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PARTICIPANTSCONTENTSJames Q. Del Rosso, D.O., F.A.O.C.D.Clinical Assistant ProfessorDepartment of DermatologyUniversity of NevadaSchool of MedicineLas Vegas, NVWHAT’S NEW IN THEMEDICINE CHEST?BY JAMES Q. DEL ROSSO, D.O., F.A.O.C.D.PAGE 3ADVANCES IN ROSACEA THERAPYBY DIANE M. THIBOUTOT, M.D.PAGE 7Diane M. Thiboutot, M.D.Professor of DermatologyDepartment of DermatologyPenn State Milton S. HersheyMedical CenterHershey, PAACNE: THERAPEUTIC DILEMMASBY JULIE C. HARPER, M.D.PAGE 10ACNE AND THE ADULT FEMALEJulie C. Harper, M.D.Clinical Associate ProfessorDepartment of DermatologyUniversity of AlabamaSchool of MedicineBirmingham, ALBY DIANE M. THIBOUTOT, M.D.PAGE 14MANAGING ATOPIC DERMATITISBY JAMES S. TAYLOR, M.D.PAGE 16HMP COMMUNICATIONSJames S. Taylor, M.D.Section Head Industrial DermatologyDepartment of DermatologyCleveland Clinic FoundationCleveland, OHArticles in this supplement are basedon selected presentations from the 2007Winter Clinical Dermatology Conference®held on January 13 – 17, 2007, inKohala Coast, HI.EDITORIAL STAFFSPECIAL PROJECTS EDITOR STEFANIE TULEYAEXECUTIVE EDITOR LARISA HUBBSSENIOR EDITOR ELLEN MEYERDESIGN AND PRODUCTIONART DIRECTOR KAREN COPESTAKESCREATIVE DIRECTOR VIC GEANOPULOSPRODUCTION DIRECTOR KIM CHESKYPRODUCTION MANAGER TRISH MORRISBUSINESS STAFFPUBLISHER JOE MORRISNATIONAL SALES MANAGER PHIL LEBRESCOPROJECT MANAGER LINDSAY SHELLYCIRCULATION MANAGER BONNIE SHANNON83 GENERAL WARREN BLVD, SUITE 100, MALVERN, PA 19355(800) 237-7285 • (610) 560-0500 • FAX (610) 560-0501

WINTER CLINICAL DERMATOLOGY CONFERENCE PROCEEDINGSWHAT’S NEW IN THEMEDICINE CHEST?NEW INSIGHTS INTO ADVANCES IN FORMULATION TECHNOLOGY,APPLICATION TECHNIQUES AND MORE.BY JAMES Q. DEL ROSSO, D.O., F.A.O.C.D.James Q. Del Rosso, D.O.,F.A.O.C.D.What do we have tochoose from as treatmentoptions for ourpatients? Are there new optionsto choose from — new medications,new active ingredients, ornew vehicle formulations? Insome cases the answer is “yes”,and some newer products maymake a big difference in treatmentoutcomes in disease statessuch as seborrheic dermatitis,acne, rosacea and more.SEBORRHEIC DERMATITISSeborrheic dermatitis is a condition with many components— inflammation, scaling and proliferation of Malasseziafurfur, the latter playing a pro-inflammatory role that serves todrive inflammation.Shampoos are very important in delivering medication to thescalp, and there is a newer formulation, which is a prescriptionsalicylic acid 6% shampoo (Salex). Its indication is for scalp psoriasis,but it makes sense to apply this treatment for seborrheicdermatitis. The lathering formulation contains humectants andconditioners that maintain the texture of the hair. There also havebeen some studies with repeated applications that demonstratedthat there are no adverse effects on hair treated with permanentwave solution and hair that is dyed, which is very importantto many patients. In vitro testing evaluating ocular irritationdemonstrated no significant problems with this formulation.NEW NON-STEROIDAL FORMULATIONS FORATOPIC DISEASESInitially, there was some confusion about how some of thenewer non-steroidal “barrier repair prescription devicecreams” should be utilized. There is now more informationavailable on MimyX and Atopiclair. Although they may beeffective as monotherapy for less severe presentations ofatopic dermatitis, they are usually used adjunctively during aflare as part of a topical combination regimen incorporatinggood skin care with a corticosteroid and/or a calcineurininhibitor. Between flares they are used along with good skincare to sustain remission.MimyX contains a substance called PEA, which is an innateanti-inflammatory compound that is deficient in the skin ofpatients with atopic dermatitis. MimyX has been shown todecrease signs and symptoms of atopic dermatitis, improvesleep score quality, prolong time between flares and reducethe need for “rescue therapy” with topical corticosteroids. Theformulation mimics lipid components of the stratum corneum,thereby restoring barrier function. It is also free of potentiallyallergenic or irritating emulsifiers, perfumes and dyes.Atopiclair contains several components including glycyrrhetinicacid, which exhibits anti-inflammatory activity, andlipids that serve to repair epidermal barrier function. It hasbeen shown that Atopiclair may decrease signs and symptomsof atopic dermatitis and reduce the amount of timepatients need to use topical corticosteroids, allowing for moredisease-free days. It is not recommended that either of theseagents be used in place of moisturizers. There are no restrictionson sites of skin application, age or duration of use withthese particular formulations.CeraVe, a newer ceramide-based skincare line, utilizesmultivesicular emulsion technology and includes a hydratingcleanser, a moisturizer lotion and a moisturizer cream. Arecent study utilizing corneometry testing showed thatCeraVe cream exhibited skin hydration results comparable toMimyX, and superior to several other brand formulations.FOAM VEHICLE FORMULATIONSVersaFoam represents a patented family of advancedtopical foam delivery systems associated with effectiveSUPPLEMENT TO SKIN & AGING • MAY 2007 • 3

