, recurrences often can beprevented by continued applications of either azelaic acidor metronidazole. 7,11CONCLUSIONOur march to understand and successfully treat all subtypesof rosacea continues. In general, our treatments work. We doneed more successful and safe treatments for rosacea, especiallyfor the erythematotelangiectatic type. Because rosacea is commonand because current research is exploring out-of-the boxcauses, these treatments will likely be forthcoming. ■References1. Odom R, Dahl M, Dover J, et al. Standard management options forrosacea, part 1: overview and broad spectrum of care. Cutis. 2009;84(1):43–47.2. Odom R, Dahl M, Dover J, et al. Standard management options forrosacea, part 2: options according to subtype. Cutis. 2009;84(2):97–104.3. Abram K, Silm H, Maaroos HI, Oona M. Risk factors associated withrosacea. J Eur Acad Dermatol Venereol. 2009 Oct 23. [Epub ahead of print]4. Papageorgiou P, Clayton W, Norwood S, Chopra S, Rustin M. Treatmentof rosacea with intense pulsed light: significant improvement and long-lastingresults. Br J Dermatol. 2008;159(3):628–632.5. Goldgar C, Keahey DJ, Houchins J. Treatment options for acne rosacea.Am Fam Physician. 2009;80(5):461–468.6. Elsaie ML, Choudhary S. Updates on the pathophysiology and managementof acne rosacea. Postgrad Med. 2009;121(5):178–186.7. Dahl MV, Katz HI, Krueger GG, et al. Topical metronidazole maintainsremissions of rosacea. Arch Dermatol. 1998;134(6):679–683.8. Draelos ZD. Assessment of skin barrier function in rosacea patients witha novel 1% metronidazole gel. J Drugs Dermatol. 2005;4(5):557–562.9. Del Rosso JQ. The use of moisturizers as an integral component of topicaltherapy for rosacea: clinical results based on assessment of skin characteristicsstudy. Cutis. 2009;84(2):72–76.10. Draelos ZD, Ertel K, Berge C. Niacinamide-containing facial moisturizer improvesskin barrier and benefits subjects with rosacea. Cutis. 2005;76(2):135–141.11. Thiboutot DM, Fleisher AB, Del Rosso JQ, Rich P. A multicenter studyof topical azelaic acid 15% gel in combination with oral doxycycline asinitial therapy and azelaic acid 15% gel as maintenance monotherapy. JDrugs Dermatol. 2009;8(7):639–648.6 May 2010 ■ Supplement to Skin & Aging


ACNE VULGARIS STATUS REPORTJames Q. Del Rosso, DOLas Vegas, NVAcne vulgaris is the most common dermatologic disorderencountered in ambulatory dermatology practicein the United States, accounting forapproximately 12% of all visits to dermatology offices. 1Despite the availability of several non-prescription acneproducts at pharmacies and peddled on the internet or viainformercials on television, many people still find they aredisappointed by the “overpromise and underdeliver” ofthese alleged miracle treatments once they are used. Anyonewho treats patients with acne knows that management ofacne does not rely on a quick fix, but rather requires understandableand simple patient education, incorporationof a convenient and rational treatment plan that is correlatedwith acne severity, an understanding that it may take2 to 3 months to see visible evidence of good improvement,the willingness of the patient to consistently adhereto a treatment program, and proper follow-up.The following discusses clinically relevant informationon acne pathogenesis and newer therapeutic options.INFLAMMATION IN ACNE STARTS EARLYThere is more emerging cogent evidence to supportthat inflammation starts early in the course of acne lesiondevelopment before the onset of visible inflammation andpresence of inflammatory lesions. 2 Additionally, scar formation,usually presenting as pitted scarring, may occurafter resolution of superficial acne vulgaris with presenceof only moderate visible inflammation, and without thepresence of deep inflammatory acne. 3 The evidence supportingthis observation is supported by the following:• Inflammatory cytokine expression has been noted insome assays from comedonal acne lesions, which maynot yet be colonized by Propionibacterium acnes. 4• Innate immune response appears to be operative earlyin the course of acne lesion development. 5• Inflammatory acne lesion development may occurwithout the presence of a pre-existing comedone inapproximately one-fourth of acne lesions. 6The importance of recognizing the role of subclinicalinflammation in acne lesion development may significantlyinfluence how treatment is initiated and sustained.Effective treatment of acne vulgaris appears to warrantboth reduction in microcomedo formation and the bluntingof the inflammatory cascade associated with acne.OPTIMAL USE OF BENZOYL PEROXIDE-CLINDAMYCIN FORMULATIONSCOMBINED WITH A TOPICAL RETINOIDWhen using a benzoyl peroxide (BP) 5%-clindamycinphosphate (clinda) 1.2% combination formulation oncedaily (usually in the morning) along with a topicalretinoid once daily (usually in the evening), available datasupport the concurrent use of these agents at the initiationof therapy. 7–9 This approach resulted in greater reductionin acne lesions over the 12-week duration ofclinical trials completed with three topical retinoids (adapalene,tretinoin microsphere, tazarotene), as compared touse of a topical retinoid alone, or delaying use of the topicalretinoid. The availability of more tolerable formulationsof topical retinoids and BP-clinda gel resulted invery favorable cutaneous tolerability.BENZOYL PEROXIDE 2.5%-CLINDAMYCIN GEL: A NEWER FORMULATIONA more recent additional to the BP-clinda gel menu ofoptions is an aqueous gel containing BP 2.5% and clindamycinphosphate 1.2%. Percutaneous penetration studiesdemonstrate that this formulation delivers BP intohuman skin as well as or better than a BP 5% gel, dependingon the comparator. 10 Additionally, cumulative irritationstudies support the use of BP 2.5%, with cutaneoustolerability better than BP 5% and equivalent to BP 1%. 10Pivotal studies comparing the combination gel to itsactive components or vehicle, all applied once daily for12 weeks, demonstrated markedly greater efficacy andhighly favorable tolerability with the combination formulation.11 Overall, BP 2.5%-clinda gel has been studiedin approximately 3,000 patients with marked efficacydemonstrated in all severities of acne.Median reductions in total acne lesions at 12 weekswere 54.1% and 44.4% in patients with moderate and severeacne vulgaris, respectively. 12 Median inflammatory lesionreductions in patients with moderate and severe acnevulgaris were shown to be 68% and 47.8%, respectively, at12 weeks. 12 Approximately one-fourth of patients enrolledin the pivotal studies were non-Caucasian, with 81% ofSupplement to Skin & Aging ■ May 2010 7


The 2010 CME interactive quiz winners: Karen Chen, MD (second from left); Sandra Wu, MD; and Shellie Marks, MD. Theyare joined by Mark Lebwohl, MD (far left); James Q. Del Rosso, DO (second from right); and Darrell S. Rigel, MD, MS.all patients reporting that they were “satisfied” with theresults of their treatment with BP-2.5%-clinda gel.ADAPALENE 0.1%-BENZOYL PEROXIDE 2.5%: THE FIRST TOPICALCOMBINATION CONTAINING A RETINOID AND BPThe combination aqueous gel formulation containing adapalene(adap) 0.1% and BP 2.5% combines the antimicrobialeffects of BP with the anti-comedonal and direct anti-inflammatoryproperties of a topical retinoid (adapalene). Thepivotal trials evaluating the efficacy of BP-adap gel appliedonce daily demonstrated the superiority of the combinationgel over the active components and the vehicle. 13In a 12-month study evaluating the use of once daily applicationof only BP-adap gel, median reductions in total,inflammatory and noninflammatory lesion counts were70.8%, 76% and 70%, respectively at 12 months. 14 Over the12-month duration of the long-term trial, there was no evidenceof loss of therapeutic effect, no patients discontinuedtreatment with BP-adap gel due to lack of efficacy, and asin the pivotal studies, cutaneous tolerability was highly favorable.As this formulation does not contain an antibiotic,antibiotic resistance is not a potential concern.COMBINATION THERAPY WITH TOPICAL DAPSONEDapsone 5% gel applied twice daily has been shown to beeffective for acne vulgaris in both pivotal trials and a 12-monthlong term study. 15,16 In a study of dapsone 5% gel applied twicedaily used in combination with either adapalene 0.1% gel oncedaily (group 1), BP 4% gel once daily (group 2), or a moisturizeronce daily (group 3), optimal efficacy was observed in thosesubjects treated with topical dapsone and the topical retinoid. 17 Meanpercent reductions in total acne lesions at 12 weeks were 51%,46%, and 39% in groups 1, 2 and 3, respectively.BENZOYL PEROXIDE CLEANSERS: NEWER FORMULATIONSBP prescription cleanser formulations are prescribedvery commonly by dermatologists and are highly adaptableto use on the face and trunk. A BP 6% cleanser usedonce daily in combination with a topical retinoid oncedaily has been shown to produce a twofold greater reductionin facial inflammatory acne lesions than a topicalretinoid alone over 12 weeks. 18Additionally, this same BP 6% cleanser formulation usedonce daily on the face has been shown to markedly reducePropionibacterium acnes colony counts over 3 weeks, includingreduction in P. acnes strains determined to be resistantto erythromycin, doxycycline and minocycline. 19 Morerecently, the same BP cleanser formulation has been incorporatedinto a large cleansing cloth, in concentrationsof 6% or 3%, adaptable for use on the face and trunk. Apatient-preference study demonstrated that the vast majorityof subjects preferred use of the BP 6% cloth as comparedto the same 6% formulation used as a liquidcleanser, and as compared to a BP 4% creamy wash. 20Microsphere (microsponge) topical delivery provides aslower release of an active ingredient, such as BP ortretinoin, allowing for reduction in cutaneous irritationwithout apparent sacrifice of efficacy. 21,22 A BP 7% microspongecleanser has been shown to produce substantivityof BP on skin after washing, rinsing and drying. 228 May 2010 ■ Supplement to Skin & Aging


