GOAL - The Dermatologist


GOAL - The Dermatologist

CONTINUING MEDICAL EDUCATIONGOAL: To provide dermatologists, residents and dermatologyphysician assistants with up-to-date information onthe treatment and management of patients with acne andactinic keratosis.TARGET AUDIENCE: This activity is designed for dermatologists,resident and dermatology physician assistants. No prerequisitesrequired.LEARNING OBJECTIVES: At the conclusion of this activity, theparticipant should be able to:• Recognize the prevalence and pathogenesis of acne toimprove treatment outcomes• Summarize the mechanisms of action and discuss thepractical applications of the latest acne treatments• Evaluate various treatment methods, with specific focuson pharmacologic agents to improve patient quality oflife for those affected by acne• Discuss the pathogenesis, identification process,and differential diagnoses when diagnosing actinickeratosis (AK)• Describe currently used therapies in the treatment of AK• Analyze the prognosis for the different stages and theefficacy of treatment optionsThe Johns Hopkins University School of Medicine takesresponsibility for the content, quality and scientific integrity ofthis CME activity.ACCREDITATION STATEMENT: The Johns Hopkins UniversitySchool of Medicine is accredited by the Accreditation Council forContinuing Medical Education (ACCME) to provide continuingmedical education for physicians.CREDIT DESIGNATION STATEMENT: The Johns HopkinsUniversity School of Medicine designates this educational activityfor a maximum of 2 AMA PRA Category 1 Credits. Physiciansshould only claim credit commensurate with the extent of theirparticipation in the activity.The estimated time to complete this educational activity:2 hours.RELEASE DATE: November 15, 2007. EXPIRATION DATE:November 15, 2009. After reading this monograph, participantsmay receive credit by completing the CE test and evaluation,and receiving a score of 70% or higher.DISCLAIMER STATEMENT: The opinions and recommendationsexpressed by faculty and other experts whose input isincluded in this program are their own. This enduring materialis produced for educational purposes only. Use of The JohnsHopkins University School of Medicine name implies review ofeducational format, design and approach. Please review thecomplete prescribing information of specific drugs or combinationsof drugs, including indications, contraindications,warnings and adverse effects, before administering pharmacologictherapy to patients.This program is supported by an educational grant fromDermik Laboratories.FACULTYFULL DISCLOSURE POLICY AFFECTING CME ACTIVITIES:As a provider accredited by the Accreditation Council for ContinuingMedical Education (ACCME), it is the policy of Johns Hopkins UniversitySchool of Medicine to require the disclosure of the existence of any significantfinancial interest or any other relationship a faculty member or aprovider has with the manufacturer(s) of any commercial product(s) discussedin an educational presentation. The Program Directors andParticipating Faculty reported the following:PROGRAM DIRECTORSBernard A. Cohen, M.D., F.A.A.P.Professor, Department of Dermatology and PediatricsJohns Hopkins University School of MedicineDirector of Pediatric DermatologyJohns Hopkins Children’s CenterBaltimore, MarylandDr. Cohen reports receiving grants/research support from Astellas and Novartis.Rachel Nussbaum, M.D.Instructor of DermatologyJohns Hopkins University School of MedicineDirector, Dermatology Inpatient Consultation ServiceThe Johns Hopkins HospitalDirector, Photopheresis Unit, Department of DermatologyBaltimore, MarylandDr. Nussbaum reports having no significant financial or advisory relationshipswith corporate organizations related to this activity.PARTICIPATING FACULTYJulie C. Harper, M.D.The Dermatology and Skin Care Center of Birmingham, PCClinical Associate ProfessorThe University of Alabama at BirminghamBirmingham, AlabamaDr. Harper reports serving as a consultant for Intendis; receiving honorariafrom Allergan Inc, Ranbaxy and Stiefel; and serving on the speakers’ bureausfor Allergan Inc and Stiefel.Joseph L. Jorizzo, M.D.Professor and Former (Founding) ChairDepartment of DermatologyWake Forest University School of MedicineWinston-Salem, North CarolinaDr. Jorizzo reports receiving honoraria for speaking for Amgen Inc, Astellasand Sanofi-Aventis.Susan C. Taylor, M.D.Former DirectorSkin of Color CenterSt. Luke’s Roosevelt Hospital CenterAssistant Clinical Professor of DermatologyCollege of Physicians and SurgeonsColumbia UniversityNew York, New YorkDr. Taylor reports performing contracted research for Aczone, Amgen Inc, BarrierTherapeutics, Doak, Galderma, Genzyme, Johnson & Johnson, Leo Pharmacy,Medicis, Palomar, Stiefel and Teva; serving as a clinical investigator for Allergan Inc,Barrier Therapeutics, Dermik Laboratories, Galderma, Johnson & Johnson,Medicis, Neutrogena, Novartis, Palomar, Stiefel and Teva; serving on the speakers’bureaus for Allergan Inc, Barrier Therapeutics, Bradley, Dermik Laboratories, Doak,Galderma, Johnson & Johnson, Medicis, Novartis, Procter & Gamble and Stiefel;and serving on the advisory boards for Astellas, Barrier Therapeutics, Beieresdorf,Connetics, Dermik Laboratories, Duac, Galderma, Johnson & Johnson, Medicis,Procter & Gamble, Skin Medica and Stiefel.Unapproved/unlabeled drug references: No faculty member hasindicated that their article will include information on off-label products.

INTRODUCTIONNOT JUST SKIN DEEP: NEW CONCEPTS &APPROACHES TO ACNE & “ACTINIC KERATOSIS”By Bernard A. Cohen, M.D., F.A.A.P., and Rachel Nussbaum, M.D.Acne vulgaris and actinic keratosis (AK) are twocommon skin disorders, which are becomingincreasingly prevalent in the United States. As aresult, dermatology specialists and patients are becomingmore concerned about the sequelae of these conditionsand improving patient care.According to the National Institute of Arthritis andMusculoskeletal and Skin Diseases, nearly 17 million peoplein the United States have acne. 1 Although acne typicallypresents during puberty and usually resolves by age 30,it can occur well into adulthood. 2 While self-limiting at times,acne can lead to scarring and psychological anguish. 3 Atleast four factors are thought to play a role in the pathogenesisof acne, including follicular hyperkeratinization,Propionibacterium acnes, inflammation and sebum production.Successful acne management targets these fourpathophysiologic factors and reduces the inflammationcaused by acne, 4,5 prevents scarring 6,7 and reduces the riskof psychosocial comorbidity. 8 Topical retinoids and antibacterialagents address the first three factors, and therefore,are often considered the mainstay of acne treatment. 4,5,9Recent studies demonstrate increasing resistance to earlyantibiotics used for acne, and this should be taken intoaccount when designing a treatment plan. 10 Clinical investigatorshave shown that adding a benzoyl peroxide-containingproduct to the treatment regimen can minimizeantimicrobial resistance and increase efficacy. 10-13 Sebumproduction is addressed topically by choice of vehicle andskin care. Other options include concomitant oral contraceptives,spironolactone or isotretinoin. 13 Clinical outcomesmay be improved by using combination therapy. 5,6,10,11Skin cancer is the most widespread of all cancers. 14More than 1 million cases of nonmelanoma skin cancer arediagnosed annually in the United States, the majority ofwhich are sun-induced. 14 AKs are typically asymptomaticscaly patches and plaques, resulting from chronic ultravioletexposure and are more prevalent with increasingage. 15,16 These premalignant lesions serve as a “reliablemarker” 15 to identify those individuals at risk for developingsquamous cell carcinoma (SCC). 15 The ability to identifyand treat AKs before progression to invasive SCC is themost important goal of management. Therapeutic optionsfor AKs include cryosurgery, surgical excision with or withoutcurettage or electrodesiccation, topical pharmaceuticalagents and photodynamic therapy (PDT). A combinationapproach can be used to enhance tolerance, complianceand efficacy. Patient education (ie, the importance of sunprotection), monthly self skin examinations and routine skinsurveillance by a dermatology professional 17 are vital in theprevention of AKs and subsequent skin cancer.This supplement to Skin & Aging includes the proceedingsfrom a Johns Hopkins CME symposium held on August3, 2007, in New York, NY. The primary objective was to reinforceand enhance the clinician’s knowledge of the pathogenesisand recognition of acne and AKs, while focusing oneffective treatment to achieve optimal patient outcomes.In the opening article, Susan C. Taylor, M.D., fromColumbia University, in New York, NY, presents a concisesynopsis of the etiology and psychological impact of acne.She then evaluates current management strategies foracne, with an emphasis on reducing the risk of antibioticresistance and post-inflammatory hyperpigmentation, particularlyin patients with skin of color. Next, Joseph L.Jorizzo, M.D., from Wake Forest University School ofMedicine in Winston-Salem, NC, provides an overview ofAK, focusing on the prevalence and risk factors, evolutionto SCC, histology and prevention. Treatment goals and avariety of management options are subsequently reviewed.The supplement concludes with four case studies presentedby Julie C. Harper, M.D., from the University of Alabamaat Birmingham. She applies the novel information presentedby her colleagues to clinical practice by designing treatmentplans for different patients. ■Dr. Cohen is a Professor in the Departments ofDermatology and Pediatrics at Johns Hopkins UniversitySchool of Medicine and Director of PediatricDermatology at Johns Hopkins Children’s Center inBaltimore, MD.Dr. Nussbaum is Instructor of Dermatology atJohns Hopkins University School of Medicine,Director of the Dermatology Inpatient ConsultationService at The Johns Hopkins Hospital, and Directorof the Photopheresis Unit, Department ofDermatology at Johns Hopkins Medical Institutions inBaltimore, MD.SUPPLEMENT TO SKIN & AGING • NOVEMBER 2007 • 3