IS WEIGHT-DEPENDENTDOSING IMPORTANT?Weight-dependent dose response is an issue thathas received more attention recently in dermatology,especially in relation to newer oral therapies foracne and rosacea.Analyses from the pivotal trials performed with antiinflammatorydose doxycycline (Oracea), administered asone capsule daily, calculated the absorption of doxycyclineand the clinical response correlated with mg per kg.Results demonstrated that increased patient weightwas associated with a lower doxycycline serum level.However, clinical response (drug efficacy) was independentof patient weight.These results suggest that anti-inflammatory dose doxycycline— controlled-release doxycycline 40 mg (Oracea)administered once daily — achieves optimal or near-optimalanti-inflammatory effect for treatment of rosacea.An extended-release minocycline tablet (Solodyn)has been evaluated in >1,100 patients. Researcherswere able to demonstrate that a dose of 1 mg/kg/dayproved to be as effective at 2 mg/kg/day and3 mg/kg/day for treatment of acne vulgaris. However,unlike the higher daily dosage regimens, patients treatedwith the extended-release tablet formulation ofminocycline at 1 mg/kg/day exhibited a side effectprofile comparable to placebo, and the lowest rate ofvestibular side effects.penetration of active ingredient and easy spreadability. Untilrecently, the hydroethanolic foam (HF) vehicle was the onlyform available, utilized with betamethasone valerate 0.12%foam (Luxiq, 1999), clobetasol propionate 0.05% foam(Olux, 2000) and clindamycin phosphate 1% foam (Evoclin,2004). The advantages of HF foam demonstrated in severaltrials include effective skin penetration of active ingredientinto diseased skin (ie. psoriatic plaques) withoutadverse impact on safety (topical and systemic), favorableefficacy, and a high overall level of patient preference dueto rapid penetration, easy spreadability, lack of residue andabsence of staining. However, due to high ethanol content,application to eczematous skin has been associated withstinging in some patients.As a result, the first petrolatum-based emulsion foam (EF)product, free of ethanol, was developed, incorporating desonide0.05%. Desonide 0.05% EF foam (Verdeso) is FDAapprovedfor treatment of atopic dermatitis in patients asyoung as 3 months of age. The efficacy and safety of thisdesonide formulation was evaluated in a double-blind, vehicle-controlled4-week Phase III trial inclusive of 387 activelytreated subjects. More recently, clobetasol propionate 0.05%has been incorporated into an EF formulation (Olux-E).The VersaFoam HF, is a “quick-break” foam that immediatelydisappears on contact with the skin because of rapiddissolution after exposure to normal skin temperature. Luxiqand Olux are the two products that utilize this particular technology.As the foam dissolves immediately upon skin contact,medication is best placed in the cap to allow the patientto more easily manage and direct application. A second formof HF product is slightly modified, using a higher meltingpoint upon contact with skin. As a result, the foam is “slowbreak”. This type of HF is used with the Evoclin formulation.The Evoclin can is held upright, with application veryamenable to a larger surface area, such as the chest andback. The patient can apply individual mounds of foam to differentareas before diffusely spreading the product as theapplied foam melts more slowly.The new VersaFoam EF vehicle used with desonideexhibits different formulation characteristics than the HFproduct. The EF and HF VersaFoams both demonstratethe advantages of easy use, lack of residue and easyspreadability based on patient preference assessments,and both facilitate optimal skin penetration of activeingredient based on studies completed in human skin.However, the EF is devoid of ethanol and exhibits emollientproperties due to the excipients contained in thevehicle. The EF is petrolatum-based, and also containslight mineral oil, and is “designed” for application toeczematous or dermatitic skin. Essentially, EF is a “nobreakfoam”, sitting in place after application to skin for along duration with very slow melting. After application,gentle spreading allows for easy distribution and rapidpenetration. In studies, 70% of patients found EF to bemoisturizing, with the majority expressing preferenceover other vehicles they have used, such as lotions,creams and ointments.THE RESURRECTION OF DESONIDEDesonide, used in clinical practice for 25 years, continuesto be the low-potency topical corticosteroid most frequentlyprescribed by dermatologists based on recognizedprescription databases. Approved by the FDA in September2006, desonide 0.05% foam (Verdeso) is indicated for thetreatment of atopic dermatitis in patients 3 months of ageand older. This product, formulated as an EF foam, was testedin terms of penetration versus branded desonide 0.05 %4 • MAY 2007 • SUPPLEMENT TO SKIN & AGING

WINTER CLINICAL DERMATOLOGY CONFERENCE PROCEEDINGSFigure 1. In Vitro Skin Penetration of DesonideEmulsion Foam (Verdeso) vs Desowen FormulationsVERSAFOAM-EF ~ PETROLATUM-BASED FOAM / NO ETHANOLFigure 2. Desonide 0.05% HydroGel (Desonate)Investigator Global AssessmentClear or Almost Clear ~ Week 4Desonide (ng) Concentration4003002001000Verdeso FoamDesowen CreamDesowen OintmentTime (h)% Subjects70DESONIDE GEL (n=425)6050403020100BaselineWeek 2Almost ClearClearWeek 4creams (DesOwen, Tridesilon) and ointments (DesOwen,Tridesilon) (Figure 1). As demonstrated with the HF foamscontaining betamethasone valerate 0.12% (Luxiq) and clobetasolpropionate 0.05% (Olux) in studies versus theirappropriate comparators, the EF allows for maximal penetrationof active ingredient into skin. This factor accounts forthe quickness and ease of penetration after application andfavorable efficacy results in clinical trials.The pivotal clinical studies of desonide 0.05% foam evaluateda variety of different efficacy parameters in patientsas young as 3 months of age. The study design demandedthat the product reach a high bar in order to achieve success.After 4 weeks of twice-daily application, 58% ofactively treated patients were rated as clear or almost clearas compared to 21% of those treated with the vehicle.Pruritus was resolved or very minimal at the 4-week endpointin 67% of patients treated with desonide 0.05% foamversus 26% of vehicle-treated subjects. As would beexpected with a petrolatum-based formulation, the incidenceof application-site tolerability reactions such asstinging proved to be 70% at baseline to

ENHANCING TREATMENTS WITH THERIGHT SKINCARE REGIMENSThere is quite a bit of evidence now that shows that dermatology-recommendedskincare regimens are provingto enhance therapeutic benefit of topical therapies foracne and rosacea. These regimens can reduce signs andsymptoms of the underlying disease and are proven toreduce skin irritation associated with topical therapy.One recent study specifically evaluated a brand liquidcleanser (Cetaphil Daily Facial Cleanser) in patients withmild acne vulgaris who were not undergoing acne therapyor using a moisturizer. Early in the course of thetrial, there was a reduction in lesion counts, which maybe captured as “vehicle effect” in a clinical trial. As skincareproduct use is specified and controlled in mostclinical trials, specific skincare regimens contribute toefficacy and tolerability results along with medicationsthat are used. The combination of the skincare regimenplus the medication equals the final result of a study,especially with disorders such as acne, rosacea oratopic dermatitis.Researchers were able to demonstrate in anotherstudy that there was no impairment of epidermal barrierfunction in patients with rosacea who were onlybeing treated with another liquid cleanser (CetaphilGentle Skin Cleanser). There was no increase intransepidermal water loss (TEWL), and corneometryparameters remained stable over the course of the trial.Dermatologist-directed skincare regimens help toimprove therapeutic results and reduce the potentialfor skin irritation, which may occur in association withuse of topical medications.THE IMPORTANCE OF THE DELIVERY SYSTEMIt has been shown that the azelaic acid 15% gel(Finacea) formulation provides greater penetration of azelaicacid into the skin than the 20% cream, even thoughthere is 5% more active ingredient in the cream. It has todo with delivery characteristics of the vehicle and the particulatenature of the active compound. Although FDAapprovedfor rosacea, studies have demonstrated thatazelaic acid 15% gel is effective for treatment of acne vulgaris,with efficacy comparable to topical benzoyl peroxideand to topical clindamycin shown in independently performedanalyses. Azelaic acid is also helpful in reducingpost-inflammatory hyperpigmentation.A new pump delivery system has been applied to bothbenzoyl peroxide 5%-clindamycin 1% gel (Benzaclin), andboth strengths of tretinoin microsphere gel (Retin-A Micro),0.04% and 0.1%. The tretinoin microsphere gel pump isavailable as 50 grams per canister. Each pump is meteredto deliver a fixed amount of product, with 400 pumps availableper container. The manufacturer suggests that twopumps are enough to adequately spread to evenly cover theface with diffuse application. If so, with a common applicationfrequency of once daily, one will utilize 60 pumps per 30days (two pumps per day). Ideally, a single canister shouldthen last 6.6 months. If the clinician suspects that moremedication needs to be administered for adequate facialcoverage and a patient is then instructed to apply fourpumps per day, a canister would then last 3.3 months. Inboth cases, the metering capability of the pump deliverysystem provides the ability to quantify use and to more preciselyeducate patients on how much medication to apply.COMBINATION THERAPYTopical retinoids, benzoyl peroxide, clindamycin, azelaicacid and sulfacetamide-sulfur are all effective when usedalone, but more so when used in combination.One recent study looked at the newly approved clindamycinphosphate 1.2% and tretinoin 0.025% gel (Ziana) ina once-a-day formulation. The 12-week trial of patients whohad moderate to severe acne vulgaris demonstrated that thecombination outperformed each of the individual componentsin this particular trial. Long-term tolerability assessmentdemonstrated that more than 90% of the patients treated upto 12 months had no burning, no stinging and no itching.Another recent study demonstrated enhanced therapeuticbenefit when anti-inflammatory dose doxycycline(Oracea) once daily is used in combination with once-dailyapplication of metronidazole 1% gel (Metrogel 1%).A GROWING ARMAMENTARIUMNew delivery systems and vehicles are expanding ourarmamentarium by providing a greater number of optionsfor our patients. As responses to treatment, tolerability andproduct preferences vary among patients, it is very importantthat new products be developed and released.References on file with the author.Dr. Del Rosso is Clinical Associate Professor ofDermatology at the University of Nevada School ofMedicine and Dermatology Residency Director at ValleyHospital Medical Center in Las Vegas.6 • MAY 2007 • SUPPLEMENT TO SKIN & AGING