This formulation also proved to be very well tolerated,with a skin tolerability profile equivalent to an establishedbranded non-therapeutic skin cleanser. 22ORAL ANTIBIOTIC THERAPY IN ACNE VULGARISOral antibiotics, especially minocycline and doxycycline,are commonly prescribed for the treatment of moderateand severe acne vulgaris, in combination with arational topical regimen. 23 The following observationshave been made with oral antibiotic agents in the treatmentof acne based on clinical trials:• Minocycline, formulated as an extended-releasetablet, is as effective in reducing inflammatory acnelesions at a dose of 1 mg/kg/day, as compared with2 mg/kg/day, or 3 mg/kg/day. 24• Extended-release minocycline administered at a doseof 1 mg/kg once daily was shown to be associatedwith markedly fewer acute vestibular adverse events(eg dizziness, vertigo) than higher doses (2 mg/kg/dayand 3 mg/kg/day), and was comparable to placebo. 24• A 24-month study completed with extended-releaseminocycline tablets that were administered at a dose of1 mg/kg/day in subjects with acne vulgaris demonstratedno reports of hyperpigmentation, drug-associatedlupus-like syndrome, or drug-hypersensitivity reaction. 25• Enteric-coated doxycycline is associated with a lower incidenceof gastrointestinal side effects than non-entericcoated, immediate-release doxycycline formulations. 26CONCLUSIONMany advances in acne treatment have depended on thedevelopment of new technologies designed to improve howactive ingredients are delivered. In the case of topical therapies,reduction in cutaneous irritation without loss of efficacyis a major goal of research on vehicle technology.With oral antibiotics, modifications of drug release may reducethe rate and severity of adverse reactions. Althoughformulation advances may not seem to be major breakthroughsat face value, reducing cutaneous irritation whilesustaining efficacy, and decreasing the incidence of side effectswith oral antibiotics, leads to better overall patient adherencewith treatment. Better adherence leads to a greaterlikelihood of a favorable outcome with treatment. ■References1. Weinstock MA, Boyle M. Statistics of interest to the dermatologist . In:Theirs BH, Lang PG (eds.). Year Book of Dermatology. Philadelphia: ElsevierMosby, 2007, p. 49.2. Wang KC, Zane LT. Recent advances in acne vulgaris research: insightsand clinical implications. Adv Dermatol. 2008;24:197–209.3. Kim G, Del Rosso JQ. Acne scarring: status report on treatment andmanagement. Cosmetic Dermatol. 2009;22(2):68–72.4. Bhambri S, Del Rosso JQ, Bhambri A. Pathogenesis of acne vulgaris: recentadvances. J Drugs Dermatol. 2009;8(7):615–618.5. Kim J. Review of the innate immune response in acne vulgaris: activationof toll-like receptor 2 in acne triggers the inflammatory cytokine responses.Dermatology. 2005;211(3):193–198.6. Do TT, Zarkhin S, Orringer JS, et al. Computer-assisted alignment andtracking of acne lesions indicate that most inflammatory lesions arise fromcomedones and de novo. J Am Acad Dermatol. 2008;58(4):603–608.7. Del Rosso JQ. Study results of benzoyl peroxide 5%/clindamycin 1%topical gel, adapalene 0.1% gel, and use in combination for acne vulgaris. JDrugs Dermatol. 2007;6(6):616–622.8. Kircik L. Community-based trial results of combination clindamycin1%-benzoyl peroxide 5% topical gel plus tretinoin microsphere gel 0.04%and 0.1% or adapalene 0.1% in the treatment of moderate to severe acne.Cutis. 2007;80(Suppl 1):10–14.9. Tanghetti E, Abramovits, Solomon B, et al. Tazarotene versus tazarotene plusclindamycin/benzoyl peroxide in the treatment of acne vulgaris: a doubleblind,randomized, parallel-group trial. J Drugs Dermatol. 2006;5(3):256–261.10. Bucks D, Sarpotdar P, Yu K, et al. The development and optimization ofa fixed combination of clindamycin and benzoyl peroxide aqueous gel. JDrugs Dermatol. 2009;8(7):634–638.11. Thiboutot D, Zaenglein A, Weiss J, et al. An aqueous gel fixed coimbinationof clindamycin phosphate 1.2% and benzoyl peroxide 2.5% for theonce-daily treatment of moderate to severe acne vulgaris: assessment of efficacyand safety in 2813 patients. J Am Acad Dermatol. 2008;59(5):792–800.12. Webster G, Rich P, Golg MH, et al. Efficacy and tolerability of a fixedcombination of clindamycin phosphate (1.2%) and low concentration benzoylperoxide (2.5%) aqueous gel in moderate or severe acne subpopulations.J Drugs Dermatol. 2009;8(8):736–743.13. Gollnick HP, Draelos Z, Glenn MJ, et al. Adapalene-benzoyl peroxide, aunique fixed-dose combination topical gel for the treatment of acne vulgaris:a transatlantic, randomized, double-blind, controlled study in 1670patients. Br J Dermatol. 2009;161(5):1180–1189.14. Pariser DM, Westmoreland P, Morris A, et al. Long-term safety and efficacyof a unique fixed-dose combination gel of adapalene 0.1% and benzoylperoxide 2.5% for the treatment of acne vulgaris. J Drugs Dermatol.2007;6(9):899–905.15. Draelos ZD, Carter E, Maloney JM, et al. Two randomized studiesdemonstrate the efficacy and safety of dapsone gel 5% for the treatment ofacne vulgaris. J Am Acad Dermatol. 2007;56(3):439.e1–10.16. Lucky A W, Maloney JM, Roberts J, et al. Dapsone gel 5% for the treatmentof acne vulgaris: safety and efficacy of long-term (1-year) treatment. JDrugs Dermatol. 2007;6(10):981–987.17. Fleischer AB Jr, Shalita A, Eichenfield LF, et al. Dapsone gel 5% in combinationwith adapalene gel 0.1%, benzoyl peroxide gel 4%, or moisturizerfor the treatment of acne vulgaris: a 12-week, randomized, double-blindstudy. J Drugs Dermatol. 2010;9(1):33–40.18. Shalita AR, Rafal ES, Anderson D et al. Comparative efficacy and safety oftretinoin 0.1% microsphere gel alone and in combination with benzoyl peroxide6% cleanser for treatment of acne vulgaris. Cutis. 2003;72(2):167–172.19. Leyden JJ, Wortzman M, Baldwin EK. Antibiotic-resistant Propionibacteriumacnes suppressed by a benzoyl peroxide cleanser 6%. Cutis. 2008;82(6):417–421.20. Del Rosso JQ. A 6% benzoyl peroxide foaming cloth cleanser used inthe treatment of acne vulgaris: aesthetic characteristics, patient preferenceconsiderations, and impact on patient compliance with treatment. J ClinAesthet Dermatol. 2009;2(7):26–29.21. Smith S, Morhenn V, Webster G. The characteristics and utility of solidphase porous microspheres: a review. J Drugs Dermatol. 2006;5(10):969–974.22. Del Rosso JQ. Benzoyl peroxide microsphere formulations: what is thescience supporting microsphere vehicle technology and clinical use? J ClinAesthet Dermatol. 2009;2(9):45–53.23. Del Rosso JQ, Kim G. Optimizing use of oral antibiotics in acne vulgaris.Dermatol Clin. 2009;27(1):33–42.24. Leyden JJ. Extended-release minocycline-first systemic antibiotic approvedfor the treatment of acne: introduction. Cutis. 2006;78(4S):4–5.25. Del Rosso JQ, Baldwin H, Keri J, et al. Current approach to acne management:a community-based analysis. Cutis. 2009;83 (6 Suppl):5–21.26. Del Rosso JQ, Bhambri S, Kim G. Use of oral doxycycline for community-basedmethicillin-resistant Staphylococcus aureus (CA-MRSA) infections.J Clin Aesthet Dermatol. 2009;2(9):45–50.Supplement to Skin & Aging ■ May 2010 9