References1. National Institute of Arthritis and Musculoskeletal and Skin Disease.What Is Acne? Fast Facts: An Easy-to-Read Series of Publications forthe Public. Available at: http://www.niams.nih.gov/hi/topics/acne/ffacne.htm.Accessed September 7, 2007.2. American Academy of Dermatology Public Resource Center. Acne.Available at: http://www.aad.org/public/Publications/pamphlets/Acne.htm.Accessed September 2, 2007.3. Mbuagbaw J, Abongwa C, Ozoh G, Blackett KN. The Prevalence ofAcne Vulgaris in Secondary School Students In Yaoundé, Cameroon.The Internet Journal of Dermatology. Available at:http://www.ispub.com/ostia/index.php?xmlFilePath=journals/ijd/vol5n2/acne.xml. Accessed September 1, 2007.4. Millikan LE. The rationale for using a topical retinoid for inflammatoryacne. Am J Clin Dermatol. 2003;4:75-80.5. Zaenglein AL, Thiboutot DM. Expert committee recommendations foracne management. Pediatrics. 2006;118:1188-1199.6. Goodman G. Managing acne vulgaris effectively. Aust Fam Physician.2006;35:705-709.7. Cantatore-Francis JL, Glick SA. Childhood acne: evaluation and management.Dermatol Ther. 2006;19:202-208.8. Purvis D, Robinson E, Merry S, Watson P. Acne, anxiety, depressionand suicide in teenagers: a cross-sectional survey of New Zealand secondaryschool students. J Paediatr Child Health. 2006;42:793-796.9. Leyden JJ, Shalita A, Thiboutot D, et al. Topical retinoids in inflammatoryacne: a retrospective, investigator-blinded, vehicle-controlled,photographic assessment. Clinical Therapeutics. 2005;27:216-224.10. Leyden JJ, Del Rosso JQ, Webster GF. Clinical consideration in thetreatment of acne vulgaris and other skin disorders: focus on antibioticresistance. Cutis. 2007;79:9-25.11. Leyden JJ. Antibiotic resistance in the topical treatment of acne vulgaris.Cutis. 2004;73:6-10.12. Del Rosso JQ. Antibiotic resistance: overview and significance indermatology. Cutis. 2005;76:12-18.13. Strauss JS, Krowchuk DP, Leyden JJ, et al. Guidelines of care foracne vulgaris management. J Am Acad Dermatol. 2007;56:651-663.14. American Cancer Society. Prevention and early detection. Available at:http://www.cancer.org/docroot/PED/content/ped_7_1_What_You_Need_To_Know_About_Skin_Cancer.asp. Accessed September 1, 2007.15. Salasche SJ. Epidemiology of actinic keratoses and squamous cellcarcinoma. J Am Acad Dermatol. 2000;42:S4-S7.16. Warino L, Tusa M, Camacho F, et al. Frequency and cost of actinickeratosis treatment. Dermatol Surg. 2006; 32:1045-1049.17. US Preventive Services Task Force. Screening for skin cancer recommendationsand rationale. Am J Prev Med. 2001;20:44-46.Address correspondence to: Bernard A. Cohen, M.D.,F.A.A.P., Professor, Department of Dermatology and Pediatrics,Johns Hopkins University School of Medicine, Director ofPediatric Dermatology, Johns Hopkins Children’s Center, DavidM. Rubenstein Child Health Building, Room 2107, Division ofPediatric Dermatology, 200 North Wolfe Street, Baltimore, MD21287. E-mail: bcohen2@jhmi.edu.HMP COMMUNICATIONSEDITORIAL STAFFSPECIAL PROJECTS EDITOR STEFANIE TULEYAEXECUTIVE EDITOR LARISA HUBBSSENIOR EDITOR ELLEN MEYERDESIGN AND PRODUCTIONART DIRECTOR KAREN COPESTAKESPRODUCTION DIRECTOR KIM CHESKYPRODUCTION MANAGER TRISH MORRISCREATIVE DIRECTOR VIC GEANOPULOSBUSINESS STAFFGROUP PUBLISHER JEREMY BOWDENNATIONAL ACCOUNT MANAGER ROBYN TANZERADVERTISING SALES MANAGER PHIL LEBRESCOADVERTISING SALES ASSOCIATE BRAD LACEYPROJECT MANAGER LINDSAY SHELLYCIRCULATION MANAGER BONNIE SHANNON83 GENERAL WARREN BLVD, SUITE 100, MALVERN, PA 19355(800) 237-7285 • (610) 560-0500 • FAX (610) 560-0501CONTENTSNOT JUST SKIN DEEP:NEW CONCEPTS & APPROACHES TOACNE & “ACTINIC KERATOSIS”All articles in this supplement are based onproceedings from a Johns Hopkins CMEsymposium held on August 3, 2007, in New York, NY.PROCEEDINGSACNE: A CLINICAL UPDATESUSAN C. TAYLOR, M.D.PAGE 5ACTINIC KERATOSIS:A CLINICAL UPDATEJOSEPH L. JORIZZO, M.D.PAGE 9CASE STUDIESPRACTICAL APPLICATIONSAND INSIGHTSJULIE C. HARPER, M.D.PAGE 13CME TEST INFORMATIONPAGE 18CME TESTPAGE 19EDITORIAL DEVELOPMENTThis supplement has been developed byAdvanced Studies in Medicine.SENIOR MEDICAL EDITORLAURA CUZZOCREAMEDICAL WRITERSHERI L. ROLEWSKI, MSN, CRNP, BC4 • NOVEMBER 2007 • SUPPLEMENT TO SKIN & AGING

NOT JUST SKIN DEEP: NEW CONCEPTS & APPROACHES TO ACNE & “ACTINIC KERATOSIS”FIGURE 2. Follicular HyperkeratinizationReprinted with permission from 1 Fois 1 Jour. Acne treatment. Available at:http://www.1fois1jour.fr/international/acneE.html. Accessed on August 15, 2007. 4PSYCHOLOGICAL IMPACT OF ACNEIt is important not to underestimate the psychological impactof acne. Gupta and Gupta 12 looked at the psychological impactof acne and psoriasis, using the Carroll Rating Scale forDepression to determine the prevalence of depression and suicidalideation among patients with dermatologic conditions. Ascore greater than 10 is consistent with clinical depression. Theyfound that in patients with non-cystic facial acne (n=72), a largepercentage scored in the range of depression (mean score,11.2), which was similar to patients with psoriasis (n=138; meanscore, 13.4). Findings suggest that even mild-to-moderate facialacne can be associated with significant depression and suicidalideation. This underscores the importance of recognizingdepression as a psychiatric comorbidity and the emotionalimpact of acne on patients should not be taken lightly.TREATMENT OF ACNEThere is a confusing array of treatment options.However, by targeting the various factors that trigger acne,the clinician can design a systematic treatment regimen.Topical agents include benzoyl peroxide, retinoids (eg,tretinoin, adapalene and tazarotene) and antibiotics.Systemic acne therapy includes oral antibiotics (eg, erythromycin,tetracycline, doxycycline and minocycline), hormonalagents (eg, oral contraceptives and spironolactone)and isotretinoin. Combination topical agents have beenshown to be more effective than using single agents alone.What Is New?Research has brought several new developments to theacne forefront, and studies appear favorable. Adapalene isnow available in a stronger 0.3% strength, clindamycin hasbeen paired with 0.025% tretinoin in a combination product,and benzoyl peroxide has been shown to minimizeantimicrobial resistance in P. acnes, with or without theaddition of topical antibiotics.Adapalene 0.3% gel. Adapalene 0.3% gel was recentlyFDA-approved. Thiboutot et al 13 performed a multi-centered(653 subjects ≥12 years old in 33 centers), double-blind, randomized(2:2:1) trial in which they compared the efficacy of0.3% adapalene gel with 0.1% adapalene gel versus vehiclefor 12 weeks. The primary endpoint was clearing — eithertotal clearing or almost total clearing. The results indicatedthat almost 25% of patients in the 0.3% adapalene groupwere rated as clear or almost clear. About 17% of patients inthe 0.1% adapalene group were rated as clear or almostclear. This compares to 10% of the vehicle control. This particularstudy had a diverse group of individuals (approximately70% white, 10% black, 12% Hispanic and 4% Asian).When evaluating the adverse events (ie, erythema, scaling,dryness, stinging and burning) of the 0.3% versus the 0.1%adapalene, there were more adverse events in the 0.3% adapalenegroup (approximately 22%) compared to approximately12% in the 0.1% adapalene group. Adapalene gel 0.3% wasassociated with a significantly greater treatment success rateand reduction in total and inflammatory lesion count frombaseline than adapalene 0.1% or vehicle gel. Although thestudy indicates increased efficacy with 0.3% adapalene gelcompared to the 0.1% version, adverse events are alsoincreased with the 0.3% adapalene gel. However, the authorsconfirmed that all of the therapies were well tolerated.Clindamycin 1%/tretinoin 0.025% versus each agentalone. James Leyden, M.D., et al 14 evaluated two randomized,double-blind controlled trials (n=2,219), looking at theefficacy and safety of a combination of clindamycin 1% concentrationwith tretinoin 0.025% concentration, compared toeach ingredient alone, as well as a placebo for 12 weeks.They found that the combination of clindamycin 1%/tretinoin0.025% in one product out-performed both clindamycin 1%or tretinoin 0.025% alone or vehicle control. Adverse eventsreported included dryness, desquamation, burning, erythema,pruritis, sunburn and irritation (combination: 19%, clindamycin1%: 5%, tretinoin 0.025%: 17%, vehicle: 5%).Clindamycin 1.2%/tretinoin 0.025% versus each agentalone. A combination of three trials (Study 1: n=1,252; Study2: n=1,288; Study 3: n=2,010) reported by Schlessinger andPlott 15 compared clindamycin 1.2% and tretinoin 0.025%combination therapy versus each alone versus vehicle.Inclusion criteria were 20 to 100 noninflammatory lesions, 20to 50 inflammatory lesions, and two or fewer nodules. Primaryendpoints were Evaluator’s Global Severity Scale of “clear” or“almost clear” or at least two grades of improvement, and thepercent improvement in two of three lesion counts (inflammatory,noninflammatory and total) from baseline to week 12.Similar to the previous study, the percent of patients whoachieved the primary efficacy endpoint of clear or almost clearwas superior with the combination product at 25% comparedto 19% in the clindamycin 1.2% group, 17% in the tretinoin6 • NOVEMBER 2007 • SUPPLEMENT TO SKIN & AGING