WINTER CLINICAL DERMATOLOGY CONFERENCE PROCEEDINGSADVANCES IN ROSACEATHERAPYA REVIEW OF AVAILABLE THERAPIES.BY DIANE M. THIBOUTOT, M.D.Rosacea has several differentappearances. Thereare four well-defined subtypesof rosacea:1. erythemato-telangiectatic2. inflammatory3. phymatous4. ocularThe most typical appearancethat many of our patientsDiane M. Thiboutot, M.D. have is subtype 1 (erythematotelangiectatic).This facialredness is one of the symptoms that bothers patientsthe most, and our greatest challenge in the area ofrosacea is to try to develop therapies that can target thistype of redness.This article will cover several therapies for rosacea, providedata on how the therapies rate in clinical trials, discusspotential side effects and provide other general informationabout rosacea. This article will review new informationregarding oral, topical and physical therapies for rosacea,as well as over-the-counter products that can help withredness. And, while flushing is one of the most difficultaspects of rosacea to control, this article will not focus onit because no effective treatment exists for flushing.THERAPEUTIC APPROACHOne of the first things to discuss with rosacea patientsis what constitutes a good skincare regimen. Discuss sunprotection, avoidance of trigger factors and proper skinand eye care. Explain the rationale behind the choices fordifferent therapies. What’s the advantage of an oral therapycompared to a topical therapy? Should they both beused together? When should a patient use oral therapy?When should a patient use the topical therapy? These arequestions that patients have.ORAL THERAPIESOral therapies target the inflammatory lesions and ocularrosacea, flushing, and the very extreme or recalcitrant tracesof rosacea. For the extreme or recalcitrant rosacea,isotretinoin can be used. However, in my experience, patientsseem to do well while taking isotretinoin, but unlike with acne,when patients stop the isotretinoin, the rosacea comes backand it tends to be just as bad.Tetracyclines can target inflammatory activity. Tetracyclines candownregulate the expression of proinflammatory cytokines. Theycan inhibit the production of arachidonic acid metabolites, whichlead to inflammation. They can inhibit angiogenesis, reactive oxygenspecies, neutrophil chemotaxis and matrix metalloproteinases.This newest product in this category is an anti-inflammatorydose doxycycline in a 40-mg controlled release formulation(Oracea). It’s formulated with 30 mg of doxycycline in animmediate release, and then 10 mg that’s released over time.This is FDA approved as a once-daily treatment of rosacea,and at this dose it does not kill bacteria.With regular doxycycline 50 mg twice a day, you exceed thelevel needed to kill bacteria, which would, therefore, raise concernsabout bacterial resistance. With Oracea’s formulation, it neverreaches that antimicrobial level, so it doesn’t kill the bacteria, yet itstill has the beneficial anti-inflammatory properties of tetracycline.There were two Phase III pivotal trials in patients withrosacea for Oracea. 1 They were 16-week studies with 537patients. In the first study, the reduction in inflammatorylesions was about 60%. In the second study there was areduction in inflammatory lesions on the order of 50%.In terms of safety for Oracea, there was no antimicrobialactivity. There was no evidence of adverse events. One of theadvantages to using the sub-antimicrobial dose of doxycyclineis that patients don’t get the side effects associated withfull dose antibiotics. The contraindications and warnings 2 aresimilar to those found in any tetracycline, such as hypersensitivityand risk of tooth discoloration.SUPPLEMENT TO SKIN & AGING • MAY 2007 • 7

Attendees learning during a presentation at the Winter Clinical Dermatology Conference Hawaii. ®It’s important to note that for almost all rosacea treatments,the reduction rates in inflammatory lesions are very similar.Reduction rates range from 48% to 55% or 60%. Obviously,there are differences among therapies and differences amongour patients — it’s a matter of finding the right treatment regimenthat works for a particular patient.TOPICAL THERAPIESThe primary topical therapies are metronidazole (MetroGel,Noritate), azelaic acid (Finacea) and sulfacetamide/sulfurproducts (Avar, Clenia, Plexion, Rosac, Rosanil, Rosula,Sulfacet-R, Klaron and Ovace). 3 These therapies have beenstudied and approved for use in rosacea. Secondary topicaltherapies that are used in rosacea, but that have not been ashighly studied, include clindamycin, erythromycin and benzoylperoxide. Other agents, tretinoin and the topical calcineurininhibitors, have been used on a case-by-case basis.Metronidazole is available as 1% gel or cream and also as a0.75% generic formulation. The 1% metronidazole gel(MetroGel) is in a vehicle containing 92% water and HAS-3 (amixture of three hyrdo-solubilizing agents: niacinamide, betadexand a low concentration of propylene glycol). A comparative invitro study compared the penetration of the 1% gel to the 1%cream. 4 The study found that there was much more of the gelcontained within the skin compared to the cream. In terms ofreduction in inflammatory lesions, after 10 weeks there wasabout a 67% reduction. The global assessment or percentageof patients assessed with a score of clear, mild or almost clearafter the 10 weeks included about 73% of patients.The 1% gel is indicated for the inflammatory lesions ofrosacea. Burning, skin irritation, dryness, transient redness,metallic taste, tingling, numbness of extremities and nausea areside effects associated with topical use of metronidazole.Azelaic acid 15% (Finacea) was one of the first productsthat was re-formulated from a cream to a gel. It was formulatedas a stable aqueous, polyacrylic-acid-based gel. Severalstudies showed a higher percentage of dissolved azelaic acidin gel (25%) versus cream (3%), for improved drug releaseand bioavailability. A hairless mouse study showed there isalso a higher absorption into skin (25.3%) with the gel ascompared to the cream (3.4%).Efficacy and safety for azelaic acid 15% to treat moderatepapulopustular rosacea was evaluated in three Phase III, multicenter,double-blind, randomized studies (n=955). 6,7 Data fromthe Phase III trials show that the reduction in inflammatory lesionswas about 54% after 12 weeks of treatment. In one study, 6 thefacial erythema of the patients was also rated. The percentage ofpatients who had improvement in erythema was statistically significantlydifferent from the placebo group with 45% of patients inthe azelaic acid group showing improvement in erythema comparedto 28% in the placebo group (p