PHOTODYNAMIC THERAPYAND SELECTED OFF-LABEL USESBarbara A. Gilchrest, MDBoston University School of MedicineBoston, MAPhotodynamic therapy (PDT) uses light activation ofa photosensitizer to generate highly reactive oxygenintermediates, which results in tissue injury andnecrosis for a therapeutic purpose. PDT is approved forfocal treatment of actinic keratoses (AKs), but the recentliterature suggests some interesting uses for this potentnew modality in treating a number of dermatologic disordersoff-label.TOPICAL PHOTOSENSITIZERS FOR PDTPDT is unusual in that manufacturers must securedrug/device combination approval, which is generallyquite complicated and which makes for difficulty in determiningwhich treatment component is responsible fora specific effect. There are four FDA-approved photosensitizers;two are for topical use (Table 1).The first is aminolevulinic acid (ALA), sold by DUSAPharmaceuticals as Levulan Kerastick. It is approved inconjunction with a specific blue light source, the Blu-UTherapeutic Illuminator. The other is methyl aminolevulinate(MAL), sold by Galderma as Metvixia, and approvedfor use in 2008 with a red light source, the Aktilite. ALAcomes in an alcohol-based solution, and MAL in a peanutoil-based cream. Both ALA and MAL are actually prodrugs,metabolized in the skin to protoporphyrin IX,which is the active drug.Because MAL has been approved in Europe and elsewherefor many years, there are several long-term studies availablefrom overseas. In the United States, there have been pivotalstudies for AK approval of both MAL and ALA, but informationis still emerging, particularly with regard to off-label use. 1,2ABSORPTION (ACTIVATION) SPECTRUM FOR PORPHYRINSThe activation spectrum for porphyrins is primarily inthe blue range, or so-called Soret Band. The ability of ablue photon of light to activate porphyrins is muchgreater than that of longer wavelengths, but there are multipleminor absorption peaks throughout the visible spectrum.As a result, the Blu-U light approved for use withALA is the most efficient, but therapeutically adequate activationcan be achieved with other wavelengths and othersources, such as the Aktilite approved for use with MAL(Figure 1). In particular, the pulsed dye laser and intensepulsed light are sources that can also activate porphyrins.Different wavelengths of light penetrate to differentdepths in human skin. 3 For example, 400 nm of blue lightpenetrates through the epidermis and into the superficialdermis, while red light — around 630 nm, the peak omissionfor the Aktilite — penetrates considerably deeper, andmay thus offer an advantage in treating dermal lesions.PDT TREATMENT CAPABILITIES AND PATHWAYBoth drug/device combinations are approved to treat AKs.Outside the United States, MAL is also approved to treatBowen’s disease and superficial basal cell carcinomas (BCCs).PDT has at least partial selectivity for AKs and squamouscell carcinomas (SCCs) relative to normal epidermis.First, the prodrug exhibits increased penetrationthrough the altered stratum corneum of these premalignantand malignant lesions relative to normal skin. Second,in the case of SCCs and possibly also AKs, a lowerintracellular iron ion concentration retards conversion ofthe photosensitizing protoporphyrins to heme, the finalmolecule in the synthetic pathway and itself non-photosensitizing.Thus, relative to normal keratinocytes, the cellsin AKs and SCCs contain more active drug at the time oflight exposure and are proportionally more damaged.PDT IN PRACTICEMy colleagues and I in the Department of Dermatologyat Boston University have employed PDT in a mannerthat is different from the FDA-approved protocol inseveral ways. First, we have used ALA-PDT to treat broadareas; for example, the entire face of a person with multipleAKs rather than the visible keratoses alone. We havealso used a much shorter incubation period: 1 hour,rather than 14 to 18 hours, as FDA-approved based onthe pivotal trials for the Levulan Kerastick.Our PDT group treats the entire face (or other part ofthe body broadly) because visible keratoses occur in thesetting of diffusely photodamaged skin. Histologically, theskin surrounding clinically-detected keratoses is often asabnormal and dysplastic as the lesion itself and in termsof cancer risk, the goal of PDT is not only to remove visiblelesions, but to prevent the appearance of skin cancer.Therefore, it makes sense to treat the entire field.We use the shorter ALA incubation time because it islong enough to allow for therapeutic photosensitization10 May 2010 ■ Supplement to Skin & Aging


Winter Clinical Dermatology Conference ProceedingsTABLE 1. Available topical photosensitizers for PDTCompound Aminolevulinic acid (ALA) Methyl aminolevulinate (MAL)Final active metabolite Protoporphyrin IX Protoporphyrin IXPreparation Solution Peanut oil-based creamBrand name Levulan (DUSA Pharmaceuticals) Metvix, Metvixia (Galderma)Approval in United States Europe, United States, Australia, New ZealandApproved for AKs only AKs, Bowen’s disease, sBCCs, nBCCs (Europe)Co-approved light Blue light Red lightsourcebut minimizes the mechanism-associated adverse effectsof pain during light exposure, followed by redness andswelling of the treated area lasting up to a week or more.The longer the incubation time, up to 18 to 24 hours,the higher the concentration of protoporphyrin in theskin — and the more painful the treatment. The literatureemphasizes the pain associated with PDT, 4–6 but for mostpatients, the 1-hour incubation time leads to a well tolerateddiscomfort that is not a barrier to therapy.When the entire face is treated using a 1-hour incubation,redness and swelling following the light exposure must still beanticipated and is very bothersome for many patients, at peakcomparable to the peak reaction observed in patients undergoingbroad area treatment with 5-fluorouracil or imiquimodfor facial AKs. Importantly, however, this phototoxicity reactionpeaks after 24 hours and usually resolves over 4 to 7 days, incontrast to the weeks of sustained inflammation for other fieldtherapies. Off the face, this PDT protocol causes minimal tono visible phototoxicity, but as also observed using the FDAapprovedprotocol is less efficacious than on facial skin, probablydue to lesser absorption of ALA.TREATING AKS WITH FULL-FACE PDTUsing our protocol, the typical patient has moderate tosevere redness and mild swelling one day after PDT thatresolves within one week. Most people find the 1 hourincubation followed by the standard 10 J/cm 2 Blu U exposurequite tolerable. In our experience, it successfullyreduces signs of photoaging, improves pigmentation irregularityand tactile quality of skin, and tightens skin insome patients. 7 It also removes visible AKs as effectivelyas the FDA-approved protocol for focal AK treatment. 7A400BluU500IPLWavelength, l (nm)PDLAktiliteFigure 1. Porphyrin absorption spectrum and commonlyused PDT light sourcesWe compared improvement in keratoses for three incubationtimes. We saw the same degree of resolution —about 90% of AKs disappearing at 1 month and still goneat the 5-month follow-up — for inclubation times of1, 2 or 3 hours. 7 This result is the same as in the pivotaltrials with the 14- to 18-hour overnight incubation.We also evaluated improvement in photodamage usingthe Griffiths Scale for individual factors: skin quality, finewrinkling, mottled pigment and sallowness. While thechanges are subtle — dropping from 4 or 5 on the GriffithsScale to between 3 and 4 across the board — improvementswere statistically significant for all these parametersof photodamage after just one treatment. What’s more, thisis the same degree of improvement seen after 6 months inpivotal trials for retinoic acid applied daily to photodamagedfacial skin 7 or after a medium-depth TCA peel, in theexperience of my co-investigator, Dany Touma. 7600Supplement to Skin & Aging ■ May 2010 11