NOT JUST SKIN DEEP: NEW CONCEPTS & APPROACHES TO ACNE & “ACTINIC KERATOSIS”0.025% group and 10% in the vehicle group. Adverse eventsincluded itching, burning and stinging (combination: 27%, clindamycin1.2%: 22%, tretinoin 0.025%: 27%, vehicle: 22%).In summary, several different trials have demonstratedthe combination of clindamycin coupled with tretinoin waseffective or more efficacious than both monotherapies inachieving either clear or almost clear status. This combinationhas shown a significant ability to reduce inflammatory,noninflammatory and total lesion counts in acne vulgaris.6% benzoyl peroxide in antibiotic-resistant P. acnes. Amajor concern in the treatment of acne is antibiotic resistance.Leyden performed a study in which he evaluated resistant P.acnes strains and treated those patients with a 6% benzoylperoxide wash. There were 30 patients enrolled with P. acnesstrains resistant to erythromycin, tetracycline, doxycycline orminocycline. These patients washed daily for 3 weeks. Theywere supervised and subsequent counts were obtained. TotalP. acnes and individual antibiotic-resistant strain counts wereobtained at baseline and after weeks 1, 2 and 3.After week 1 of therapy with 6% benzoyl peroxide wash, asignificant reduction of the total resistant P. acnes strains wasfound. After week 3, there was a greater than 2 logarithmreduction in total P. acnes (ie, in all antibiotic-resistant strains).Results suggest that daily washing with 6% benzoyl peroxidewash reduces antibiotic-sensitive and antibiotic-resistantstrains of P. acnes after week 1 of therapy, which is helpfulinformation concerning the use of benzoyl peroxide in treatingpatients with acne. Combination products containing benzoylperoxide and the topical antibiotics have been shown to bothprevent the development of antibiotic resistance in patientswith acne and confer significant clinical improvement topatients who have already developed antibiotic resistance. 16Tazarotene versus tazarotene plus clindamycin 1%/benzoylperoxide 5%. Tanghetti et al 17 evaluated a multi-centered,randomized, double-blinded parallel-group trial with 121 patientswith moderate-to-severe acne. They compared the adjunctiveuse of clindamycin 1%/benzoyl peroxide 5% gel or vehicle gelevery morning in combination with tazarotene cream 0.1% everyevening in patients with moderate-to-severe inflammatory acne.Patients were treated for 12 weeks. Primary endpoints includedcomedo and inflammatory lesion counts. Secondary endpointsincluded adverse events. They concluded the combination ofusing clindamycin 1% and benzoyl peroxide 5% gel in the morningand tazarotene cream 0.1% at night resulted in significantlygreater reduction in comedo count versus tazarotene monotherapy(mean reduction, 70% vs 60%). Among patients with abaseline papule and pustule count greater than 25, a significantlygreater reduction in inflammatory lesion count was noted (meanreduction, 63% vs 52%) with the combination. A lower incidenceof peeling (10% vs 18% and dryness 8% vs 12%) was a favorablebenefit of the coupled agents.FIGURE 3. PIH on a Patient with Skin of ColorPIH = post-inflammatory hyperpigmentation. Reprinted with permission from Hoffman D.Image name: Moderate_Mixed_Acne_1_030713. Dermatlas. Available at: http://www.dermatlas.org/ derm/IndexDisplay.cfm?ImageID=-688207995. Accessed October 30, 2007. 20SKIN OF COLOR: ACNE ANDHYPERPIGMENTATIONAccording to several practice surveys, acne vulgaris andparticularly PIH comes out in the top 10 diagnoses of practicesurveys involving patients with skin of color. 18,19 With skin ofcolor patients, early and aggressive management is essentialto prevent PIH and scarring. Frequently, these patients presentwith the chief complaint of dark marks or blemishes. It isthe PIH that truly concerns them because those pigmentedmacules can last for months, whereas an acne lesion typicallyresolves within 1 week or so (See Figure 3). 20 It is importantto balance aggressive efficacy with non-irritating topical therapythat does not inflame uninvolved skin.Treatment of Hyperpigmentation and Acne inPatients of ColorWhen treating patients with skin of color, therapy shouldtarget acne as well as PIH. An additional depigmenting agentmay be necessary. Maintenance therapy to prevent the formationof new comedomes leading to acne and PIH, coupledwith sunscreens, should be emphasized in the treatment ofpatients with skin of color. In addition, clinicians should advisethese patients to avoid the sun and use sun protection.In a 12-week, multicentered (41 centers), investigator-blinded,randomized, prospective, community-based trial (n=353),Kircik et al compared the efficacy and tolerability of the combinationof 1% clindamycin/5% benzoyl peroxide gel (C-BPO)coupled with tretinoin microsphere (RAM) 0.04%, RAM 0.1%or adapalene gel 0.1% in a subset of patients of color withmoderate-to-severe acne. 21 In addition to assessing improvementof the acne, PIH was evaluated in the skin of color population.C-BPO was used in the morning, and a differentretinoid was used at night (ie, RAM 0.04%, RAM 1% or adapalenegel 0.1%). Approximately 50% of the patients enrolledwere Caucasian and 50% were patients with skin of color. 21,22Hyperpigmentation was assessed using a 6-point scale with0 being absent and 5 being very severe. The overall populationSUPPLEMENT TO SKIN & AGING • NOVEMBER 2007 • 7

NOT JUST SKIN DEEP: NEW CONCEPTS & APPROACHES TO ACNE & “ACTINIC KERATOSIS”started out with slight hyperpigmentation at baseline. After 4, 8and 12 weeks of therapy with RAM 0.04%, adapalene gel0.1% or RAM 0.1%, a decrease in the severity of the hyperpigmentationwith all three retinoids for the overall populationwas noted. Looking at the skin of color cohort, includingAsians, Hispanics and African-Americans, total hyperpigmentationwas rated at slight-to-mild (1.75). Although there wasefficacy with the RAM 0.1% and a suggestion with the adapalenegel 0.1%, the mean change from baseline (p=0.0045) ofthe total skin of color cohort in regard to hyperpigmentationindicated that the RAM 0.04% performed best. The authorsuggests that the combination of C-BPO and a topical retinoidwould be beneficial for acne and PIH, no matter the retinoid. 21The African-American subset of patients started out withmild-to-moderate (2.35) hyperpigmentation at baseline. After4, 8 and 12 weeks, a subtle trend toward improvement of PIHwas noticed with the RAM 0.04% and adapalene gel 0.1%.There was a trend toward more rapid and greater resolution ofPIH in the combination C-BPO + adapalene gel 0.1% treatedAfrican-American patients. In the Hispanic population, themean baseline severity was slight-to-mild (1.6), and after treatment,the mean change was quite significant in the RAM0.04% group with some improvement in the adapalene gel0.1% group. Finally, the Asian cohort’s baseline hyperpigmentationwas slight (1.17), but improvement was indeed noticedas the study progressed, particularly with the RAM 0.04%.There was a trend toward more rapid and greater resolutionwith the combination C-BPO and the adapalene gel 0.1% andthe RAM 0.04% in the Asian cohort. 21,22 However, all threeretinoids in combination with C-BPO can help reduce hyperpigmentation,while clearing acne in patients of color.Tazarotene 0.1% CreamGrimes and Callender 23 evaluated tazarotene 0.1% cream forPIH and acne vulgaris in darker skin in a multi-centered (twocenters), double-blind, randomized, vehicle-controlled study(n=74). Subjects had mild-to-moderate facial acne and acneinducedPIH with noticeable pigmentary lesions. Tazarotene0.1% cream versus vehicle was used once daily for up to 18weeks and was effective in reducing PIH. Compared to vehicle,tazarotene resulted in significantly greater global improvementfor PIH and acne, reductions in overall disease severity for PIHand acne, reductions in pigmentary intensity of hyperpigmentedlesions and reductions in area of hyperpigmented lesions.CONCLUSIONSAcne and the sequelae can deeply impact individualsphysically and emotionally. Several new acne therapies havebeen shown to be safe and efficacious, while minimizing theresistance of P. acnes and PIH. Concomitant treatment ofPIH is crucial for skin of color patients with acne. The mechanismof action is still unknown for hyperpigmentation. Anadditional depigmenting agent may still be required for optimumresults. All topical retinoids have shown efficacy atdecreasing epidermal pigmentation while minimizing follicularhyperkeratinization. Furthermore, using retinoids in combinationwith C-BPO has been shown to reduce antibiotic resistanceand hyperpigmentation in patients with acne.Remember that reinforcing education on daily sun protectionis essential, even to those patients with skin of color. ■Address correspondence to: Susan C. Taylor, M.D.,932 Pine Street, Philadelphia, PA 19107. E-mail:drstaylor1@aol.com.References1. Thiboutot D. Acne: 1991-2001. J Am Acad Dermatol. 2002;47:109-117.2. Berson DS, Shalita AR. The treatment of acne: the role of combinationtherapies. J Am Acad Dermatol. 1995;32:S31-S41.3. Stop Acne Systems. What is acne? Available at: http://www.stopacne.com/asp/aboutacne.asp.Accessed August 15, 2007.4. 1 Fois 1 Jour. Acne treatment. Available at: http://www.1fois1jour.fr/international/acneE.html.Accessed August 15, 2007.5. Thiboutot D, Gilliland K, Light J, Lookingbill D. Androgen metabolism insebaceous glands from subjects with and without acne. Arch Dermatol.1999;135:1041-1045.6. Gollnick H. Current concepts of the pathogenesis of acne: implicationsfor drug treatment. Drugs. 2003;63:1579-1596.7. Downing DT, Stewart ME, Wertz PW, Strauss JS. Essential fatty acidsand acne. J Am Acad Dermatol. 1986;14:221-225.8. Thiboutot D, Harris G, Iles V, et al. Activity of the type 1 5-alpha reductaseexhibits regional differences in isolated sebaceous glands and wholeskin. J Invest Dermatol. 1995;105:209-214.9. Thiboutot D. Acne and the adult female: tips on when and how to usehormonal therapy. Skin & Aging. 2007;15(suppl):14-15.10. Webster GF. Inflammation in acne vulgaris. J Am Acad Dermatol.1995;33:247-253.11. Valacchi, G, Rimbach, G, Saliou, C et al. Effect of benzoyl peroxide onantioxidant status, NF-kB activity and interleukin-1 alpha gene expressionin human keratinocytes. Toxicology. 2001;165:225-234.12. Gupta MA, Gupta AK. Depression and suicidal ideation in dermatologypatients with acne, alopecia areata, atopic dermatitis, and psoriasis. Br JDermatol. 1998;139:846-850.13. Thiboutot D, Pariser DM, Egan N, et al. Adapalene gel 0.3% for thetreatment of acne vulgaris: A multicenter, randomized, double-blind, conrolled,phase III trial. J Am Acad Dermatol. 2006;54:242-250.14. Leyden J, Krochmal L, Yaroshinsky A. Two randomized, double-blind,controlled trials of 2219 subjects to compare the combination clindamycin/tretinoinhydrogel with each agent alone and vehicle for the treatmentof acne vulgaris. J Am Acad Dermatol. 2006;54:73-81.15. Schlessiner J, Plott T. Efficacy of a clindamycin and tretinoin combinationproduct for acne vulgaris: results from 3 double-blind, placebo controlled,phase III trials. J Am Acad Dermatol. 2007;56:AB19. Abstract P126.16. Taylor GA, Shalita AR. Benzoyl peroxide-based combination therapies foracne vulgaris: a comparative review. Am J Clin Dermatol. 2004;5:261-265.17. Tanghetti E, Abramovits W, Soloman B, et al. Tazarotene versestazarorene plus clindamycin/benzoyl peroxide in the treatment of acne vulgaris:a multicenter, double-blind, randomized parallel-group trial. J DrugsDermatol. 2006;5:256-26118. Callender V. Acne in ethnic skin: special considerations for therapy.Dermatol Ther. 2004;17:184-195.19. Taylor S, Cook-Bolden F, Rahman, Z, Strachan D. Acne vulgaris in skinof color. J Am Acad Dermatol. 2002;46:S98-S106.20. Hoffman D. Image name: Moderate_Mixed_Acne_1_030713.Dermatlas. Available at: http://www.dermatlas.org/derm/IndexDisplay.cfm?ImageID=-688207995. Accessed October 30, 2007.21. Kircik L. Community-based trial results of combination clindamycin 1%-benzoyl peroxide 5% topical gel plus tretinoin microsphere gel 0.04% or0.1% or adapalene gel 0.1% in the treatment of moderate to severe acne.Cutis. 2007;80:10-14.22. Taylor S. Utilizing combination therapy for ethnic skin. Cutis. 2007; 80:15-20.23. Grimes P, Callender V. Tazarotene cream for postinflammatory hyperpigmentationand acne vulgaris in darker skin: a double-blind, randomized,vehicle-controlled study. Cutis. 2006;77:45-50.8 • NOVEMBER 2007 • SUPPLEMENT TO SKIN & AGING