WINTER CLINICAL DERMATOLOGY CONFERENCE PROCEEDINGSOne study evaluated the effects of a pulsed dye laser in16 patients with erythematotelangiectatic rosacea. 9 After twotreatments at 8-week intervals, patients showed improvement intheir symptoms, quality of life scores and erythema. In anotherstudy that also evaluated pulsed dye laser therapy, 10 patientswith papulopustular rosacea with erythema and telangiectasiaunderwent half-face treatments. 10 They had an average of 2.4treatments until symptoms resolved. There was a mixedresponse in terms of improvement of papules and pustules.These physical therapies seem to be more effective at targetingtelangiectasia and erythema, while papules and pustules are bettertargeted by the topical and oral medical therapies discussed.In terms of intense pulsed light therapy, there is a need formore controlled trials for evaluating this treatment for rosacea. Ina 2003 study, 11 four patients with erythema and telangiectasiaunderwent five treatments with Photoderm VL 15 nm-light at 3-week intervals. Patients were assessed at baseline and 1 monthfollowing the last treatment. Results showed there was a 30%decrease in blood flow using Doppler, a 29% decrease in thearea of the cheek involved with telangiectasia and a 21%decrease in erythema using computer analysis of photographs.Therapies for rhinophyma, an area that can make a bigdifference in patients’ appearances, include cold steel excision,CO 2 laser, the cauterizing scalpel and a combination ofthese treatments.OVER-THE-COUNTER PRODUCTSIn the past year, a significant number of advances in over-thecountertherapies have emerged. Some moisturizers, sunscreensand cleansing products now contain natural ingredientsthat in vitro studies and small clinical studies have suggestedmight help to improve erythema in rosacea patients, and probablyin acne patients as well. One such ingredient isLicochalcone, which is found in the Eucerin brand of the antirednessproducts. It is a licorice root extract that inhibits lipoxygenase,which is in the arachidonic acid pathway. The productsinclude claims for reduction of sebum production, sun protectionand reduction of facial redness. Although it is not knownhow they were all tested, it is known that this ingredient caninhibit this particular enzyme and may then reduce erythema.The Aveeno and Purpose anti-redness lines of skin care containfeverfew. Feverfew is an allergen, but for these products feverfewhas been modified so that it’s not antigenic, and it seems towork well in these over-the-counter lines for reducing redness.MANY OPTIONS FOR ROSACEAIn summary, the medical treatments work best against theinflammatory lesions. The medical treatments also may helpwith erythema, though results are not consistent and it’s difficultto predict which patients will see improvement in erythema.The physical modalities seem to be the most effective forthe telangiectasia and for persistent erythema. Lifestyle modificationcan also help. Patients need to avoid trigger factors,and there are simple everyday modifications patients canmake to improve their conditions. For example, a lot of peoplewith rosacea may be blow-drying their hair, and the heatof the hair dryer can be irritating and lead to flare. Air-dryinghair could help avoid a flare. Cosmetics, such as green-tintedfoundations and makeup, help to mask the erythema.There are many options for rosacea, but there is no oneright answer, there is no one magic medication. Working withpatients to develop regimens they can adhere to and beingwilling to adjust those regimens as needed will make a big differencein successful patient outcomes. ■Dr. Thiboutot is Professor of Dermatology at ThePennsylvania State University College of Medicine, MiltonS. Hershey Medical Center in Hershey, PA.REFERENCES1. Data on file, CollaGenex Pharmaceuticals, Inc.2. Oracea (prescribing information). Newtown, Pa; CollaGenexPharmaceuticals, Inc; 2006.3. Nally JB, Berson DS. Topical therapies for rosacea. J DrugsDermatol. 2006 Jan;5(1):23-6.4. Dow G, Basu S. A novel aqueous metronidazole 1% gel withhydrosolubilizing agents (HSA-3). Cutis. 2006 Apr;77(4 Suppl):18-26.5. Data on file – Galderma Study Report #0215-R5.C-01-02.6. Thiboutot D, Thieroff-Ekerdt R, Graupe K. Efficacy and safety ofazelaic acid (15%) gel as a new treatment for papulopustularrosacea: results from two vehicle-controlled, randomized phaseIII studies. J Am Acad Dermatol. 2003 Jun;48(6):836-845.7. Elewski BE, Fleischer AB Jr, Pariser DM. A comparison of 15%azelaic acid gel and 0.75% metronidazole gel in the topicaltreatment of papulopustular rosacea: results of a randomizedtrial. Arch Dermatol. 2003 Nov;139(11):1444-1450.8. Liu RH, Smith MK, Basta SA, Farmer ER. Azelaic acid in the treatmentof papulopustular rosacea: a systematic review of randomizedcontrolled trials. Arch Dermatol. 2006 Aug;142(8):1047-1052.9. Tan SR, Tope WD. Pulsed dye laser treatment of rosaceaimproves erythema, symptomatology, and quality of life. JAmAcad Dermatol. 2004 Oct;51(4):592-599.10. Berg M, Edstrom DW. Flashlamp pulsed dye laser (FPDL) did not curepapulopustular rosacea. Lasers Surg Med. 2004;34(3):266-268.11. Mark KA, Sparacio RM, Voigt A, Marenus K, Sarnoff DS.Objective and quantitative improvement of rosacea-associatederythema after intense pulsed light treatment. Dermatol Surg.2003 Jun;29(6):600-604.SUPPLEMENT TO SKIN & AGING • MAY 2007 • 9

ACNE: THERAPEUTIC DILEMMASSOLUTIONS FOR COMMON PROBLEMS WHEN TREATING ACNE.BY JULIE C. HARPER, M.D.Julie C. Harper, M.D.Many dermatologiststhink of acne as verystraightforward. In fact,many dermatologists say thatacne is something that their midlevelprovider treats, and that theyonly treat acne patients if somethingis going awry. Unfortunately,sometimes things do go awry.This article will focus on someof the common therapeuticdilemmas you may run intowhen treating acne patients.DILEMMA 1: TREATING ACNE IN THEPREGNANT FEMALEWhether a patient is pregnant or trying to become pregnant,she has to be treated differently than a femalepatient who is not contemplating pregnancy. Here is arundown of typical acne treatments and what is and is notsafe for pregnant patients.Tetracyclines. This is really the root of the way that we normallytreat acne patients. However, tetracyclines areCategory D, so not a good choice for pregnant patients or forthose contemplating pregnancy. Tetracyclines can causestaining of the deciduous teeth, enamel hypoplasia, and maycause a decrease in bone growth as well.Erythromycin. This Category B treatment is a safe alternativein pregnancy both topically and systemically. While not atreatment of choice for patients not pregnant or trying to getpregnant, it is a good option for pregnant patients. Avoiderythromycin estolate, though, because it has been shown tocause elevation of the liver transaminase in the mother andshould be avoided in pregnancy.Clindamycin. Also a Category B drug, this can be usedsafely in this patient population. There have been no problemswith intravenous, topical or oral application of clindamycinduring pregnancy.Benzoyl peroxide. Although this is considered CategoryC, it is completely metabolized in the skin to benzoic acid,it enters the dermal vasculature as benzoate or benzoicacid, and it is excreted unchanged by the kidney. It is consideredsafe during pregnancy, but studies of chronic usehave not been done.Azelaic Acid. This Category B drug can be used safely totreat pregnant females. However, in my experience, I’ve hadgreat success with azelaic acid in rosacea, but not as muchin acne, so I don’t normally use this in my acne patients.Topical Retinoids. I think every acne patient should beon a topical retinoid unless she is pregnant or contemplatingpregnancy. Tretinoin and adapalene fall into Category Cand Tazarotene is Category X, but no matter which category,these should not be used in patients who are pregnantor trying to become pregnant. Case reports exist describingcongenital malformations with both tretinoin and adapaleneuse during pregnancy.DILEMMA 2: SENSITIVE SKIN AND IRRITATIONFROM TOPICALSThis is a problem we all deal with every day, and it can bea dilemma. There are patients who will present to you afterthey’ve already seen five other dermatologists, and have triedeverything that you have in your armamentarium topically, andthey just don’t tolerate anything.The first thing we need to determine is, what is sensitiveskin? Subjectively, it is reduced tolerance to environmentalfactors and/or to the application of topical products. 1Objectively, signs of sensitive skin to look for in patientsinclude dry, rough skin, disturbance of barrier function,hyper reaction of skin blood vessels, increased transcutaneouspenetration of water soluble chemicals andenhanced immune responsiveness. 210 • MAY 2007 • SUPPLEMENT TO SKIN & AGING