We concluded that using this protocol to treat a photodamagedface with multiple AKs was as safe and effectiveas the FDA-approved protocol for treating AKs, and thatone session resulted in improvement in photoaging thatwas roughly equivalent to 6 months of retinoic acid orone TCA peel.EXPERIENCE WITH SKIN CANCERSThe International Society for Photodynamic Therapy inDermatology developed recommendations in 2005 based onthe experience of European dermatologists with MAL PDT: 8• PDT treatment of actinic keratoses is highly effectivewith excellent cosmesis, and is recommended as firstlinetherapy.• Bowen’s disease responds as well to PDT as actinickeratoses and is recommended as first-line therapy.• PDT is highly effective for both superficial and nodularbasal cell carcinomas. 8• There is insufficient evidence to recommend routineuse of PDT for invasive squamous cell carcinoma.In the last 5 years, additional studies strongly suggestthat periodic broad area PDT can reduce the incidenceof AKs and SCCs in high risk patients with severe diffusephotodamage, including organ transplant recipients,11, 12and of basal cell carcinomas (BCCs) in patients with Gorlinsyndrome (basal cell nevus syndrome). 13, 14 The optimumbroad-area PDT regimen is still unknown, and willlikely vary according to the patient’s severity of photodamageand tolerance for post-treatment erythema.OTHER USES OF PDTWe generally treat these patients with basal cell nevussyndrome at monthly intervals until the incidence of newBCCs has substantially decreased, and then at intervalsthereafter that depend on the rate at which they are developingmore skin cancers. We have also observed thattopical or intralesional Levulan Blu U therapy eradicatesmany BCCs, without scarring, while improving the appearanceof scarred and photodamaged skin. In a randomizedprospective study, researchers followed 97 patients(105 total BCCs) 5 years after surgical excision or MALPDT (the only form of PDT approved in Europe) fornodular BCCs. Recurrence rate in the PDT group wasslighty but not statistically higher than in the excised lesionsgroup, and the PDT group exhibited substantiallybetter cosmesis both short- and long-term. 15I anticipate we’ll soon see more off-label uses for MALPDT in the literature. For example, Tierney and Hanke,in studies soon to be published, have examined a numberof possible indications for MAL PDT and skin cancer,such as delineating tumor margins before surgery fortreatment of multiple BCCs in basal cell nevus syndromepatients. Their experience was similar to ours: They foundthat 27 of 27 superficial BCCs and 11 of 12 nodularBCCs resolved after two treatments. They reported excellentcosmesis and faster healing with PDT at 6-monthfollow-up. ■References1. Tschen EH, Wong DS, Pariser DM, et al; Phase IV ALA-PDT ActinicKeratosis Study Group. Photodynamic therapy using aminolaevulinicacid for patients with nonhyperkeratotic actinic keratoses ofthe face and scalp: phase IV multicentre clinical trial with 12-monthfollow up. Br J Dermatol. 2006;155(6):1262–1269.2. Nestor MS, Gold MH, Kauvar AN, et al. The use of photodynamictherapy in dermatology: results of a consensus conference. J DrugsDermatol. 2006;5(2):140–154.3. Kochevar IE, Taylor CR, Krutmann J. Fundamentals of cutaneousphotobiology and photoimmunology. In: Wolff K, Goldsmith LA, KatzSI, et al (eds). Fitzpatrick’s Dermatology in General Medicine, 7th Edition.New York: McGraw-Hill;2007.4. Warren CB, Karai LJ, Vidimos A, Maytin EV. Pain associated withaminolevulinic acid-photodynamic therapy of skin disease. J Am AcadDermatol. 2009;61(6):1033–1043.5. Mikolajewska P, Iani V, Juzeniene A, Moan J. Topical aminolaevulinicacid- and aminolaevulinic acid methyl ester-based photodynamictherapy with red and violet light: influence of wavelength onpain and erythema. Br J Dermatol. 2009 ;161(5):1173–1179.6. Steinbauer JM, Schreml S, Kohl EA, et al. Photodynamic therapy indermatology. J Dtsch Dermatol Ges. 2010 Feb 3. [Epub ahead of print]7. Touma D, Yaar M, Whitehead S, Konnikov N, Gilchrest BA. A trial ofshort incubation, broad-area photodynamic therapy for facial actinickeratoses and diffuse photodamage. Arch Dermatol. 2004;140(1):33–40.8. Braathen LR, Szeimies RM, Basset-Seguin N, et al; InternationalSociety for Photodynamic Therapy in Dermatology. Guidelines on theuse of photodynamic therapy for nonmelanoma skin cancer: An internationalconsensus. International Society for Photodynamic Therapyin Dermatology, 2005. J Am Acad Dermatol. 2007;56(1):125–143.9. Caekelbergh K, Nikkels AF, Leroy B, et al. Photodynamic therapyusing methyl aminolevulinate in the management of primary superficialbasal cell carcinoma: clinical and health economic outcomes. JDrugs Dermatol. 2009;8(11):992–996.10. Souza CS, Felicio LB, Ferreira J, et al. Long-term follow-up oftopical 5-aminolaevulinic acid photodynamic therapy diode laser singlesession for non-melanoma skin cancer. Photodiagnosis PhotodynTher. 2009;6(3–4):207–213.11. Apalla Z, Sotiriou E, Chovarda E, et al. Skin cancer: preventive photodynamictherapy in patients with face and scalp cancerization. A randomizedplacebo-controlled study. Br J Dermatol. 2009 Oct 26. [Epub ahead of print]12. Willey A, Mehta S, Lee PK. Reduction in the incidence of squamouscell carcinoma in solid organ transplant recipients treated with cyclicphotodynamic therapy. Dermatol Surg. 2009 Nov 4. [Epub ahead of print]13. Oseroff, A. R., Shieh, S., Frawley, N. P., Cheney, R., Blumenson, L.E., Pivnick, E. K., et al. (2005). Treatment of diffuse basal cell carcinomasand basaloid follicular hamartomas in nevoid basal cell carcinomasyndrome by wide-area 5-aminolevulinic acid photodynamic therapy.Arch Dermatol, 141(1), 60-67.14. Gilchrest, B. A., Brightman, L. A., Thiele, J. J., & Wasserman, D. I.(2009). Photodynamic therapy for patients with Basal cell nevus syndrome.Dermatol Surg, 35(10), 1576-1581.15. Rhodes LE, de Rie MA, Leifsdottir R, et al. Five-year follow-upof a randomized, prospective trial of topical methyl aminolevulinatephotodynamic therapy vs surgery for nodular basal cell carcinoma.Arch Dermatol. 2007;143(9):1131–1136.12 May 2010 ■ Supplement to Skin & Aging


MANAGEMENT OFPIGMENTARY DISORDERSPearl E. Grimes, MDLos Angeles, CAPigmentation disorders such as vitiligo and melasma aretruly life-altering conditions for the patients who sufferfrom them, causing enormous psychological devastation.1,2 If we treat these patients, we can substantially improvetheir quality of life. This article will cover issues relatedto both hypo- and hyperpigmentation disorders.VITILIGOAlthough vitiligo is indeed a therapeutically challenging disease,current therapies can improve the lives of many patients.Surgical procedures and use of high-potency topical steroidsare both well established treatments for vitiligo, so this articlewill focus on other therapies, such as topical modulators, vitaminD analogs, targeted phototherapy and antioxidants. 3,4There are several considerations to keep in mind when choosinga therapy:Severity of disease. Topical agents are most effective in patientswith limited body surface area (BSA), in particular thosewith 5% to 10% involvement. Agents such as tacrolimus andhigh- and mid-potency topical steroids are highly effective. 5Anatomic location. Anatomic sites are key variables intreating vitiligo. Maximal pigmentation typically occurs onface and neck areas. The most therapeutically challengingareas are hands, feet and male genitalia.Patient age. The best outcomes can be achieved in children,because their melanocytes appear to be more responsiveto therapeutic intervention.Progression of disease. It’s important to stabilize moderateto rapidly progressive vitiligo so therapy can be carried out effectively.In adults, 3 mg/kg daily of prednisone for up to 2weeks or pulsed therapy using betamethasone 5 mg twiceweekly or dexamethasone 5 mg once a week are effective. Mypreferred modality in adults is up to three intramuscular triamcinoloneinjections every 4 to 6 weeks. In children, I recommend5 mg to 10 mg of prednisone daily for up to 2 weeks.THERAPEUTIC MODALITIESCalcineurin inhibitors. Tacrolimus and pimecrolimushave moved to the forefront of treating patients with limitedvitiligo. 6 Studies show twice-daily application achievesmaximal efficacy on the face and neck. 6 In my practice, Iprescribe a high-potency steroid for use in the morningand tacrolimus at night to “jump start” repigmentation,then switch to tacrolimus twice daily. Burning and stingingare common side effects that don’t preclude the drug’s use.These symptoms usually subside with continued use. Becauseof the FDA Black Box warning, I don’t use them incombination with ultraviolet (UV) light.Vitamin D analogs. The efficacy of vitamin Danalogs remains controversial. Most studies suggest thatvitamin D analogs as monotherapy probably don’t work. 6However, some studies indicate that vitamin D analogsenhance the efficacy of narrowband UVB light comparedwith narrowband UVB alone. 7Narrowband UVB light. Multiple studies document theefficacy and safety of narrowband UVB phototherapy in childrenand adults with vitiligo. 8,9 It’s important to inform patientsthat this is not an instant therapy; it requires 6 to 12 months oftreatment. Home phototherapy units — handheld or panels —are an option for patients who can’t come into the office threetimes a week or reside in an area where narrowband therapy isnot available. Narrowband UVB treatments are safe. The worstcomplication we’ve observed from home units is mild to moderatephotosensitivity. Hence, we’ve had no major complicationsnor observed an increase in skin cancers..Targeted phototherapy. Excimer lasers work well inindividuals with localized lesions, as you can limit thenumber of treatments to the affected areas due to the reportedenhanced efficacy of these units and decreaselong-term cumulative UV light exposure. For patientswho can come in two to three times a week, I find theexcimer laser or combination UVA/UVB targeted phototherapyunits most effective.Antioxidants/vitamins. New studies on the pathogenesisof vitiligo suggest that oxidative stress is probably a majorcause or possibly a trigger for the aberrant immune responsein patients with vitiligo. 10,11 I use a high-potency multivitaminin combination with antioxidants, C, E and alpha lipoic acid.These vitamins increase the body’s natural supply of glutathione,one of the strongest antioxidants.Always ask patients if they’re taking herbal supplements;prolonged use of supplements such as echinacea and goldenseal can activate immune response, causing progression of thedisease. We’ve observed this phenomenon in many patients.Supplement to Skin & Aging ■ May 2010 13