NOT JUST SKIN DEEP: NEW CONCEPTS & APPROACHES TO ACNE & “ACTINIC KERATOSIS”PROCEEDINGSACTINIC KERATOSIS:A CLINICAL UPDATEJOSEPH L. JORIZZO, M.D.Actinic keratosis (AK) is seen commonly in dermatologypractice. Although it is still being debated, manybelieve that AK actually represents an incipient form ofsquamous cell skin cancer (SCC). 1,2 When evaluating a biopsyunder a microscope, the histologic features of a hypertrophicAK and SCC are similar. AKs are, at the very least,considered to be precancerous. More than 1 million newcases of skin cancer are diagnosed in the United States eachyear, 3 and of those, an estimated 200,000 to 300,000 individualsare diagnosed with SCC each year, 4 therefore, it is importantto treat AKs to avoid the progression to invasive SCC.Studies have shown that more than 5 million Americans haveat least one AK. 5 Risk factors include fair-skin phenotype, geographiclocation (ie, closeness to equator), immunosuppression(eg, HIV-positive patients, those receiving organ transplants andpatients with cancer) and supplementary sources of ultravioletradiation (ie, artificial tanning and occupational exposure). Theprevalence dramatically increases with age, which is indicative ofthe strong correlation between the amount of cumulative sunexposure and the occurrence of AK, as well as the fact thatimmune surveillance lessens with age. Occurrence of AK is higherin men than in women. In a survey conducted in Tennessee,26.5% of men and 10.2% of white women had one or moreAKs. By age 75, 63.6% of the men had AKs. 6 Prevalence alsoincreases with proximity to the equator. In Australia up to 60% ofthe population older than 40 years has AKs. 7,8AK PROGRESSION TO SCCOne concern in the treatment of AK is preventing progressionto invasive SCC, a disease that may account for up to34% of deaths from skin cancer among persons aged 65 to84 years. 9 The progression of AKs to invasive SCC occurs in0.1% to 10% of cases, 7,10 and 3% of these SCC metastatize. 11Although AK lesions have markers that show all the featuresof SCC, they are held in check at the early stage by cellularimmunity. Decreasing immune surveillance with increasingage and immunosuppression from chemotherapy, HIV infectionor immunosuppressant medications in transplantpatients results in increased development of AKs.Immunosuppression is an important factor in the concept ofAKs, in situ SCC and invasive SCC as a continuum, andshould be kept in mind when treating patients with AKs.Chronic progression of AKs to SCC correlates with the evolutionof histologic features. Characteristics include epidermalhyperplasia with a partial-thickness proliferation of keratinocytesexhibiting cytologic atypia, loss of polarity, nuclear pleomorphismand disordered maturation. As it progresses to invasiveSCC, proliferations may be long and slender or bulbous extensionsinto the papillary dermis. In Figure 1, underlying solarelastosis of the dermis coupled with extension of atypical cellsalong adnexal structures suggests SCC; however, the atypia isnot full thickness and considered to be premalignant. Givenenough time, 0.1% to 10% of AKs will progress to SCC. 7,10,12PREVENTION OF AKPrevention is fundamental in the management of AKsand photoaged skin. It is important to inform patients of therisks of AK and advise them to avoid excessive exposure tosunlight during peak sunlight hours (10 a.m. to 4 p.m.);avoid prolonged periods around reflective surfaces, such aswater; wear protective clothing and a wide-brimmed hat;and apply a broad-spectrum (UVA/UVB) sunscreen (sunprotection factor 15 or higher) liberally. 11,13-15 Reliable datanow show that ultraviolet light induces a suppressor T-cellsubset, 16,17 which suppresses immunesurveillance andallows for progression of AKs to SCC. Using daily sunscreensthat block UVA and UVB light can greatly reducethe incidence of AKs and subsequent skin cancer. 13-18TREATMENT GOALS AND OPTIONSWhen treating photoaged skin, the primary goal is eradicationof AKs to prevent future morbidity. However, it is becomingmore common for patients to expect dermatologists toprovide comprehensive wellness care for diseases of the skin,so the secondary goal is to improve the cosmetic appearance,self-esteem and, ultimately, quality of life. This can be donewith elective treatments, such as chemical peels and laserresurfacing, which may reduce signs of photodamage, includingfine lines/wrinkles, textural alterations, diffuse dyschromias,yellowing and mottling of the skin. 19SUPPLEMENT TO SKIN & AGING • NOVEMBER 2007 • 9

NOT JUST SKIN DEEP: NEW CONCEPTS & APPROACHES TO ACNE & “ACTINIC KERATOSIS”PDTPhotodynamic therapy is a novel modality used to treatAK that has shown promise in respect to efficacy and tolerance.Aminolevulinic acid (ALA) plus light involves the topicalapplication of 20% ALA. It preferentially localizes in theabnormal AK/SCC cells and upon exposure to blue light,ALA is converted to protoporphyrin IX, which producesoxygen intermediates that destroy the abnormal AK/SCCcells. Efficacy of ALA is well established. 21FIGURE 1. Hypertrophic Actinic KeratosisReprinted with permission from Hosler G. Image name: actinic_keratosis_2_060130.Dermatlas.Available at: http://dermatlas.org/derm/IndexDisplay.cfm?ImageID=1138552043. Accessed August 17, 2007. 12A variety of treatment options are available for the treatmentof AKs — cryosurgery, curettage/shave removal, chemicalpeels, photodynamic therapy (PDT) and topical therapies.Combination therapy often is most effective. When selecting atreatment, there are several factors to consider, including apatient’s overall risk of SCC; the types, number and locationsof lesions; patient preference; cosmetic prognosis; and cost.CryosurgeryCryosurgery is one of the most convenient methods to treatAKs, and most dermatology offices are equipped with liquidnitrogen. It is often more efficient to examine patients with suchan agent at hand, particularly for those with a history of hypertrophicAK. AK lesions are more sensitive to cryotherapy comparedto normal cells, and it can treat multiple lesions quickly.Studies have shown that cryotherapy has up to a 99% successrate 1-year post-surgery. 20 Adverse effects include local erythema,blisters, crusts, weeping, pain and secondary infection.Hypopigmentation is a common and undesirable sequelae ofcryotherapy. 11 It can be reduced by using the least possibleamount of cryosurgery and then properly taking care of thewound to prevent secondary infection or other effects that couldlead to hypopigmentation. Provide patients with instructions forcare of wounds and reinforce the importance of compliance.Curettage/Shave RemovalExtensive photodamage often parallels the number ofsuspicious lesions that patients present with, thus it can bedifficult to distinguish between AK and SCC clinically.Removal of AK lesions with curettage/shave removal permitshistologic examination and a 95% to 99% success ratehas been reported. Adverse effects include pain, scarring,and hypo- or hyperpigmentation. 11Topical TherapyTopical therapy is available in a variety of creams and solutions.The tolerability of reactions, duration, size availability, andcost differs for each product as shown in Table 1. 22,233% diclofenac gel. 3% diclofenac gel is a well-known,nonsteroidal anti-inflammatory drug used for arthritis that can beused to treat AK, although the mechanism of action is unknown.This novel formulation (3% diclofenac in 2.5% hyaluronan gel)can be used to treat multiple AKs and does not require surgery. 24A comparison study (n=30) was conducted by Smith et al, 25which evaluated the efficacy and tolerability of 3% diclofenacsodium gel and 5-fluorouracil (5-FU) cream in the treatment ofAK of the face and scalp. The 3% diclofenac gel was used for90 days and the 5-FU cream for 28 days. Both demonstratedsignificant efficacy; however less inflammation was demonstratedwith 3% diclofenac gel, despite the longer treatment periodof 60 to 90 days. This generated significant patient satisfaction.Also, photosensitivity or phototoxicity is not induced with 3%diclofenac gel alone or in combination with sunscreens. 26Imiquimod 5%. This novel immune response modifier canbe used to treat multiple AK lesions 27 and does not requiresurgery. Although the exact mechanism of action remainsunclear, it appears that this treatment uses the immune systemto reject these AK lesions from below. A phase III, randomized,multi-centered (18 centers), double-blind, parallelgroup, vehicle-controlled study (n=286) evaluated the efficacyof imiquimod 5% cream compared with vehicle in the treatmentof AKs on the face and balding scalp. This study includedpre- and post-treatment biopsy specimens. The creamwas applied once per day, 3 days per week, for 16 weeks.Imiquimod (57.1%) favored the complete clearance rate comparedto vehicle (2.2%) dramatically. The most common sideeffects were erythema (30.6%), scabbing/crusting (29.9%)and erosions/ulcerations (10.2%). 280.5%-FU. Topical 0.5%-FU inhibits DNA synthesis, leadingto impaired AK growth when compared to growth of normalcells. It is available in once-daily formulation and can be usedto treat multiple and subclinical lesions 29 ; surgery is notrequired. Typical adverse effects, such as burning, itching, redness,flaking and peeling, can be managed with the applicationof topical hydrocortisone (0.5% to 1.0%). 11 Weiss et alconducted a randomized, double-blind, multicentered, parallel-groupstudy (n=177) to evaluate safety and efficacy of0.5%-FU compared with vehicle once daily for 1, 2 or 4 weeks.10 • NOVEMBER 2007 • SUPPLEMENT TO SKIN & AGING