WINTER CLINICAL DERMATOLOGY CONFERENCE PROCEEDINGSPREGNANCY RISK CATEGORIESDrugs are categorized as A, B, C, D or X based on their potential risk in pregnancy.Category AControlled studies show these drugs show no risk. There are not very many drugs that fitinto this category. Thyroid hormone, folic acid and prenatal vitamins are some of the feware considered to be part of this category.Category BThese drugs show no evidence of risk to humans. Either animal findings show risk buthuman findings do not, or if no adequate human studies have been done, animal findingsare negative. Erythromycin and clindamycin fit into this category.Category CRisk with drugs in this category cannot be ruled out. Human studies are lacking and animalstudies are either positive for fetal risk or they are lacking as well. However, potentialbenefits may justify the potential risk.Category DPositive evidence for risk exists. Investigational or post-marketing data show risk tothe fetus. However, potential benefits may outweigh the potential risk. Tetracyclinesfall into this category.Category XDrugs in this category are contraindicated in pregnancy. Studies in animals or humans, orinvestigational post-marketing reports have shown fetal risk, which clearly outweighs anybenefit to the patient.Dr. James Leyden published some interesting findings inthe Journal of Drugs and Dermatology. 3 He studied agroup of patients, some with normal skin, some with sensitiveskin, and he used different concentrations and differenttypes of retinoids. He also used different formulations orvehicles. He found that having a sensitive skin history wasthe biggest indicator of how well patients would toleratethese retinoids down the line.Formulation did matter, but not in the way many of uswould assume. All gels are not more irritating than allcreams. Tazarotene gel was more irritating than tazarotenecream but then the adapalene gel was better toleratedthan adapalene cream. Similarly with the Retin-A products,the gels were better tolerated than the creams. Keep inmind the gels of today are a little different than some of theones that we’ve used in the past. It doesn’t mean that thecream formulation is always going to be the one that’s easierfor the patient to tolerate. Concentration played a role,too. If the lower concentration of retinoid was applied tothe skin, there was less irritation.So how do we treat sensitive skin patients? First of all, takethe time to prescribe and recommend skincare products,and eliminate things that are potentially irritating. Encouragesunscreen use in every patient because ongoing sun andenvironmental damage can break down the barrier function.Prescribe lower concentrations and less-irritating formulationsof topical products. Consider alternate-day dosing or ashort-contact therapy.DILEMMA 3: ORAL CONTRACEPTIVESAND ANTIBIOTICSOf all the alleged antibiotic-oral contraceptive interactions,76% involve rifampin (Rifadin, Rimactane, Rofact). 4Rifampin is a potent inducer of cytochrome p450, whichincreases the metabolism of oral contraceptives andother medications.SUPPLEMENT TO SKIN & AGING • MAY 2007 • 11

The hypothesis is that antibiotics decrease the gut florathat are needed to further degrade inactive metabolitesof the oral contraceptives to activate the drug duringenterohepatic recirculation.There have been studies in the dermatology literaturethat actually looked to see if there was a difference inpregnancy rates between women who were on oral contraceptivepills alone versus on oral contraceptives andantibiotics together. In one study, 5 281 women weresurveyed. Thirty-four women had used a low-estrogenoral contraceptive pill and antibiotics for a combinedtotal of 71 years. One woman on tetracycline and oralcontraceptive pills for 12 months did become pregnant.This gave an overall pregnancy rate of 1.4%. The typicalfailure rate of an oral contraceptive pill — withoutperfect use — is 3%.Another slightly larger study 6 looked at 356 women onbirth control pills and antibiotics compared to 425 onbirth control pills alone. The pregnancy rate betweenthose two groups was not statistically different (1.6% vs.0.96%, respectively).DILEMMA 4: DOXYCYCLINEAND PHOTOTOXICITYThe reported incidence of this is low; it’s less than 5%, 7but it is something we all see. Most commonly, it is seenon the dorsum of the hands. Patients will complain ofstinging and burning before they even see any erythema.Keep in mind that these phototoxic eruptions are doserelated. 8 If a patient is going to be in the sun a lot or ishaving problems while on doxycycline, decrease thedose or have the patient take it just once a day.Also, Oracea, the low-dose doxycycline, is a goodoption. It’s 40 mg per day and studies for this drug havehad zero reports of phototoxicity, which lends support tothe fact that a lower dose of doxycycline should be lessassociated with problems of phototoxicity.DILEMMA 5: ISOTRETINOINAND TRIGLYCERIDESA report by Dr. Lee Zane, which recently was publishedin Archives of Dermatology, found abnormal lab valuesduring treatment with isotretinoin. 9 In this particular study,abnormal values were found 44% of the time that triglycerideswere measured, 31% of the time cholesterol wasmeasured, and 11% of the time hepatic transaminasewas measured. He also looked at platelets, white bloodcell counts and hemoglobin levels, and those werealmost not even on the charts.There are no real guidelines on how we should monitorthese labs during isotretinoin therapy, but I always checktriglycerides, cholesterol and liver function tests.REGISTER YOUR ISOTRETINOINPATIENT, OFFER CONTRACEPTIVECOUNSELING, DISCUSS RISKS ANDBENEFITS, AND GET THAT NEGATIVEPREGNANCY TEST.Normal triglycerides are less than 150 mg/dl, borderlinehigh triglycerides are 150 mg/dl to 199 mg/dl,high triglycerides are 200 mg/dl to 499 mg/dl, andthen very high is greater than 500 mg/dL. Patients with levelsgreater than 1000 mg/dl have a high risk for pancreatitis.We do know that isotretinoin can increase triglycerides,total cholesterol, and low-density lipoprotein (LDL) cholesterol.However, there are some things we can do to helpprevent this. Non-pharmacological approaches for patientswho have hypertriglyceridemia as a result of isotretinoin areweight loss, reduced carbohydrate intake (low-carb dietsmay decrease triglyceride levels by 20% to 28%), decreasedalcohol consumption and increased exercise. 10The fibrates (gemfibrozil, fenofibrate) can reducetriglycerides by 25% to 50%. Gemfibrozil 600 mg recommended. Niacin can reduce triglycerides by20% to 40%. Niacin 1.5 to 2 grams per day is typical.Start with niacin 500 mg at bedtime for 1 month andthen increase to 1000 mg at bedtime. Flushing may belessened by taking a chewable aspirin 30 minutes priorto taking niacin.Fish oil, or omega-3 fatty acids, can reduce triglyceridesby 30% to 40%. Fish oil is available over thecounter in 1 gram capsules (3 grams per day can lowertriglycerides by 30% and 9 grams by 50%). Somepatients won’t tolerate the smell of it; taking it with otherfood should help to downplay the smell and the taste ofthe fishiness.Statins will lower LDL and total cholesterol and lowertriglycerides by up to 30%. If a patient has both elevationsin cholesterol and triglycerides, he or she might dobetter with a statin.12 • MAY 2007 • SUPPLEMENT TO SKIN & AGING