David Pariser, MD, was awarded 2010 Clinical Educatorof the Year at the 2010 Winter Clinical DermatologyConference — Hawaii ® .We now have studies showing that the combination of narrowbandUVB plus antioxidants is superior to narrowbandUVB alone.Emerging therapies. There are several studies showingthat polypodium leucotomos has a synergistic effect withnarrowband UVB phototherapy and PUVA in patientswith vitiligo. 12,13 Also 5-fluorouracil has demonstrated efficacy.It stimulates melanogenesis and melanocyte proliferation.In addition, several recent studies have documentedthe efficacy of PGE2 as a repigmenting agent. It enhancesbasic fibroblast growth factor mRNA expression.Depigmentation therapy. This is used in patients withgreater than 40% BSA affected who don’t respond to repigmentationtherapies or have no desire to undergo repigmentation.Historically, we’ve used monobenzylether ofhydroquinone (benoquin 20% cream). Commercial preparationsare no longer on the market; however, pharmacistscan compound benoquin.TREATING HYPERPIGMENTATIONDisorders of hyperpigmentation also cause significantpsychological despair. Common disorders for hyperpigmentationinclude melasma and post-inflammatory hyperpigmentation.Multiple advances have been made inthe treatment of these disorders: new combinationbleaching agents, monotherapy bleaching agents, sunscreens,resurfacing procedures and laser technologies.Bleaching agents. The overwhelming majority ofbleaching agents work by inhibiting the transcription oractivation of the tyrosinase enzyme. For example, retinoidsinterfere with pre-melanin synthesis by blocking the MITFgene, which blocks transcription of tyrosinase. Tyrosinaseglycosylation can be inhibited with N-acetylgucosamine.However, most available agents are either competitiveor noncompetitive inhibitors of tyrosinase, as theseachieve the best results. Other agents, such as nicotinamides,increase melanosome transfer by reducing epidermalturnover. Agents such as topical steroids andlicorice control inflammation. The current thinking isthat it’s more efficacious to use agents that impact at leasttwo pathways in a formulation.Maximal efficacy can be achieved with combinationformulations. Combination formulations include hydroquinone4%, tretinoin 0.05%, fluocinolone 0.01%; hydroquinone4%, retinol 0.3%; hydroquinone microentrapped4%, retinol 0.15%; hydroquinone, glycolic acid 10%; hydroquinone,glycolic acid 10% plus hyaluronic acid; andmequinol, tretinoin 0.01%.Of the triple-combination bleach formulations, Tri-Luma (hydroquinone 4%, tretinoin 0.05%, fluocinolone0.01%) remains the leader, despite a competitive genericmarket. Multiple global studies now document the efficacyof triple-combination bleaching. 14–16 However,questions linger regarding whether this drug causes atrophyor telangiectasias.In a study by Bhawan, Grimes and Pandya, 70 patientswere treated with triple-combination bleaching once aday for 12 weeks, then were switched to a twice-weeklymaintenance regimen for the remaining 12 weeks. 17Biopsies were performed at baseline, 12 and 24 weeks.No cases of atrophy occurred, and there was only a verymild increase in telangiectasias between weeks 12 and 24.Another study compared the micro-entrapped 4% formulationof hydroquinone with hydroquinone 4% andretinol 0.3% and triple-combination bleaching. 18 The results:the micro-entrapped formulation produced superiorresults compared with the hydroquinone 4% with 0.3%retinol, and exhibited comparable efficacy to triple-combinationbleaching.My practice gets many referrals of patients who havebeen through, but are unresponsive to, all the 4% formulations.At this point, I recommend switching to a higherhydroquinone concentration — 5% to 10%. Hydroquinonehas gotten a bad reputation for undesirable effects,but it’s OK to use it at these concentrations whenappropriate. The most common side effect is irritantcontact dermatitis; ochronosis is uncommon in theUnited States, probably fewer than 40 published cases.I’ve seen no cases of malignancies, liver enzyme elevation,or permanent hypopigmentation or depigmentationinduced by hydroquinone. 18,19Cosmeceuticals. The hyperpigmentation treatmentmarketplace is changing rapidly — worldwide sales ofbleaching agents are expected to increase to $9.2 billionby 2013. Multiple cosmetic companies are now in themarketplace and focusing on cosmeceuticals and botanicalagents that impact hyperpigmentation. To that end,we’ll probably see multiple new topical agents and an-14 May 2010 ■ Supplement to Skin & Aging