NOT JUST SKIN DEEP: NEW CONCEPTS & APPROACHES TO ACNE & “ACTINIC KERATOSIS”Before After Before AfterFIGURE 2. Chemical PeelsReprinted with permission from Dermatology, Inc. Procedure information: chemical peels. Available at: http://www.dermatologyinc.com/Chemical.html. Accessed August 17, 2007. 34Patient photographs courtesy of Dr. Steven B. Hopping, Washington, DC.Efficacy was assessed by lesion counts and clearance andsafety was gauged by monitoring for adverse events. Of thosetreated with 0.5%-FU at 4 weeks, 88.7% had a reduction inlesions and 47.5% achieved total clearance, which was significantlyhigher compared to vehicle (34.4% and 3.4%, respectively).Mild-to-moderate facial irritation was the primaryadverse event, which lasted 15 to 17 days post-treatment. 30Interval (pulse) therapy with 5-FU. Although there is aknown risk of burning, itching and inflammation with all formulationsof topical FU, there has been well documented evidencethat FU acts as chemotherapy and suppresses inflammationwhen used alone or in combination. An excessiveinflammation response is not necessary when using FU toachieve reduction of AK, 31 and all AK treatments typicallyinvolve a localized inflammatory response, which can besocially disruptive. Interval (pulse) therapy with 5-FU can potentiallyovercome such adverse, unwelcome reactions, withoutreducing efficacy. It often involves varying the frequency ofapplication, which allows for delivering a lower than recommendeddose. In a study by Pearlman, 10 patients completedan interval (pulse) therapy study using topical 5-FU for multiplefacial AKs and applying it 1 to 2 days per week for an averageof 6 to 7 weeks. 32 This method cleared 98% of the lesions.Irritation was limited to erythema without disruption to theirsocial or business lives due to altered appearance. At 9months, six available patients remained 86% clear of lesions.This study suggests efficacy can be obtained without excessiveirritation.Chemical PeelsChemical peels are useful for cosmetic facial rejuvenationand eliminating photoaging skin and AKs (See Figure2). 33,34 Peels may be performed at superficial, medium ordeep levels, depending on the extent of damage. Sideeffects include stinging, irritation and inflammation.Combination therapy with 5-FU also can be considered. 35,36Combination TherapyThere is no ideal monotherapy for the treatment of AK,thus combination therapy is often used because it hasthe potential to enhance treatment efficacy. Diverse combinationtherapies are available, including cryotherapyplus a choice of topical therapy; shave removal followedby topical therapy; and topical retinoids followed by 5-FU. There are ongoing studies of the efficacy of differentcombination therapies. One such study was a recentprospective, multi-centered, randomized, double-blind,vehicle-controlled clinical trial (n=144, ≥5 facial AKlesions). Investigators examined the 6-month outcome ofa 1-week course of 0.5%-FU followed by cryosurgery. 37Topical 0.5%-FU was used once daily for 7 days. At 4weeks follow-up, the remaining lesions were treated withcryosurgery. The primary endpoints were reduction inAKs from baseline to 4 weeks and 6 months. At 4 weeks,the mean AK lesion count reduced by 62.4% in the0.5%-FU group versus 28.8% in the vehicle group, andcomplete clearance was achieved in 16.7% of patients inthe 0.5%-FU group versus 0% in the vehicle group. Atto 6 months, the mean lesion count was reduced by 67%in the 0.5%-FU plus cryosurgery group, and significantlymore patients had complete clearance (30%) in the0.5%-FU plus cryosurgery group than vehicle group(7.7%). Although the mean lesion count was reducedwith the addition of cryosurgery at week 4, there was stilla high occurrence of AKs at 6-month follow-up, showingthe need for continued surveillance.COSMETIC CONSIDERATIONSIndividuals desire products that do not feel heavy orgreasy, thus new formulations are being developed toaddress these concerns. This can be seen with the latest“microsphere” vehicle formulation of 0.5%-FU, which has amore favorable irritation profile than the precursors and ispreferred by patients. 30 In addition, treatments, such aschemical peels, which enhance appearance while treatingAKs, are being used more often. 19 Other options include laserresurfacing, non-invasive lasers, radiofrequency devices,hyaluronic acid gels, poly-L-lactic acid injections, permanentSUPPLEMENT TO SKIN & AGING • NOVEMBER 2007 • 11