WINTER CLINICAL DERMATOLOGY CONFERENCE PROCEEDINGSDILEMMA 6: ISOTRETINOIN ANDINFLAMMATORY BOWEL DISEASEThis is a problem we have known about for a long time.It is in the iPLEDGE manual that isotretinoin can causeabdominal and stomach problems. Recently, a newreview 11 looked at the FDA Medwatch, which is a voluntaryreporting system where individuals, whether physiciansor consumers or manufacturers, can voluntarily callthe FDA and report adverse events.There were 85 cases of inflammatory bowel diseaseassociated with isotretinoin between 1997 and 2002. TheNaranjo adverse drug reaction probability scale was usedto evaluate the association between these. Based on thisindex, 5% of these 85 cases were deemed highly probable,68% were probable, 27% were possible and 0 caseswere deemed doubtful.Most of these cases occurred when the isotretinoin wasgiven, inflammatory bowel disease symptoms developed,the medication was stopped, and those symptoms wentaway. These patients were re-challenged. They weregiven isotretinoin again, and the inflammatory bowel diseasecame back. It is not conclusive whether or not this isjust coincidence, but it’s important to be aware of thiseffect in clinical practice.REMEMBER, ONCE YOU REGISTERYOUR FEMALE PATIENTS, YOU HAVE AFULL 90 DAYS TO WRITE THE FIRSTPRESCRIPTION BEFORE THEY AREKICKED OUT OF THE iPLEDGE SYSTEM.DILEMMA 7: iPLEDGERecently, there has been good news regardingiPLEDGE. There is no longer a 30-day lockout for femalesof non-childbearing potential or for males, so the programcan be simple for these patients.For females of childbearing potential, it’s still a little bittricky. Start oral contraceptives before starting a patient onisotretinoin — the patient may see excellent results withthe oral contraceptive and never need to start isotretinoin.Remember, once you register your female patients, youhave a full 90 days to write the first prescription beforethey are kicked out of the system. And in my experience,if you’re going to use an oral contraceptive pill, it takesabout 90 days to see a result with acne. So if you do reallywant to try that before starting the patient onisotretinoin, the second you prescribe that oral contraceptivepill, register the patient in iPLEDGE. You then have that90-day window that first time. Once a patient has filled herprescription, she only has 60 days each time.Register your patient, offer contraceptive counseling, discussrisks and benefits and get that negative pregnancytest. The first pregnancy test can be done with a dipstick inyour clinic. Every other pregnancy test from that point onhas to be done in a CLIA-certified lab. ■Dr. Harper is Clinical Associate Professor ofDermatology, University of Alabama at Birmingham inBirmingham, AL.REFERENCES1. Sparavigna A, Pietro A, Setaro M. Sensitive skin: correlation withskin surface microrelief appearance. Skin Res Technol. 2006Feb;12(1):7-10.2. Roussaki-Schulze AV, Zafiriou E, Nikoulis D, et al. Objective biophysicalfindings in patients with sensitive skin. Drugs Exp ClinRes. 2005;31 Suppl:17-24.3. Leyden J, Grove G, Zerweck C. Facial tolerability of topicalretinoid therapy. J Drugs Dermatol. 2004 Nov-Dec;3(6):641-651.4. Hersh EV. Adverse drug interactions in dental practice: interactionsinvolving antibiotics. Part II of a series. J Am Dent Assoc.1999 Feb;130(2):236-251.5. London BM, Lookingbill DP. Frequency of pregnancy in acnepatients taking oral antibiotics and oral contraceptives. ArchDermatol. 1994 Mar;130(3):392-393.6. Helms SE, Bredle DL, Zajic J, et al. Oral contraceptive failure rates andoral antibiotics. J Am Acad Dermatol. 1997;36(5 Pt 1):705–710.7. Maibach H. Second-generation tetracyclines, a dermatologicoverview: clinical uses and pharmacology. Cutis. 1991Nov;48(5):411-417.8. Layton AM, Cunliffe WJ. Phototoxic eruptions due to doxycycline--adose-related phenomenon. Clin Exp Dermatol. 1993Sep;18(5):425-427.9. Zane LT, Leyden WA, Marqueling AL, Manos MM. A populationbasedanalysis of laboratory abnormalities during isotretinoin therapyfor acne vulgaris. Arch Dermatol. 2006 Aug;142(8):1016-1022.10. Dunbar RL, Rader DJ. Demystifying triglycerides: a practicalapproach for the clinician. Cleve Clin J Med. 2005Aug;72(8):661-6, 670-2, 674-675 passim.11. Reddy D, Siegel CA, Sands BE, Kane S. Possible associationbetween isotretinoin and inflammatory bowel disease. Am JGastroenterol. 2006 Jul;101(7):1569-1573.SUPPLEMENT TO SKIN & AGING • MAY 2007 • 13

MANAGING ATOPIC DERMATITISIN ADULTSTHE BEST TREATMENTS FOR THE WORST CASES.BY JAMES S. TAYLOR, M.D.According to the AmericanAcademy of Dermatology’s(AAD’s) Guidelines of Careon its Web site (,atopic dermatitis is defined as achronic inflammatory pruritic skindisease that is more common inchildren than in adults. IgE levelsare often elevated, and patientshave a personal and family historyJames S. Taylor, M.D. of type 1 allergy symptoms. Thereis no single distinguishing feature oragreed-upon laboratory test for the diagnosis.The following is a personal perspective for evaluating andtreating patients with severe atopic eczema.Though atopic dermatitis is more common in children, italso affects adults. In fact, this condition can have severenegative effects on patients’ quality of life.A cross-section of findings in severe cases includesworsening of eczema, especially of the hands and face,dissemination, and secondary infection with weeping,draining lesions. Itching is often constant, worse in the winterbut often in hot weather as well, and accompanied bymarked excoriation and lichenfication, especially of theface, hands, periorbital areas and trunk. Patients in wetwork occupations, such as cosmetologists, machinists andhealthcare workers, may be significantly impaired from performingtheir activities of daily living at home, at school andat work. Friends and family may complain of the constantscratching, scale and foul odor when infected.Topical treatments may burn when applied and are reportedto not be effective. Patients have seen multiple dermatologistsand allergists, especially with accompanying allergicrhinitis and asthma and with persistence may abandon allopathiccare for homeopathic physicians. Long-term atopicdermatitis patients may present with striae from constant topicaland/or systemic corticosteroid use, a history of hospitalizationfor erythrodermic flares and occasional suicidalideations. Patients with the most severe forms of the diseasemay be applying for Social Security Disability and or Workers’Compensation. This is a typical representation of the worstcases of atopic dermatitis.ATOPIC DERMATITIS IN ADULTSThere are three patterns of presentation of atopic dermatitisin adults. The first includes patients who have never been freeof disease since childhood. The second includes patientswhose atopic dermatitis disappeared in childhood, then reappearedas typical atopic dermatitis in adulthood. And the thirdincludes patients whose childhood atopic dermatitis disappeared,then reappeared in adulthood under a different guise,such as hand eczema, which is not recognized as related tothe childhood disease.In adults, atopic dermatitis typically affects the hands.Chronic hand eczema is seen in 60% to 70% of adults withatopic dermatitis. It also commonly involves the head, neck,and periocular and eyelid areas. Exfoliative erythroderma isseen in the most severe cases.CLINICAL COMPLICATIONS OFATOPIC DERMATITISIt’s important to be aware of clinical complications such asinfection with Staphylococcus aureus. A less common butmore troublesome infection is molluscum contagiosum, whichrequires modification of topical and systemic treatment. Herpessimplex causing Kaposi’s varicelliform eruption is an importantcomplication that should not be overlooked. Other complicationsinclude lymphedema of the hands from recurrent cellulitisand lymphangitis, which is fortunately infrequent, and the morecommon stasis dermatitis with autoeczematization.Erythroderma with high output congestive heart failure is rare inmy experience. Flares of atopic eczema may be triggered by16 • MAY 2007 • SUPPLEMENT TO SKIN & AGING