Winter Clinical Dermatology Conference Proceedingstioxidants that suppress hyperpigmentation. 20 Overall, Ithink this paradigm shift will be good in that more efficaciousproducts will be available to dermatologists.Resurfacing procedures. Microdermabrasion, peels,IPL, lasers and fractional photothermolysis are among theresurfacing procedure options for patients with pigmentarydisorders. When deciding which therapy to use, considerthat there’s a much wider margin of safety when treating anindividual who has skin type 1 to 3, versus an individualwith 4 to 6. In addition, melanocytes in darker skin have alabile nature and can be very unpredictable in their responsesto resurfacing procedures. Finally, assess the chronicityof the disease you are treating and calculate therisk-benefit ratio of each procedure option.I perform microdermabrasions and peels — more-superficialprocedures — every 2 to 4 weeks in combination withtopical bleaching agents applied daily to achieve optimal results.Complications do occur, but are often easier to amelioratecompared to more aggressive procedures.Fractional photothermolysis has become extremely popularon the back of early data: the pilot study reported 60%of patients achieved 75% to 100% repigmentation; a histologystudy of melasma looked at biopsies at 3 monthsand found a decrease in melanocytes, melanin and keratinocytes.21,22 However, a study by Naito et al showedmean improvement of just 35%. 23 Further, a more recentstudy showed that, while 17% of patients improved at 24weeks, 13% were worse. 24Studies suggest the limited efficacy of fractional photothermolysisfor melasma, especially in patients withdarker skin. 25 Melanocytes don’t take well to heat and,while this modality can work, patients too often relapse.If fractional photothermolysis is working for your patientswith no complications, continue. But novicesshould proceed with care and caution, knowing thereare no cures (particularly for melasma) and many patientswill relapse.CONCLUSIONSome general therapeutic guidelines to keep in mind:• Patients with mild melasma or mild post-inflammatoryissues can be treated with lower-strength formulas,such as cosmeceuticals or 2% hydroquinone.• Many patients with moderate to severe disease willclear with combination bleaching formulations usedalone or in combination with resurfacing procedures.• Consider lasers for patients who are truly recalcitrantand who have pigment in the dermis that will otherwiseprevent substantial outcomes.• Given the chronicity of melasma, most patients willachieve maximal benefit from an aggressive phase oftreatment followed by a maintenance phase, includingthe daily use of broad-spectrum sunscreens at all times.Overall, the future of managing pigmentation holdsmuch to be excited about. ■References1. Jalel A, Soumaya GS, Hamdaoui MH. Dermatology life quality indexscores in vitiligo: reliability and validity of the tunisian version. Indian JDermatol. 2009;54(4):330–333.2. Talsania N, Lamb B, Bewley A. Vitiligo is more than skin deep: a surveyof members of the Vitiligo Society. Clin Exp Dermatol. 2009 Dec 8. [Epubahead of print]3. Grimes PE. Vitiligo. In: Dermatology for Skin of Color. Kelly AP, TaylorSC (eds). China: The McGraw-Hill Companies, 2009.4. Ference JD, Last AR. Choosing topical corticosteroids. Am Fam Physician.2009;79(2):135–140.5. Lo YH, Cheng GS, Huang CC, Chang WY, Wu CS. Efficacy and safetyof topical tacrolimus for the treatment of face and neck vitiligo. J Dermatol.2010;37(2):125–129.6. Grimes PE, Soriano T, Dytoc MT. Topical tacrolimus for repigmentationof vitiligo. J Am Acad Dermatol. 2002;47(5):789–791.7. Kullavanijaya P, Lim HW. Topical calcipotriene and narrowband ultravioletB in the treatment of vitiligo. Photodermatol Photoimmunol Photomed.2004;20(5):248–251.8. Mavilia L, Mori M, Rossi R, et al. 308 nm monochromatic excimerlight in dermatology: personal experience and review of the literature. GItal Dermatol Venereol. 2008;143(5):329–337.9. Gawkrodger DJ, Ormerod AD, Shaw L, et al; Therapy Guidelines andAudit Subcommittee, British Association of Dermatologists; Clinical StandardsDepartment, Royal College of Physicians of London; Cochrane SkinGroup; Vitiligo Society. Guideline for the diagnosis and management of vitiligo.Br J Dermatol. 2008;159(5):1051–1076.10. Jalel A, Yassine M, Hamdaoui MH. Oxidative stress in experimental vitiligoC57BL/6 mice. Indian J Dermatol. 2009;54(3):221–224.11. Jeong TJ, Shin MK, Uhm YK, et al. Association of UVRAG polymorphismswith susceptibility to non-segmental vitiligo in a Korean sample.Exp Dermatol. 2010 Feb 16. [Epub ahead of print]12. Parsad D, Pandhi R, Dogra S, Kumar B. Topical prostaglandin analog(PGE2) in vitiligo — a preliminary study. Int J Dermatol. 2002;41(12):942–945.13. Kapoor R, Phiske MM, Jerajani HR. Evaluation of safety and efficacyof topical prostaglandin E2 in treatment of vitiligo. Br J Dermatol.2009;160(4):861–863.14. Torok HM. A comprehensive review of the long-term and short-termtreatment of melasma with a triple combination cream. Am J Clin Dermatol.2006;7(4):223–230.15. Que SK, Bergstrom KG. Hyperpigmentation: old problem, new therapies.J Drugs Dermatol. 2009;8(9):879–882.16. Torok HM, Jones T, Rich P, Smith S, Tschen E. Hydroquinone 4%,tretinoin 0.05%, fluocinolone acetonide 0.01%: a safe and efficacious 12-month treatment for melasma. Cutis. 2005;75(1):57–62.17. Bhawan J, Grimes P, Pandya AG, et al. A histological examination forskin atrophy after 6 months of treatment with fluocinolone acetonide0.01%, hydroquinone 4%, and tretinoin 0.05% cream. Am J Dermatopathol.2009;31(8):794–798.18. Grimes PE. An efficacy study of 3 commercially available hydroquinone4% treatments for melasma. Cutis. 2007;80(6):497–502.19. Nordlund JJ, Grimes PE, Ortonne JP. The safety of hydroquinone. J EurAcad Dermatol Venereol. 2006;20(7):781-787.20. Berson DS. Natural antioxidants. J Drugs Dermatol. 2008 Jul;7(7 Suppl):s7–12.21. Rokhsar CK, Fitzpatrick RE. The treatment of melasma with fractionalphotothermolysis: a pilot study. Dermatol Surg. 2005;31(12):1645–1650.22. Goldberg DJ, Berlin AL, Phelps R. Histologic and ultrastructural analysisof melasma after fractional resurfacing. Lasers Surg Med. 2008;40(2):134–138.23. Naito SK. Fraction photothermolysis treatment for resistant melasma inChinese females. J Cosmet Laser Ther. 2007;9(3):161–163.24. Lee HS, Won CH, Lee DH, et al. Treatment of melasma in Asian skinusing a fractional 1,550-nm laser: an open clinical study. Dermatol Surg.2009;35(10):1499–1504.25. Tierney EP, Kouba DJ, Hanke CW. Review of fractional photothermolysis:treatment indications and efficacy. Dermatol Surg.2009;35(10):1445–1461.Supplement to Skin & Aging ■ May 2010 15


TOPICAL THERAPIES FOR PSORIASISLinda Stein Gold, MD | Detroit, MIJerry Bagel, MD | New York, NYMark Lebwohl, MD | New York, NYThis article will examine key topical treatments for psoriasis— including vitamin D analogues, phototherapy andcombination therapies — as well as tips for avoiding cutaneousatrophy and compounding pearls.TOPICAL VITAMIN D THERAPYTopical vitamin D-receptor modulators calcipotriol (theEuropean name for calcipotriene), tacalcitol and calcitriolhave been available in Europe for some time. 1 The FDA approvedcalcipotriene (Dovonex) in 1994 and, more recently,calcitriol ointment (Vectical). A fixed-dose product combiningcalcipotriene and betamethasone dipropionate is alsoavailable in an ointment (Taclonex) and a topical suspension(Taclonex Scalp).Calcipotriene is an effective drug; however it tends tobe irritating, especially the ointment formulation, in up to20% of patients. Tacalcitol is less irritating but also notquite as effective. This leaves a gap for an effective, welltoleratedtreatment.Trials indicate calcitriol can fill this gap. In one Phase III pivotaltrial, 839 patients with mild to moderate psoriasis weretreated in a double-blind, vehicle-controlled study BID for8 weeks. 2 Calcitriol on its own was found to be very safe andtook about 2 weeks to achieve statistically significant differenceversus placebo. By the end of 8 weeks, about 37% of patientshad achieved clear or almost-clear results.There is one long-term, 1-year study examining calcitriolointment’s safety and efficacy in treating psoriasis. 3 The proportionof patients who were clear or almost-clear after3 months was 11.1%; after 6 months, 22.1%; after 9 months,37.3%; and, after 12 months, 47.1%.Systemic side effects were minimal: just 10 isolated cases(3.1% of patients) of point elevations in serum calcium levelsafter 52 weeks of the study. 3 One patient had two points elevation,but in 9 of 10 of these patients, the elevation waswithin 5% of the upper limit of normal. Finally, the incidenceof hypercalcemia was similar regardless of the body surfacearea (BSA) affected by psoriasis. Two takeaways: Calcitriol issafe for treating larger BSAs, and there is no need to monitorserum calcium levels. 4Calcitriol also can be used to treat more sensitive body areas. Asplit-body comparison of calcitriol ointment with calcipotrieneointment for the face and intertriginous areas found the formerwas statistically superior, better-tolerated, resulted in more improvementin flexural areas, had significantly lower incidence ofside effects, and was preferred by patients. 5 Calcitriol’s fast onsetalso makes it a good monotherapy option for sensitive areas.BETAMETHASONE DIPROPIONATE WITH CALCIPOTRIENECombination therapy has statistically faster and superior efficacycompared with using potent steroids twice daily andhas the added benefit of reducing potent steroid use by 50%.It was also found that the combination was statistically superiorto the individual ingredients. 6,7 In fact, superiority was observedin the scalp vehicle as early as 2 weeks and wasmaintained throughout the study. 6 In a yearlong study, the safetyprofile was good, with no evidence of tachyphylaxis when patientsused about 10 g per week. Researchers monitored patientstreating scalp and body with up to 60 g per week and foundthat 16% of patients had hypothalamic-pituitary-adrenal (HPA)axis suppression after 4 weeks; 18% did after 8 weeks. 7 Again,there was no evidence of calcium metabolism abnormalities.CLOBETASOL PROPIONATE SPRAY AND CALCITRIOLIn a study looking at sequential therapy with clobetasolpropionate spray (Clobex), patients were started on the sprayBID for 4 weeks, then switched to calcitriol ointment for therest of the study, through week 12. 8 After 4 weeks of clobetasolspray, 93% of patients were clear, almost-clear or mild.Once they had this control over the psoriasis, maintenancewas achieved over the next 8 weeks using the calcitriol andno steroids. In addition, BSA decreased with the spray andwas maintained over the course of the full 12 weeks. 8TOPICAL VITAMIN D PLUS PHOTOTHERAPYSeveral studies have looked at the use of topical vitamin Dplus phototherapy in treating psoriasis. Here is a summary ofseveral important studies in this area.• An 8-week study of 104 patients suffering with psoriasison 25% of BSA evaluated calcitriol 3 μg/g ointment BIDin combination with UVB to treat plaque psoriasis. 9 Overthe course of the randomized, double-blind, placebo-controlledstudy, patients received broadband UVB phototherapythree times weekly. (Control patients receivedpetrolatum instead of calcitriol.) After 24 treatments, 45%of patients in the calcitriol group had cleared, comparedwith 20% in the control group. PASI scores significantlyimproved — 65% versus 43%.• In a second study of 50 patients over 7 weeks, half weretreated with calcipotriol (cream) 50 μg/g BID and narrowbandUVB (nUVB) three times a week, and half weretreated with emollient and the same nUVB regimen. 10By the eighth treatment, patients in the calcipotriol grouphad improved by about 66%, while patients in the controlgroup had improved by about 50%.16 May 2010 ■ Supplement to Skin & Aging