TABLE: Topical Therapy Options for AKConcentration(Formula)5% imiquimod creamMicrosphere-encapsulated0.5% FU cream5% FU cream5% FU solution1% FU cream3% diclofenac gelApplicationTwice weekly for16 wkOnce daily for1–4 wkTwice daily for2–4 wkTwice daily for2–4 wkTwice daily for2–6 wkTwice daily for60–90 dAvailableSizesAWP*12 packets $268.3830-g tube $143.7340-g tube $249.0510-mL bottle $249.0530-g tube $139.1550-g tube100-g tube*AWP reflects brand name price.AK = actinic keratosis; AWP = average wholesale price; FU = fluorouracil.Data from Jorizzo et al 22 and Amerisource database. 23$198.45$301.51fat injections and botulinum toxin injections. 38-43 By includingcosmetic considerations in AK treatment, specialists in dermatologycan provide comprehensive wellness for the skinthat improves the patient’s self-esteem and quality of life.CONCLUSIONSWhen managing the treatment of AK, it is important toremember that it can never be considered “cured.” Longtermsurveillance is necessary, especially because theincidence of AK increases with age and is often seen withother signs of aging. Although the primary goal in AKtreatment is always to prevent future morbidity from cancer,aesthetic and wellness considerations are alsoimportant to patients. Overall patient outcomes can besignificantly improved by providing a treatment plan thatprovides individualized patient care and comprehensivewellness for the skin. ■Address correspondence to: Joseph L. Jorizzo, M.D.,Professor and Former (Founding) Chair, Department ofDermatology, Wake Forest University School ofMedicine, Medical Center Boulevard, Winston-Salem,NC 27157. E-mail: jjorizzo@wfubmc.edu.References1. Lober BA. Actinic keratosis is squamous cell carcinoma. South Med J.2000;93:650-655.2. Ackerman AB, Mones JM. Solar (actinic) keratosis is squamous cell carcinoma.Br J Dermatol. 2006;155:9-22.3. Skin Cancer Foundation. Squamous cell carcinoma. Available at:http://www.skincancer.org/squamous/index.php. Accessed August 29, 2007.4. American Cancer Society. What are the key statistics about squamous andbasal cell skin cancer? Available at: http://www.cancer.org/docroot/CRI/content/CRI_2_4_1X_What_are_the_key_statistics_for_skin_cancer_51.asp?rnav=cri. Accessed August 29, 2007.5. Salasche SJ. Epidemiology of actinic keratoses and squamous cell carcinoma.J Am Acad Dermatol. 2000;42(1 part 2):S4-S7.6. Zagula-Mally ZW, Rosenberg EW, Kashgarian M. Frequency of skin cancerand solar keratoses in a rural southern county as determined by population sampling.Cancer. 1974;34:345-349.7. Marks R, Rennie G, Selwood TS. Malignant transformation of solar keratosesto squamous cell carcinoma. Lancet. 1988;1:795-797.8. Frost CA, Green AC. Epidemiology of solar keratoses. Br J Dermatol.1994;131:455-464.9. Weinstock M. Death from skin cancer among the elderly: epidemiological patterns.Arch Dermatol. 1997;133:1207-1209.10. Dodson JM, DeSpain, J, Hewett JE, et al. Malignant potential of actinic keratosisand the controversy over treatment. A patient oriented perspective. ArchDermatol. 1991;127:1029-1031.11. Robins P. Understanding Actinic Keratoses (What you need toknow). New York, NY: Physicians’ Continuing Education, Corp; 2002.12. Hosler G. Image name: actinic_keratosis_2_060130. Dermatlas.Available at: http://dermatlas.org/derm/IndexDisplay.cfm?ImageID=1138552043. Accessed August 17, 2007.13. Poon TS, Barnetson RS, Halliday GM. Prevention of immunosuppression bysunscreens in humans is unrelated to protection from erythema and dependenton protection from ultraviolet a in the face of constant ultraviolet B protection. JInvest Dermatol. 2003;121:184-90.14. Moyal DD, Fourtanier AM. Effects of UVA radiation on an established immuneresponse in humans and sunscreen efficacy. Exp Dermatol. 2002;11:28-32.15. Skin Cancer Foundation. Prevention tips. Available at: http://www.skincancer.org/prevention/scf-tips.html.Accessed August 17, 2007.16. Hofmann-Wellenhof R, Smolle J, Roschger A, et al. Sunburn cell formation,dendritic cell migration, and immunomodulatory factor production after solarsimulatedirradiation of sunscreen-treated human skin explants in vitro. J InvestDermatol. 2004;123:781-787.17. Mizuno K, Okamoto H, Horio T. Ultraviolet B radiation suppresses endocytosis,subsequent maturation, and migration activity of langerhans cell-like dendriticcells. J Invest Dermatol. 2004;122:300-306.18. Nohynek GJ, Schaefer H. Benefit and risk of organic ultraviolet filters. RegulToxicol Pharmacol. 2001;33:285-299.19. Ghersetich I, Brazzini B, Peris K, et al. Pyruvic acid peels for the treatment ofphoto aging. Derm Surg. 2004;30:32-36.20. Lubritz RR, Smolewski SA. Cryosurgery cure rate of actinic keratoses. JAmAcad Dermatol. 1982;7:631-632.21. Piacquadio DJ, Chen DM, Farber HF, et al. Photodynamic therapy withaminolevulinic acid topical solution and visible blue light in the treatment of multipleactinic keratoses of the face and scalp: investigator-blinded, phase 3, multicentertrials. Arch Dermatol. 2004;140:41-46.22. Jorizzo JL, Carney PS, Ko WT, et al. Matching patients with therapy. Cutis.2004;74:5-8.23. Amerisource database. Chesterbrook, PA: AmerisourceBergen Corporation.Accessed September 24, 2007.24. Diclofenac sodium gel [prescribing information]. Fairfield, NJ: DoakDermatologics.25. Smith SR, Morhenn VB, Piacquadio DJ. Bilateral comparison of the efficacy andtolerability of 3% diclofenac sodium gel and 5% 5-fluorouracil cream in the treatmentof actinic keratoses of the face and scalp. Drugs Dermatol. 2006;5:156-159.26. Ortonne JP, Queille-Roussel C, Duteil L. 3% diclofenac in 2.5% hyaluronicacid (Solaraze) does not induce photosensitivity or phototoxicity alone or in combinationwith sunscreens. Eur J Dermatol. 2006;16:385-390.27. Imiquimod [prescribing information]. St. Paul, MN: 3M Pharmaceuticals; 2004.28. Szeimies RM, Gerritsen MJ, Gupta G, et al. Imiquimod 5% cream for thetreatment of actinic keratosis: results from a phase III, randomized, double-blind,vehicle-controlled, clinical trial with histology. J Am Acad Dermatol.2004;51:547-555.29. Jorizzo J. Topical treatment of actinic keratosis with fluorouracil: is irritationassociated with efficacy? J Drugs Dermatol. 2004;3:21-26.30. Weiss J, Menter A, Hevia O, et al. Effective treatment of actinic keratosis with0.5% fluorouracil cream for 1, 2, or 4 weeks. Cutis. 2002;70:22-29.31. Breza T, Taylor R, Eaglstein WH. Noninflammatory destruction of actinic keratosesby fluorouracil. Arch Dermatol. 1976;112:1256-1258.32. Pearlman DL. Weekly pulse dosing: effective and comfortable topical5-fluorouracil treatment of multiple facial actinic keratoses. J Am AcadDermatol. 1991;25:665-667.33. Gold MH, Nestor MS. Current treatments of actinic keratosis. J DrugsDermatol. 2006;5:17-25.34. Dermatology, Inc. Procedure information: chemical peels. Available at:http://www.dermatologyinc.com/Chemical.html. Accessed August 17, 2007.35. Marrero GM, Katz BE. The new fluor-hydroxy pulse peel. A combination of5-fluorouracil and glycolic acid. Dermatol Surg. 1998;24:973-978.36. Teixeira SP, de Nascimento MM, Bagatin E, et al. The use of fluor-hydroxypulse peel in actinic porokeratosis. Dermatol Surg. 2005;31:1145-1148.37. Jorizzo J, Weiss J, Furst K, et al. Effect of a 1-week treatment with 0.5% topicalfluorouracil on occurrence of actinic keratosis after cryosurgery: a randomized,vehicle-controlled clinical trial. Arch Dermatol. 2004;140:813-816.38. El-Domyati MM, Attia SK, Esmat AM, et al. Effect of laser resurfacing on p53expression in photoaged facial skin. Dermatol Surg. 2007;33:668-675.39. Hamzavi I, Lui H. Using light in dermatology: an update on lasers, ultravioletphototherapy, and photodynamic therapy. Dermatol Clin. 2005;23:199-207.40. Weiss RA, Weiss MA, Beasley KL, Munavalli G. Our approach to non-ablativetreatment of photoaging. Lasers Surg Med. 2005;37:2-8.41. Andre P. Hyaluronic acid and its use as a “rejuvenation” agent in cosmeticdermatology. Semin Cutan Med Surg. 2004;23:218-222.42. Vochelle D. The use of poly-L-lactic acid in the management of soft-tissue augmentation:a five-year experience. Semin Cutan Med Surg. 2004;23:223-226.12 • NOVEMBER 2007 • SUPPLEMENT TO SKIN & AGING

NOT JUST SKIN DEEP: NEW CONCEPTS & APPROACHES TO ACNE & “ACTINIC KERATOSIS”CASE STUDIESPRACTICAL APPLICATIONSAND INSIGHTSJULIE C. HARPER, M.D.Actinic keratoses (AKs) and acne are common skindisorders in dermatology. The previous articles providedan overview of the pathogenesis and treatmentof acne and AKs. The following four case studies provideexamples of how to put this information into practice.CASE STUDY 1: ACTINIC KERATOSISPresentationA 78-year-old man with a history of squamous cell carcinoma(SCC) and numerous AKs returns for his routinefollow-up examination (See Figure 1). 1 He wears a hat andlong sleeves when outdoors, but refuses to apply sunscreen.He is not interested in home therapy and prefers tohave lesions “burned off” while in the office.Treatment OptionsThere are a variety of options for treating patients with AKs.In this case, choices include cryotherapy alone, photodynamictherapy (PDT), or a combination of 0.5% 5-fluorouracil(FU) for 1 week followed by cryotherapy. Each treatment isdiscussed briefly below, and additional information can befound in the previous article by Joseph L. Jorizzo, M.D.Cryotherapy. Liquid nitrogen or cryotherapy is the mostcommonly used treatment for AK. 2 It is a simple and convenientmethod, which can be done quickly during an officevisit. However, there is a significant risk of hypopigmentation,which can be minimized by using a single freeze-sawcycle and reducing the duration of cryotherapy. 2PDT. This innovative treatment modality for AK hasreceived FDA approval for lesional therapy 3 ; however, “field”therapy remains off-label. Topical 5-aminolevulinic acid(ALA) is converted to protoporphyrin IX, which is a potentphotosensitizer. When it is exposed to light, protoporphyrinIX generates oxygen-free radicals, which results in destructionof AKs. 4 There are several potential light sources available,including blue light, intense pulsed light and laser. Theefficacy of PDT is comparable to that of 5-FU, and the cosmeticresults are good. 5,6 Side effects include photosensitivity,stinging and burning. Also, the incubation period for5-ALA and the cost can be inconvenient for patients.0.5%-FU for 1 week followed by cryotherapy. Often,combination therapy is found to be an effective method fortreatment of AKs. With this method, the patient is treatedwith 0.5%-FU for 1 week. Then, at the 4-week follow-up visit,any residual lesions are treated with cryotherapy. Evaluationswere determined at 4 weeks and 6 months. This methodwas studied in a prospective, multicentered, randomized,double-blind, vehicle-controlled clinical trial, discussed in furtherdetail in Dr. Jorizzo’s article. The study showed thosetreated with 0.5%-FU had better improvement in lesioncounts compared to placebo. 7 This brief 1-week treatmentcourse may be an acceptable alternative for patients who arenot interested in a traditional 2- to 4-week course of 5-FU.Treatment PlanWith this patient, the idea of a 1-week treatment with thetopical 0.5%-FU followed by cryotherapy was a practicalapproach. The use of 0.5%-FU as a “blanket” or “field” treatmentwould decrease the number of AKs that need to be“frozen off” with cryotherapy. This is a good option for patientswho come in every 2 to 3 months with more than 15 lesions.FIGURE 1. Multiple Facial AK on a 78-Year-Old ManDermnet Skin Disease Image Atlas. Actinic Keratosis Face. Available at:http://www.dermnet.com/image.cfm?imageID=18533&moduleID=12&moduleGroupID=305&groupindex=3&passedArrayIndex=46. Accessed October 29, 2007. 1SUPPLEMENT TO SKIN & AGING • NOVEMBER 2007 • 13