WINTER CLINICAL DERMATOLOGY CONFERENCE PROCEEDINGSAttendees visit the exhibit area at the Winter Clinical Dermatology Conference Hawaii. ®reactions to systemic medications, allergic contact dermatitis tonickel in metal jeans buttons and from topical therapies, trauma(dermatitis in loco minoris), and irritation from wet work and evenclothing labels and tags.DIFFERENTIAL DIAGNOSESThere are a number of disorders in the differential diagnosesof atopic eczema. With facial involvement, consider irritant andallergic contact dermatitis — direct from applied cosmetics andtherapies; occasional from a pillow, for example; or ectopic fromnail polish; systemic, connubial and airborne. Photosensitivityand other facial dermatoses should also be considered.With hand involvement, consider allergic contact dermatitis,particularly if there is a change in pattern from the palmsto the dorsum or from the web spaces to the fingertips.Contact urticaria is not uncommon and may evolve intoeczema. Hyperkeratotic, frictional and nummular eczema, ora hybrid of all of these, are diagnoses to consider.With whole body involvement, the differential diagnosesincludes chronic dermatoses, such as seborrheic, asteatoticand nummular dermatitis, lichen simplex chronicus, and psoriasis.Also don’t overlook infections and infestations, such asscabies, dermatophytosis (especially in the axilla andperineum) and HIV. Also don’t forget metabolic and geneticconditions, immunologic disorders, drug eruptions and primaryimmunodeficiencies. Pemphigus foliaceus can mimicerythroderma and exfoliative dermatitis.ADULT ECZEMA EVALUATIONWhen evaluating the adult patient with eczema, it’s importantnot to call it idiopathic, even if contact dermatitis, drugeruptions and childhood atopic eczema have been excluded.Workup should include complete dermatological and physicalexamination, including the abdomen and lymph nodes, whichshould be repeated every 3 to 6 months as needed.Rule out systemic causes of erythroderma with skin biopsies,including cultures and gene rearrangement; laboratorywork including CBC and peripheral smear, metabolic profileand Sezary cell studies; chest X-ray and imaging studies; andconsideration of biopsy of enlarged lymph nodes.Then, patch test with an expanded standard tray when theskin is clear. If you can’t clear the back entirely, patch test onlow-dose prednisone (~10 mg per day), especially with changingpatterns of dermatitis. Then also consider testing for contacturticaria, radioallergosorbent tests (RASTs) for someinhalant allergens and latex, and prick testing by an allergist.TREATING ADULT ATOPIC DERMATITISTherapy with topical corticosteroids is the first line and thevarious factors to consider when determining which one touse include site, severity, chronicity and vehicle issues. Startwith the most potent to control, then taper to daily or lessoften use. I prefer ointments such as triamcinolone, fluocinoloneand non-augmented betamethasone dipropionateover creams. There are newer formulations that deliverincreased potency. If patients are applying corticosteroidsaround the eyes, I recommend that they have their eye pressurechecked intermittently. Known side effects include atrophy,striae, rosacea, periorbital dermatitis, systemic absorptionand contact dermatitis.When topical corticosteroids demonstrate no response or arenot advisable, topical calcineurin inhibitors (TCIs) are indicatedfor short-term, non-continuous use twice a day in non-immunocompromisedpatients from 2 to 15 years of age. TCIs are goodfor the eyelids, face and folds, and also the trunk and extremities,and generally I prefer tacrolimus (Protopic), though pimecrolimus(Elidel) is also an option. Alternating a TCI with a topicalcorticosteroid is an effective treatment option.Alcohol intolerance is an interesting side effect of TCI treatmentand occurs in about 7% of patients. Patients experienceSUPPLEMENT TO SKIN & AGING • MAY 2007 • 17

a localized vascular flush reaction confined to the head andneck with a feeling of warmth; it doesn’t occur in other treatedareas. Flushing occurs between 5 to 15 minutes of alcoholingestion, fading after 60 minutes.There is a need to counsel patients about the FDA blackbox warnings for TCIs. I reassure patients and parents and tellthem that scientific evidence is lacking for neoplasia. I alsogive them the National Eczema Association statement on thisor refer them to the AAD Web site.EMOLLIENTS ARE A FIRST-LINETHERAPY FOR PATIENTS WITH MILDTO MODERATE ECZEMA, AND ANIMPORTANT ADJUNCTIVE THERAPYFOR OTHER PATIENTS WITHATOPIC ECZEMA.OTHER THERAPIESEmollients are a first-line therapy for patients with mild tomoderate eczema, and an important adjunctive therapy forother patients with atopic eczema. There are also several newprescription topical therapies available. These are steroidfree,TCI-free, and target xerosis in the compromised barrierfunction. One interesting point is that these are FDA approvedas devices and not drugs. First, Biafine was approved, followedby MimyX and Atopiclair, all of which contain a numberof lipids. More recently, Epiceram, which contains ceramides,became available. And there is also CeraVe, which is a nonprescriptionceramide-containing product.Colloidal baths can help in severe cases, and coal tar isuseful. Doxepin cream can also be used, though a number ofpatients develop allergic contact dermatitis from use of thistopical antihistamine. It was introduced in 1994 and becauseI saw so many allergic patients, I included it on my standardpatch test tray and reported 13 cases in the Archives ofDermatology in 1996. The FDA confirmed this finding in areport in the Journal of the American Academy ofDermatology in 2003. There is significant percutaneousabsorption with this drug, so it’s critically important to not useit in infants or children under the age of 12. Pramoxine-containinglotions, creams and ointments may be helpful.Lidocaine creams are being used more often, though we dosee occasional contact dermatitis from this, and diluted capsaicinhas been used. Bleach baths can also be useful inreducing recurrent cutaneous S. aureus skin infections.Topical and systemic antibiotics are also important, but shouldbe used for limited periods of time. Oral antihistamines are saidto be ineffective, though I still use them as helpful adjuncts. I preferfexofenadine 180 mg during the day and doxepin 10 mg to25 mg at night. Ultraviolet light therapy is still very important —UVA1 or narrowband UVB are more commonly used. For handand foot eczema, bath PUVA is quite helpful.SYSTEMIC THERAPYSystemic corticosteroids are effective for severe flaresof atopic dermatitis and should be used short term andintermittently. Monitor and treat for osteoporosis, especiallyif patients are or have been using systemic corticosteroidslong term.My next step would be to consider methotrexate 12.5 mg perweek or lower with appropriate laboratory and clinical monitoring.In addition to routine laboratory work I screen for hepatitis.Other systemic and emerging therapies include cyclosporine,interferon gamma and probiotics. Of these, cyclosporine is anexcellent drug for quickly controlling severe flares of widespreadand recalcitrant disease, but long-term use is limited. Next, considerazathioprine or mycophenolate mofetil, with appropriatelaboratory monitoring, though data on efficacy is limited. Thereis insufficient data on leukotriene inhibitors.In terms of the biologics, the most data exist for omalizumab(Zolair) and efalizumab (Raptiva). Of these, ourdepartment has had limited experience with good resultsfrom efalizumab, but caution for Staphylococcus infectionand thrombocytopenia is warranted. Some data exist foretanercept (Enbrel) and infliximab (Remicade), adalimumab(Humira) and alefacept (Amevive).A MULTI-FACTORIAL DISEASEAtopic dermatitis is a multi-factorial genetic and environmentaldisease. It’s important to identify the complicationsand treatable associations such as contact dermatitis, andthe approach for treating the worst cases will probablydepend on patient experience and acceptance.Severe disseminated, recalcitrant atopic eczema is one ofthe most impairing and disabling skin diseases and topicaltherapy clearly is often not adequate. In these cases one hasto consider systemic therapy, and hopefully there will benewer or less-toxic therapies in the future. ■Dr. Taylor is Head of the Section of IndustrialDermatology at the Cleveland Clinic and he is VicePresident-Elect of the American Academy of Dermatology.18 • MAY 2007 • SUPPLEMENT TO SKIN & AGING