Winter Clinical Dermatology Conference Proceedings• Another 8-week study with two multi-center cohorts examinedcalcipotriol ointment combined with broadbandUVB. 11 Cohort A’s 101 patients received calcipitriol BID onone side of the body, and calcipitriol BID plus UVB on theother side. Cohort B’s 81 patients received UVB plus vehicleon one side, UVB plus calcipotriol BID on the other.The best results were seen in cohort A patients who got calcipotrioland UVB: 60% improvement was seen by week 2, 82%improvement by week 8, and 57% clearance rate overall after8 weeks. Results seen in cohort B patients were less consistent:32% clearance by the end of 8 weeks for calcipotriol plus UVB,compared with 30% clearance for UVB plus vehicle.• In a 10-week study of 120 patients with psoriasis over 30%of BSA and average PASI of 18, 69% of patients treated withcalcipotriol cream plus PUVA achieved PASI 90, while 37%of the PUVA plus vehicle patients did the same. 12 PASI improvedin 87% of the combination group, compared with62% in the other group. Further, the dose of PUVA neededwas 30% less for patients in the combination group.• A 110-patient study shows the importance of priming patientsbefore the first dose of phototherapy, so we can decreasethe number of treatments needed to achieve clearor almost clear. 13 The first phase lasted 2 weeks and consistedof a washout. The second phase, also 2 weeks, wasa randomized, double-blind treatment with calcipitriolointment or placebo ointment BID to all plaques. Thethird phase, 10 weeks, consisted of PUVA three times aweek plus either calcipotriol or placebo ointment.Two weeks into the third phase, PUVA-plus-calcipotriolpatients showed 73% improvement in PASI. At the end of thestudy, 87% of patients in the calcipotriol group had a PASI75 and 72% had PASI 90 — and just 10 treatments were necessaryto clear these patients. The placebo group required 50%more PUVA treatments, but even 15 treatments is fairly quickfor these results, and is probably the result of the priming.• Do not use calcitriol before phototherapy; it can significantlydegrade upon exposure to UVA, UVB ornarrowband UVB. 14 In addition, applying ointment beforeexposure to UV light blocks UV transmission.And, though rare, using calcitriol before UV light exposurecan result in hyperpigmentation. Patients shouldwait at least 2 hours after phototherapy to use calcitriolto avoid skin irritation.TOPICAL VITAMIN D WITH SYSTEMIC AGENTSCombining topical therapy with systemic agents can be avery effective treatment for psoriasis patients. In one study, 50%of patients achieved PASI 90 within 6 weeks with calcipotriolointment plus 2 mg/kg cyclosporine, compred to 12% receivingcyclosporine plus placebo ointment. 15 Serum creatinineincreased 4% in both the calcipotriol and emollient groups inthis study, and perilesionial irritation between the groups wascomparable. Each group used the same amount of ointment,indicating a synergism between cyclosporine and topical vitaminD, as there was with phototherapy and vitamin D.Another study that utilized calcipotriol ointment with acitretin(Soriatane) looked at 130 patients over 12 weeks. 16 All patients startedwith 20 mg of acitretin every week, increasing dosage by 10 mg everyother week. A group using calcipotriol ointment was compared withanother using vehicle. After 12 weeks, two-thirds of the patients usingacitretin and calcipotriol ointment were either clear or markedly improvedcompared with 40% of the acitretin and vehicle group. Furthermore,less acitretin was needed in the calcipotriol group (1680mg) to achieve this, compared with the vehicle group (2100 mg).Another study looked at 98 patients on methotrexate withstable psoriasis. 17 Patients were taken off methotrexate; somewere put on a calcipotriol ointment regimen, and others weregiven an emollient to determine which group would stayclearer longer and then, once they’d gotten twice as bad asthey were at baseline, how the groups would respond to goingback on methotrexate and calcipotriol.It was 113 days before the calcipotriol group had a flare,versus 35 days for the emollient group. Patients stayed clearfor 120 days in 41% of calcipotriol cases, compared with 17%of emollient cases. Finally, calcipotriol patients needed significantlyless methotrexate — about 6.5 mg — to recapturebaseline status, compared with 9.9 mg for emollient patients.Finally, there’s a study in which psoriasis patients went on etanercept50 mg (Enbrel) subcutaneously twice weekly, then shiftedto 50 mg SQ once weekly and then, if they hadn’t achieved aPASI 50 after 12 weeks, received calcipotriol cream BID for4 weeks followed by calcipotriol QD for 8 weeks. 18 Only onethirdof the group captured a PASI 75 by the end 12 weeks’treatment with calcipotriol plus low-dose etanercept. Despite theweak results of this study, there is likely a place for vitaimin Dderivatives used in combination with biological agents, as otherstudies show the combination is both safe and effective.PREVENTING CUTANEOUS ATROPHYThere are steps you can take to prevent telangiectasia, steroidpurpura, striae, and all manifestations of cutaneous atrophy ofeither the epidermis, dermis or both. Ammonium lactate hasbeen shown to help thicken the epidermis and protect againstdermal thinning. 19 There is a lot of data showing that tazarotene(Tazorac) protects against cutaneous atrophy — up to 33% lessatrophy — although it has some undesirable side effects of itsown, including retinoid dermatitis. 20–22Facial and intertriginous sites are much more responsive totopical steroids — and more likely to exhibit undesirable effects.With regard to this concern in terms of dermal thinning,fluticasone propionate cream (Cutivate) has a good risk-benefitratio. 23 Fluticasone is actually inactivated as soon as it penetratesthrough the epidermis, which probably accounts for why it canbe applied daily over several weeks with no cutaneous atrophyor striae, and with low psoriasis recurrence rates. 23Tacrolimus (Protopic) and pimecrolimus (Elidel) cream onfacial and intertriginous sites are very effective and safe with regardto cutaneous atrophy. 24,25 Finally, as mentioned previously,vitamin D analogs such as calcipotriene pose no risk of cutaneousatrophy, another benefit of their inclusion in therapy. 26Supplement to Skin & Aging ■ May 2010 17