NOT JUST SKIN DEEP: NEW CONCEPTS & APPROACHES TO ACNE & “ACTINIC KERATOSIS”TABLE 1: Tips to Lessen Antibiotic ResistanceDuring Acne TreatmentLimit the duration of systemic antibiotic.Avoid rotation of antibiotics.Avoid concurrent use of oral and topical antibiotics, especiallywhen they are chemically dissimilar.– If unavoidable, include a benzoyl peroxide-containingproduct, either with it or as a wash, to minimize the risk ofresistant strains.Avoid monotherapy with antibiotics.Prescribe medications that do not promote resistance(eg, topical retinoids).Add a benzoyl peroxide-containing product to prevent andreduce resistant strains of Propionibacterium acnes.FIGURE 2. A 17-Year-Old Male with Moderate Inflammatory AcneReprinted with permission from Tomfohrde C. Acne_1_060905. Dermatlas. Availableat: http://dermatlas.med.jhmi.edu/derm/IndexDisplay.cfm?ImageID=-809791325.Accessed August 29, 2007. 8CASE STUDY 2: ACNEPresentationYou are asked to evaluate a 17-year-old boy with moderateacne who tells you he uses “whatever soap is in theshower.” He has been taking 100-mg minocycline twice aday, which was prescribed by his pediatrician, for 6 weekswith minimal improvement. Examination reveals a healthyadolescent with oily skin, comedones and inflammatorypapules and pustules on the forehead, cheeks, chin, backand shoulders (See Figure 2). 8Treatment PlanA treatment regimen should be designed based on theseverity of the disease and the patient’s ability to complywith treatment. It is important to target the four factors thattrigger acne (see Susan C. Taylor, M.D.’s article): (1) follicularepidermal hyperproliferation; (2) Propionibacteriumacnes; (3) inflammation; and (4) excess sebum.For this patient, a topical retinoid was added to his currentregimen to reverse follicular hyperkeratinization, prevent futurecomedones and provide an anti-inflammatory effect. He wascontinued on minocycline for the anti-inflammatory effect andto suppress P. acnes. A benzoyl peroxide-containing productwas added to minimize the emergence of antibiotic-resistantstrains of P. acnes and suppress comedone formation. 9Excess sebum was addressed by vehicle selection (ie, gel)and by discussing appropriate skin care, such as the use of abenzoyl peroxide cleanser or salicylic acid wash.At the initial visit, it is important to counsel the patient onthe proper use of all medications and discuss potentialadverse effects. Setting reasonable expectations of whenimprovement will be achieved (eg, the patient will see 40%to 50% improvement in 6 to 8 weeks) and discussion ofskincare methods to minimize potential irritation is a vitalpart of patient education. A 6-week follow-up appointmentshould be scheduled to evaluate the patient’s progress.Follow-upAt a 6-week follow-up visit, the patient demonstrates 40% to50% improvement. He is tolerating oral and topical medicationswell, and the current regimen is continued. The patient schedulesa follow-up visit. Eight weeks later, an approximate 80%improvement has been obtained. The current regimen is continuedand he schedules a follow-up visit in 2 months. At thisvisit, continued improvement is noted and has been sustained,thus it is necessary to plan maintenance therapy for this patient.Maintenance TherapyThere are several options for maintenance therapy in thispatient, including continuing the topical retinoid as monotherapy,continuing the benzoyl peroxide-containing product asmonotherapy, continuing with combination topical retinoidand benzoyl peroxide-containing product therapy or taperingto a lower dose of minocycline and continuing with the topicalretinoid. In this case, the patient continued with a combinationtopical retinoid and benzoyl peroxide-containing producttherapy, and he continued taking 100-mg minocyclinetwice a day. Limiting the duration of systemic antibiotics,14 • NOVEMBER 2007 • SUPPLEMENT TO SKIN & AGING

NOT JUST SKIN DEEP: NEW CONCEPTS & APPROACHES TO ACNE & “ACTINIC KERATOSIS”TABLE 2: Contraindications for Oral ContraceptionPregnancyBreast cancer (current)Breast feeding 35 years and heavy smoker (>15 cigarettes/d)HypertensionDiabetes mellitus with nephropathy, retinopathy, neuropathy,vascular diseaseDeep vein thrombosis (history or current)History of heart diseaseHistory of strokeMigraine headaches (with focal neurological symptoms at anyage or without focal neurological symptoms but >35 years of age)Cirrhosis or liver tumor (benign or malignant)while adding a benzoyl peroxide-containing product, canprevent and reduce resistant strains of P. acnes. Topicalretinoids can be continued because they do not promoteantibiotic resistance and have the ability to prevent futurecomedones, follicular hyperproliferation and inflammation.Antibiotic ResistanceIt is important to consider the potential for antibiotic resistancewhen establishing a maintenance therapy routine forpatients with acne. Dermatologists are increasingly aware ofthis problem. 9-11 Resistance occurs when the bacteria genesfor resistance are exposed to chronic antibiotic therapy. Thisexposure eradicates the susceptible bacteria (targetpathogen) and the resistant bacteria (nonpathogenic bacteria)proliferate, thus the number of bacteria can increase.The nonpathogenic bacteria that are resistant to the antibioticnow act as a reservoir of resistant genes that can betransferred to other potentially pathogenic bacteria. 10Combating resistance. Dermatology specialists canhelp limit antibiotic resistance of P. acnes simply by reevaluatingtheir individual prescribing practices used foracne and following the suggestions provided in Table 1. 9,11If a non-antibiotic topical preparation will suffice, do notprescribe antibiotics. Try to use medications that do notpromote resistance (eg, topical retinoids). When an antibioticis necessary, the duration of use should be brief. If furthertreatment is required, reuse the same antibiotic wheneverpossible to avoid resistance to both products. Addinga benzoyl peroxide-containing product to the regimen, asdone with this patient, will help prevent and reduce resistantstrains of P. acnes. Benzoyl peroxide is a broad-spectrumantibacterial agent, which contains oxidized intermediatesthat interact with and kill microbes. To date, noresistance to benzoyl peroxide has been reported. WhenFIGURE 3. A 23-Year-Old Woman with Inflammatory Androgenic AcneReprinted with permission from Tonsager M. papulopustular_acne_1_040215 Dermatlas.Available at: http://dermatlas.med.jhmi.edu/derm/IndexDisplay.cfm?ImageID=-1981279780. Accessed August 29, 2007. 13TABLE 3: Three Ways to Start Oral Contraceptionfor Acne TreatmentGet a negative urine pregnancy test, while in clinic: Start that day.Wait until the women starts her menses: Start first day of menses.Start first Sunday after her menses starts.TABLE 4: Guidelines for Spironolactone Use in Acne25–100 mg/bid: lower doses minimize side effectsCo-administer with oral contraceptive if patient is ofchild-bearing potential.– Reduce the risk of an exposed pregnancy andfeminization of the male fetus– Lessen the menstrual disturbances associated withspironolactoneused in combination with an antibiotic, benzoyl peroxideprevents the selection of the antibiotic-resistant organisms.12 Finally, try to avoid concomitant use of chemicallydissimilar systemic and topical antibiotics. 9,11 If a topicalantibiotic is necessary, be sure to include a benzoyl peroxide-containingproduct to minimize resistance.CASE STUDY 3: ACNEPresentationYou are asked to examine a 23-year-old woman whopresents with acne. She has already tried “everything” andSUPPLEMENT TO SKIN & AGING • NOVEMBER 2007 • 15

NOT JUST SKIN DEEP: NEW CONCEPTS & APPROACHES TO ACNE & “ACTINIC KERATOSIS”FIGURE 4. A 62-Year-Old Female with Multiple AKReprinted with permission from Dermnet Skin Disease Image Atlas. Actinic keratosisarm. Available at:http://www.dermnet.com/thumbnailIndex.cfm?moduleID=12&moduleGroupID=307&groupIndex=0&numcols=0. Accessed August 19, 2007. 21is now using a topical retinoid once daily and has been takingdoxycycline 100 mg twice daily for 8 weeks. She is stillbreaking out, particularly on the lower face, jawline andneck. Physical examination reveals oily skin, a few comedoneson her cheeks and nose, two inflamed nodules onher jawline and several inflammatory papules and erythemaon her chin, neck and cheeks (See Figure 3). 13Treatment PlanAs with the previous patient, the treatment plan should targetfactors that promote the development of acne. Follicularepidermal hyperproliferation and inflammation are addressedwith the continued used of the topical retinoid. She continuedto take doxycycline 100 mg twice daily to provide anadjunctive anti-inflammatory effect. Also, by avoiding rotationof the antibiotic, the risk of P. acnes resistance was minimized.A benzoyl peroxide-containing product was added toher regimen to further reduce the threat of antibiotic-resistantstrains, as well as an oral contraceptive to target the sebaceousgland activity and sebum production.Oral contraceptives for acne control. Oral contraceptiveshave been shown to be effective in targeting sebaceousgland activity and excess sebum production.However, improvement in acne is not expected until theoral contraceptive has been taken for 3 months or longer.Combination oral contraceptive pills decrease androgenproduction in the ovaries and the amount of circulatingandrogen by increasing sex hormone-binding globulin.Excess androgen results in the production of excesssebum. It is important to remember that oral contraceptivesneed to be used as supplemental therapy, becausethey do not target all four causes of acne.Oral contraceptives are used most safely in womenyounger than 35 years who do not smoke, do not havemigraine headaches and who are normotensive.Although oral contraceptives decrease androgen production,the patient’s androgen levels do not need to beabnormal for oral contraceptives to be effective. 14 Anyfemale patient with acne who is not responding appropriatelyto traditional combination therapy and does nothave contraindications to oral contraceptives is a candidate.Oral contraceptives also can be considered infemale patients planning to take isotretinoin or in thosewho are unable or unwilling to take systemic antibiotics.They may be used early in the treatment of acne, particularlywhen they are also being used for another indication(eg, desire to prevent pregnancy or premenstrualdysphoric disorder). In addition, women with signs ofhyperandrogenism (eg, hirsutism or abnormal/irregularmenstrual periods) may benefit from the antiandrogeneffects of oral contraceptives.An appropriate laboratory evaluation should be performedbefore beginning treatment with an oral contraceptiveonly if there are signs of hyperandrogenism. Make surethe patient has not taken oral contraceptive pills for at least6 weeks before laboratory analysis for an endocrine disorder.Also avoid testing near ovulation; advise laboratorytests be taken during menses or 1 week before. 14 Testsshould include serum dehydroepiandrosterone sulfate(DHEAS), free and total testosterone, luteinizing hormone/follicle-stimulatinghormone ratio (>3 indicates polycysticovarian disease) and 17-hydroxyprogesterone(helps determine androgen etiology [adrenal or ovarian]). 14A list of contraindications is provided in Table 2, 15 andthree methods for beginning oral contraceptive treatmentin acne are listed in Table 3. 16Spironolactone for acne control. Another option for reducingsebum production is oral spironolactone. 14,17 Spironolactoneis an aldosterone antagonist that binds the androgen receptor.It inhibits androgen biosynthesis in the gonads and adrenalgland and suppresses 5 α-reductase activity in the sebaceousgland. Adverse effects, which are typically dose related, includepolyuria, menstrual disturbances, gynecomastia, dizziness,headache and weight gain. Guidelines for the use of spironolactoneare provided in Table 4. 14,18,19A survey study with comparison chart review evaluatedthe long-term safety and tolerance of spironolactone inwomen with acne. 20 The women, followed for up to 8 years,had favorable results. Ninety-one surveys were analyzed,comprising 506 person-years of follow-up and 200 personyearsof spironolactone exposure. The mean length of treatmentwas 28.5 months. During the 8-year follow-up period,there were no cases of serious illness as a result of the useof spironolactone. The most common side effects experiencedwere diuresis and menstrual irregularities. Of those,15% resulted in discontinuation of the drug. Long-term useof this agent appeared to be safe.16 • NOVEMBER 2007 • SUPPLEMENT TO SKIN & AGING