ACNE AND THE ADULT FEMALETIPS ON WHEN AND HOW TO USE HORMONAL THERAPY.BY DIANE M. THIBOUTOT, M.D.When treating acne in theadult female patient,conventional therapy isa good place to start — a topicalretinoid, a benzoyl peroxide andan antibiotic. Depending on theseverity of the acne, that antibioticcan either be topical or oral. Ifthese treatments provide noimprovement for a patient, and ifDiane M. Thiboutot, M.D. there are other signs of androgenism,then I would do a hormoneevaluation. Based on findingsfrom the evaluation, I would then consider adding hormonaltherapy to the regimen. In my experience, though, I havefound that hormonal therapy by itself is not highly effective, soI typically use it as an adjuvant to conventional therapy.PATHOGENESIS OF ACNEWe know that follicular keratinization exists, and this is thearea that’s targeted by topical retinoids because topical retinoidswork very well at normalizing the follicle. We also know thatPropionibacterium acnes causes inflammation. Interestingly,Jenny Kim, M.D., Ph.D., of the David Geffen School of Medicineat UCLA, found that P. acnes bacteria can activate the Toll-likereceptor 2 (TLR2) that sits on the surface of an inflammatory cell— when the P. acnes bacteria activates the TLR2, it tells thatinflammatory cell to make cytokines. We have seen that topicalretinoids, such as adapalene and tretinoin, have been shown todecrease the expression of the TLR2 on inflammatory cells, sothat may be one of the mechanisms by which retinoids can contributeto reducing inflammation.In terms of sebum production, we know that this is a keycomponent of the pathogenesis of acne. There are really onlytwo approaches that make a significant difference for sebumproduction. One is the use of isotretinoin, and the other ishormonal therapy, which can only be used in women. Theindications for hormonal therapy to reduce sebum productionare hormonal abnormalities in the patient. However, hormonaltherapy, is a very useful adjuvant to conventional therapy,and it can be used and is effective even in women who havenormal levels of androgen. For example, if I have a patientwith moderate to severe acne for whom I’m consideringisotretinoin, I initially may start her on an oral contraceptive.Many times, oral contraceptives added to a conventional regimenare effective enough that the patient doesn’t need tostart isotretinoin. Hormonal therapy may be an alternative torepeat courses of isotretinoin in some patients.HORMONAL THERAPY INDICATIONSThere are signs that may cause you to suspect an abnormalhormone level in a patient. For instance, if a woman in her30s who never really had acne presents with severe acne witha sudden onset, you should be concerned that there could bean hormonal problem, or if the acne is associated with othersigns of excess androgens, such as hirsutism, irregular menstrualperiods and signs of hyperandrogenism.The suggested work-up for an endocrine disorderincludes serum dehydroepiandrosterone sulfate (DHEAS),total and free testosterone, LH/FSH ratio, and 17-hydroxyprogesterone.It’s important to remember that patientsmust not be taking oral contraceptives when they are testedfor an endocrine disorder — they need to be off oral contraceptivesfor at least 6 weeks prior to testing. It’s alsoimportant not to test near ovulation — have patients testedduring their period or the week prior.DHEAS is produced by the adrenal gland, so if there’s congenitaladrenal hyperplasia, DHEAS is going to be elevated.Results of >8000 ng/ml indicate adrenal tumor while results of4000 ng/ml to 8000 ng/ml indicate congenital adrenal hyperplasia.Results of total and free testosterone of 15 ng/dl to200 ng/dl indicate an ovarian tumor and mild elevations sug-14 • MAY 2007 • SUPPLEMENT TO SKIN & AGING

WINTER CLINICAL DERMATOLOGY CONFERENCE PROCEEDINGSgest polycystic ovary disease. LH/FSH ratio >3 also indicatespolycystic ovary disease. The 17-hydroxyprogesterone canhelp you to distinguish whether the source of androgen isfrom the adrenal or from the ovary.HORMONAL THERAPYHormonal therapies consist of oral contraceptives thatblock the ovarian production of androgens, glucocorticoidsthat block the adrenal production in patients with congenitaladrenal hyperplasia, and antiandrogens that block effects onskin, though there are not many of these available in theUnited States. Spironolactone functions as an antiandrogen,so oftentimes we use that off-label.Spironolactone. Many patients with chronic adult acne,with intermittent (2 to 5 per month) tender nodules, respondquite well to treatment with spironolactone. Dosing is typically25 mg to 100 mg twice a day, much lower than the dosesused for hirsutism or androgenic alopecia. Side effectsinclude breast tenderness and menstrual irregularity, and it’simportant to avoid pregnancy. Interestingly, spironolactonereduces sebum production when it’s given in an oral form,though studies of topical spironolactone don’t show anyaffect on sebum production.Glucocorticoids. If a patient’s lab results indicate a congenitaladrenal hyperplasia (elevated serum DHEAS,17-hydroxyprogesterone or testosterone), low-dose glucocorticoidsmay be prescribed, such as prednisone 2.5 mg to5 mg daily at bedtime or dexamethasone 0.25 mg to 0.75 mgat bedtime. Be aware that there is an increased risk of adrenalsuppression with dexamethasone.ORAL CONTRACEPTIVES IN ACNEThis is an area that’s always changing. In my practice,many patients are referred by gynecologists, who havealready prescribed oral contraceptives for their acne.Patients present to me and complain that they were alreadytaking something and not seeing any results. This reallyemphasizes the fact that hormonal therapy really needs tobe part of a combination regimen. It’s rare for hormonal therapyalone to be good enough for most patients.Oral contraceptives basically work by inhibiting ovulationand reducing the production of androgens from theovary. By reducing androgens, you can reduce sebumproduction and improve acne. All of the combination oralcontraceptives have the same mechanism, so they allreduce ovarian androgens, and theoretically, they shouldall help to improve acne.Oral contraceptives contain two agents: an estrogenand a progestin.Over the years, because of safety reasons, the amountof estrogen in oral contraceptives has decreased. Most ofthe newer ones have 20 micrograms of estrogen, which isconsidered low dose. These included Alesse, Mircette,Loestrin, Estrostep, Ortho Tri-Cyclen Lo and Yaz.Also, third-generation progestins have less cross-reactivitywith the androgen receptor and are more “estrogenic” withhigher levels of HDL and sex hormone-binding globulin. Oralcontraceptives with third-generation progestins includeDesogen, Ortho-Cept, Mircette, Ortho-Cyclen, Ortho Tri-Cyclen and Ortho Tri-Cyclen Lo.There’s a relatively new progestin called drospirenone. It isan analog of spironolactone, so there may be reason to thinkthat this progestin has some of the benefits on acne thatspironolactone has. There are two products that contain it —Yasmin and Yaz. Yaz is a new oral contraceptive that wasapproved as a contraceptive in April 2006 and FDA approvedfor use in acne in early 2007. One advantage of Yaz is thatpatients have only 4 days of a menstrual period.As far as the oral contraceptives that have been studiedin acne, we’re all familiar with Ortho Tri-Cyclen. It was theone that was first approved for treatment of acne. Othershave now been studied as well, and overall, all the trialswere done as a single-agent trial, so the amount of lesionreduction was typically 30% to 40%, which again is why Ithink that oral contraceptives are effective as adjuvantagents, not as single agents.THE IMPORTANCE OFA GOOD SKINCARE REGIMENWhen treating adults with acne, one of the most importantthings is to find a good regimen. The adult female patient wants toknow how to clean her skin, what to put on, what time to put it onand how much to put on, so take the time to give recommendationsabout good skin care.Recommend sun protection, the use of moisturizers, explainhow to use medications and when to use them in conjunction withcosmetics. Explain the purpose of using a retinoid, the purpose ofbenzoyl peroxide, and effects to be expected with an antibiotic.Go over all of these things, and let your patients know thatit’s going to take 8 to 10 weeks before they’re going to noticethe full effect of their current regimens and that if they’re nothappy after that time, there’s plenty more that you can do. Likemany treatments in dermatology, it’s a matter of finding the rightcombination for each individual patient. ■Dr. Thiboutot is Professor of Dermatology at ThePennsylvania State University College of Medicine, MiltonS. Hershey Medical Center in Hershey, PA.SUPPLEMENT TO SKIN & AGING • MAY 2007 • 15

Celebrating 160 yearsYesterday,Today andTomorrowStiefel Laboratories, Inc. is the largest privately-held pharmaceutical company specializingin dermatology, with a broad scope of products for skincare available around the world.With more than 3,000 employees, our network includes 30 plus subsidiaries, R&D facilitieson four continents and products marketed in more than 100 countries. We continue to buildon 160 years of success and growth by partnering with dermatologistsand patients worldwide to create a lifetime of healthy skin.Brevoxyl, Duac, MimyX, ROSAC and Rose with sunray design, SARNA, and Zeasorb are registered trademarks ofStiefel Laboratories, Inc. RevaleSkin is a trademark of Stiefel Laboratories, Inc. Luxiq, Olux, and Soriatane areregistered trademarks of Connetics Corporation. Evoclin, Olux-E, and Verdeso are trademarks of Connetics Corporation.Connetics Corporation is a wholly-owned subsidiary of Stiefel Laboratories, Inc.Stiefel Laboratories, Inc. Coral Gables, FL 33134, 1-888-STIEFEL (784-3335),©2007 Stiefel Laboratories, Inc. All rights reserved. STI-12A-2007-USA

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