COMPOUNDING TRICKS AND TIPSThe old treatment for psoriasis, anthralin (Zithranol-RR),stains the skin a very undersirable color. It takes care of thepsoriasis, but is irritating and leaves the patient with purplebrownskin. Combining tar and anthralin appeared to causesignificantly less irritation, but anthralin is degraded by tar,rendering it less effective. 27,28 This section will discuss compoundingpearls to deal with such issues.Researchers looked at the combination of calcipotrienewith various other topical medications and found that many— including salicylic acid gel and ammonium lactate — inactivateor reduce the effectiveness of calcipotriene. 29 Onestudy show that halobetasol in an anhydrous base, which isUltravate, is compatible with calcipotriene. 29 Because vehiclematters in this case, keep in mind that not every genericpreparation will be compatible. In fact, 76% of patients on amaintenance regimen that includes halobetasol and calcipotrienewere still clear or almost clear after 6 months. 30Calcitriol is very stable — it is not affected by combinations. 31This includes clobetasol spray, which it is also compatible withregardless of which is applied first, according to a study that wasin progress (but in which the blind was broken by a participant).When it comes to corticosteroids, do not assume they canbe safely combined with anything and everything. Salicylicacid dramatically increases corticosteroids’ penetration of theskin, and camphor, methol and phenol slightly increase penetration.32,33 Other substances, such as tars and urea, have noeffect. 32,33 These agents will not only increase the therapeuticeffect of the steroid, but the side effects as well. ■References1. British Association of Dermatologists. Accessed July 22, 2008. Availableat http://www.bad.org.uk/healthcare/guidelines/psorvitamin.asp2. Lebwohl M, Menter A, Weiss J, et al. Calcitriol 3 microg/g ointment inthe management of mild to moderate plaque type psoriasis: results from 2placebo-controlled, multicenter, randomized double-blind, clinical studies.J Drugs Dermatol. 2007;6(4):428–435.3. Final report [data on file]. Galderma Pharma SA. June 2004.4. Feldman SR, Gelfand JM, Stein Gold L, Jones SD. The role of topical therapyfor patients with extensive psoriasis. Cutis. 2007;79(1 Suppl 2):18–31. Review.5. Ortonne JP, Humbert P, Nicolas JF, et al. Intra-individual comparison ofthe cutaneous safety and efficacy of calcitriol 3 μg g-1 ointment and calcipotriol50 μg g-1 ointment on chronic plaque psoriasis localized in facial,hairline, retroauricular or flexural areas. Br J Dermatol. 2003;148(2):326–333.6. Lebwohl M, Menter A, Weiss J, et al. Calcitriol 3 microg/g ointment inthe management of mild to moderate plaque type psoriasis: results from 2placebo-controlled, multicenter, randomized double-blind, clinical studies.J Drugs Dermatol. 2007;6(4):428–435.7. Luger TA, Cambazard F, Larsen FG, et al. A study of the safety and efficacyof calcipotriol and betamethasone dipropionate scalp formulation in thelong-term management of scalp psoriasis. Dermatology. 2008;217(4):321–328.8. Data on file. Galderma Pharma SA.9. Ring J, Kowalzick L, Christophers E, et al. Calcitriol 3 microg g-1 ointmentin combination with ultraviolet B phototherapy for the treatment of plaquepsoriasis: results of a comparative study. Br J Dermatol. 2001;144(3):495–499.10. Woo WK, McKenna KE. Combination TL01 ultraviolet B phototherapyand topical calcipotriol for psoriasis: a prospective randomizedplacebo-controlled clinical trial. Br J Dermatol. 2003;149(1):146–150.11. Molin L. Topical calcipotriol combined with phototherapy for psoriasis.The results of two randomized trials and a review of the literature. Calcipotriol-UVBStudy Group. Dermatology. 1999;198(4):375–381.12. Torras H, Aliaga A, López-Estebaranz JL, et al. A combination therapyof calcipotriol cream and PUVA reduces the UVA dose and improves theresponse of psoriasis vulgaris. J Dermatolog Treat. 2004;15(2):98–103.13. Frappaz A, Thivolet J. Calcipotriol in combination with. PUVA a randomizeddouble blind placebo study in severe psoriasis. Eur J Dermatol. 1993;3:351–354.14. Lebwohl M, Quijije J, Gilliard J, Rollin T, Wattset O. Topical calcitriol isdegraded by ultraviolet light. J Investigative Dermatol. 2003;121(2):594–595.15. Grossman RM, Thivolet J, Claudy A, et al. A novel therapeutic approachto psoriasis with combination calcipotriol ointment and very lowdosecyclosporine: results of a multicenter placebo-controlled study. J AmAcad Dermatol. 1994;31(1):68–74.16. van de Kerkhof PC, Cambazard F, Hutchinson PE, et al. The effect ofaddition of calcipotriol ointment (50 micrograms/g) to acitretin therapy inpsoriasis. Br J Dermatol. 1998;138(1):84–89.17. Driessen RJ, van de Kerkhof PC, de Jong EM. Etanercept combined withmethotrexate for high-need psoriasis. Br J Dermatol. 2008;159(2):460–463.18. Campione E, Mazzotta A, Paternò EJ, et al. Effect of calcipotriol onetanercept partial responder psoriasis vulgaris and psoriatic arthritis patients.Acta Derm Venereol. 2009;89(3):288–291.19. Lavker RM, Kaidbey K, Leyden JJ. Effects of topical ammonium lactateon cutaneous atrophy from a potent topical corticosteroid. J Am Acad Dermatol.1992;26(4):535–544.20. Kaidbey K, Kopper SC, Sefton J, Gibson JR. A pilot study to determinethe effect of tazarotene gel 0.1% on steroid-induced epidermal atrophy. IntJ Dermatol. 2001;40(7):468–471.21. Dando TM, Wellington K. Topical tazarotene: a review of its use in thetreatment of plaque psoriasis. Am J Clin Dermatol. 2005;6(4):255–272. Review.22. Lebwohl M. Strategies to optimize efficacy, duration of remission, andsafety in the treatment of plaque psoriasis by using tazarotene in combinationwith a corticosteroid. J Am Acad Dermatol. 2000;43(2 Pt 3):S43–46.23. Lebwohl MG, Tan MH, Meador SL, Singer G. Limited application offluticasone propionate ointment, 0.005% in patients with psoriasis of theface and intertriginous areas. J Am Acad Dermatol. 2001;44(1):77–82.24. Lebwohl M, Freeman AK, Chapman MS, et al; Tacrolimus OintmentStudy Group. Tacrolimus ointment is effective for facial and intertriginouspsoriasis. J Am Acad Dermatol. 2004;51(5):723–730.25. Gribetz C, Ling M, Lebwohl M, et al. Pimecrolimus cream 1% in thetreatment of intertriginous psoriasis: a double-blind, randomized study. JAm Acad Dermatol. 2004;51(5):731–738.26. Lebwohl M, Ortonne JP, Andres P, Briantais P. Calcitriol ointment 3microg/g is safe and effective over 52 weeks for the treatment of mild tomoderate plaque psoriasis. Cutis. 2009;83(4):205–212.27. Schulze HJ, Schauder S, Mahrle G, Steigleder GK. Combined tar-anthralinversus anthralin treatment lowers irritancy with unchanged antipsoriaticefficacy. Modifications of short-contact therapy and Ingram therapy. JAm Acad Dermatol. 1987;17(1):19–24.28. Whitefield M. Degradation of anthralin by coal tar. J Am Acad Dermatol.1987;16(3 Pt 1):629.29. Patel B, Siskin S, Krazmien R, Lebwohl M. Compatibility of calcipotrienewith other topical medications. J Am Acad Dermatol. 1998;38(6Pt 1):1010–1011.30. Lebwohl M, Yoles A, Lombardi K, Lou W. Calcipotriene ointment andhalobetasol ointment in the long-term treatment of psoriasis: effects on theduration of improvement. J Am Acad Dermatol. 1998;39(3):447–450.31. Colon LE, Johnson L,Gottschalk RW, et al. Chemical Stability of CommonlyCombined Topical Psoriasis Medications Presented at: 65th AmericanAcademy of Dermatology Meeting, February 2–6, 2007; Washington, DC.32. Krochmal L, Wang JC, Patel B, Rodgers J. Topical corticosteroid compounding:effects on physicochemical stability and skin penetration rate. JAm Acad Dermatol. 1989;21(5 Pt 1):979–984.33. Polano MK, Ponec M. Dependence of corticosteroid penetration onthe vehicle. Arch Dermatol. 1976;112(5):675–680.18 May 2010 ■ Supplement to Skin & Aging


Reference: 1. Gollnick HPM, Draelos Z, Glenn MJ, et al; Adapalene–BPO Study Group. Adapalene–benzoyl peroxide, a unique fixed-dose combination topical gelfor the treatment of acne vulgaris: a transatlantic, randomized, double-blind, controlled study in 1670 patients. Br J Dermatol. 2009;161(5):1180-1189.Galderma is a registered trademark.©2010 Galderma Laboratories, L.P.Galderma Laboratories, L.P.14501 N. FreewayFort Worth, TX 76177EPI-317 Printed in USA 01/10www.epiduo.com/hcp


Epiduo ® (adapalene and benzoyl peroxide) Gel 0.1%/2.5% —A unique fixed-dosecombination developed for the first-line treatment of inflammatory and comedonal lesionswww.epiduo.com/hcp*In a phase 3 clinical trial of 1670 patients, median reduction in inflammatory lesions was 70% and median reductionin comedonal lesions was 62% at week 12.Important Safety InformationEpiduo ® Gel is a retinoid and antimicrobial combination product indicated for the topical treatment of acne vulgaris in patients 12 yearsand older. The most common adverse events associated with use of Epiduo ® Gel are erythema, scaling, dryness, stinging and burning.In addition, in clinical trials, adverse events reported in greater than 1% of patients treated with the Gel included contact dermatitisand skin irritation. Excessive exposure to sunlight and sunlamps should be avoided during treatment, and use of sunscreen productsand protective clothing is recommended. Concomitant use of irritating topical products (like products containing resorcinol, salicylic acidor sulfur) should be avoided. Epiduo ® Gel has not been tested in pregnant or nursing women, or with the elderly. Pregnancy Category C.Please see brief summary of Prescribing Information on next page.

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