NOT JUST SKIN DEEP: NEW CONCEPTS & APPROACHES TO ACNE & “ACTINIC KERATOSIS”In a separate open-labeled prospective study, the sideeffects of spironolactone and how it affected serum bloodlevels were examined. 19 In the study, 35 women were givenspironolactone 100 mg/day for 16 days each month for3 months. DHEAS and total testosterone levels were measuredbefore and after treatment. Clinically significantimprovement was noted in 85.7% of patients who had correspondingdecreased DHEAS levels after treatment. Therewas no change in the total testosterone levels. The mostcommon side effect reported was menstrual irregularities.The authors reported safety and efficacy, while suggestingspironolactone be offered as an alternative choice forwomen with acne vulgaris.CASE STUDY 4: ACTINIC KERATOSISPresentationA 62-year-old woman with a fair complexion is evaluatedfor numerous AKs on her lower extremities (See Figure 4). 21Two skin biopsies were performed and both showed AKs.She has never had skin cancer and denies a history of arsenicexposure. 21 She does have a long history of sun exposure.Treatment PlanSkin cancer is the most common form of human cancer. 22AKs and SCC have common features (see previous article byDr. Jorizzo), 23 and if left untreated, AKs can progress to SCC. 24You decide the optimal treatment for this patient is atopical retinoid in combination with topical 5-FU. A topicalretinoid accelerates the penetration of this antimitoticagent. The synergistic effect of these two topical agentshas been demonstrated in a randomized, double-blind trial(n=19). 25 In this study, 5-FU cream was applied twice daily,followed by 0.05% tretinoin cream nightly to one arm, anda control cream was applied to the opposite arm until discomfortcurtailed further applications. It was concludedthat the daily application of 0.05% tretinoin creamappeared to enhance the efficacy of topical 5-FU indestruction of AK of the arms.CONCLUSIONSThere are many factors to consider when deciding how totreat patients with AK or acne. When managing patients withAKs, it is important to identify, treat and prevent the lesions,because 0.1% to 10% progress to SCC. Individualized educationand surveillance is essential to prevent morbidity. Forpatients with acne, it is important to create a treatment planthat targets the factors that cause acne. Using combinationtherapy is an effective way to accomplish this. Adding a benzoylperoxide-containing product to topical antibioticsreduces the risk of selecting resistant P. acnes. The additionof oral contraceptive pills for women can result in furtherimprovement. Negotiating with patients about vehicles, generalskin care and frequency of application of topical agentsand administration of oral agents can improve patient comfortand enhance compliance. ■References1. Dermnet Skin Disease Image Atlas. Actinic Keratosis Face. Availableat: http://www.dermnet.com/image.cfm?imageID=18533&moduleID=12&moduleGroupID=305&groupindex=3&passedArrayIndex=46.Accessed October 29, 2007.2. Andrews MD. Cryosurgery for common skin conditions. Am FamPhysician. 2004;69:2365-2372.3. Lober BA., Fenske NA. Optimum treatment strategies for actinic keratosis(intraepidermal squamous cell carcimoma). Am J Clin Dermatol.2004;5:395-401.4. Spencer JM, Fulton J. Actinic Kerastosis. Available at:http://www.emedicine.com/derm/topic9.htm. Accessed August 19, 2007.5. Kurwa HA, Yong-Gee SA, Seed PT, Markey AC, Barlow RJ. A randomizedpaired comparison of photodynamic therapy and topical 5-fluorouracilin the treatment of actinic keratoses. J Am Acad Dermatol.1999; 41(3 Pt 1):414-8 (ISSN: 0190-9622).6. Braathen LR, Szeimies RM, Basset-Seguin N, et al. Guidelines on theuse of photodynamic therapy for nonmelanoma skin cancer: an internationalconsensus. International Society for Photodynamic Therapy inDermatology, 2005. J Am Acad Dermatol. 2007;56(1):125-143.7. Jorizzo J, Weiss J, Furst K, Vandepol C, Levy S. Effect of a 1-weekTreatment with 0.5% Topical Fluorouracil on Occurrence of ActinicKeratosis After Cryosurgery: A randomized, Vehicle-Controlled ClinicalTrial. Arch Dermatol. 2004;140:813-816.8. Tomfohrde C. Acne_1_060905. Dermatlas. Available at: http://dermatlas.med.jhmi.edu/derm/IndexDisplay.cfm?ImageID=-809791325.Accessed August 29, 2007.9. Leyden JJ. Antibiotic Resistance in the Topical Treatment of AcneVulgaris. Cutis. 2007;73(6S):6-10.10. Levy SB. The challenge of antibiotic resistance. Sci Am.1998;278(3):46-53.11. Del Rosso JQ. Antibiotic resistance: overview and significance in dermatology.Cutis. 2005;75(4 Suppl):12-18.12. Eady EA, Farmery MR, Ross JI, Cove JH, Cunliffe WJ. Effects of benzoylperoxide and rythromycin alone and in combination against antibiotic-sensitiveand -resistant skin bacteria from acne patients. Br JDermatol. 1994;131(3):331-336.13. Tonsager M. papulopustular_acne_1_040215 Dermatlas. Availableat: http://dermatlas.med.jhmi.edu/derm/IndexDisplay.cfm?ImageID=-1981279780. Accessed August 29, 2007.14. Thiboutot DM. Acne and the Adult Female. Skin & Aging.2007;15(Suppl):14-15.15. Stewart FH, Harper CC, Ellertson, CE, Grimes, DA, Sewaya, GF,Trussell, J. Clinical Breast and Pelvic Examination Requirements forHormaonal Contraception: Current Practice vs. Evidence. JAMA.2001;285:2232-2239.16. Feminist Women’s Health Center. The Pill-Oral Contraceptive.Available at: http://www.fwhc.org/birth-control/thepill.htm#use.Accessed August 22, 2007.17. Zouboulis CC, Chen WC, Thornton MJ, Qin K, Rosenfield R. Sexualhormones in human skin. Horm Metab Res. 2007;39(2):85-95.18. Harper JC. Antiandrogen therapy for skin and hair disease. DermatolClin. 2006;24(2):137-43.19. Yemisci A, Gorgulu A, Piskin S. Effects and side-effects of spironolactonetherapy in women with acne. JEADV. 2005;(19):163-166.20. Shaw JC, White LE. Long-term safety of spironolactone in acne: resultsof an 8-year followup study. J Cutan Med Surg. 2002;6(6):541-545.21. Dermnet Skin Disease Image Atlas. Actinic keratosis arm. Available at:http://www.dermnet.com/thumbnailIndex.cfm?moduleID=12&moduleGroupID=307&groupIndex=0&numcols=0. Accessed August 19, 2007.22. Rockoff A. Skin Cancer (Nonmelanoma Skin Cancer). Available at:http://www.medicinenet.com/skin_cancer/article.htm. Accessed August19, 2007.23. Lober BA, Lober CW. Actinic keratosis is squamous cell carcinoma.South Med J. 2000;93(7):650-655.24. Cockerell CJ, Wharton JR. New histopathological classification ofactinic keratosis (incipient intraepidermal squamous cell carcinoma). JDrugs Dermatol. 2005;4(4):462-467.25. Bercovitch L. Topical chemotherapy of actinic keratoses of the upperextremity with tretinoin and 5-fluorouracil: a double-blind controlledstudy. Br J Dermatol. 1987;116(4):549-552.SUPPLEMENT TO SKIN & AGING • NOVEMBER 2007 • 17

NOT JUST SKIN DEEP: NEW CONCEPTS & APPROACHES TO ACNE & “ACTINIC KERATOSIS”NOT JUST SKIN DEEP: NEW CONCEPTS &APPROACHES TO ACNE & “ACTINIC KERATOSIS”HOW DO I PARTICIPATE IN THE CME LESSON AND RECEIVE MY CERTIFICATE OF PARTICIPATION?TWO OPTIONSOption 1: Online processing (no charge)Please go to www.JHASIM.com/acne-ak.If you are unable to download your CME Certificate ofParticipation from our Web site, please e-mailwebmaster@jhasim.com or call 908-253-9001.Option 2: Mail in ($5 processing fee)• Complete CME Test and Program Evaluation• Tear out or photocopy from supplement• Mail with a $5 check* (or provide credit card information onthe Program Evaluation Form)CME Test ProcessingAdvanced Studies in MedicineP.O. Box 340 • Somerville, NJ 08876*Payable to “Advanced Studies in Medicine.”CONTINUING MEDICAL EDUCATION ACCREDITATIONThe Johns Hopkins University School of Medicine designates this educational activity for a maximum of 2 AMA PRA Category 1 Credits.Physicians should only claim credit commensurate with the extent of their participation in the activity.Release date: November 15, 2007. Expiration date: November 15, 2009.INSTRUCTIONSAfter reading “Not Just Skin Deep: New Concepts & Approaches to Acne & “Actinic Keratosis,” select the 1 best answer to eachof the following questions. At least 7 of 10 answers must be correct to receive CME credit. Estimated time for reading this issue andtaking the test is 2 hours.1) WHICH OF THE FOLLOWING IS FALSE ABOUTACTINIC KERATOSES (AKS)?a. AKs and squamous cell carcinoma (SCC) have commonfeatures.b. Untreated AKs progress to SCC 0.1% to 10% of the time.c. AKs should always be excised.d. AKs are treatable and can be managed.2) RISK FACTORS FOR AKS INCLUDE:a. Fair-skin phenotypeb. Geographic location (ie, closeness to equator)c. Immunosuppressiond. All of the above3) WHEN MANAGING AKS, THE PRIMARY GOAL INTREATMENT IS:a. Target cosmetic concernsb. Initiate aggressive combination therapyc. Prevent future morbidity from cancerd. None of the above4) WHICH COMPONENTS OF ACNE SHOULD TREAT-MENT TARGET?a. Follicular epidermal hyperproliferation and inflammationb. Propionibacterium acnesc. Excess sebumd. All of the above5) WHEN MANAGING ACNE IN THE SKIN OF COLORPOPULATION:a. Patients may need additional depigmenting therapyb. Maintenance therapy is needed to prevent formation ofnew comedomes leading to acne and PIHc. The importance of daily sunscreens and sun protectionneeds to be stressed to minimize additional PIHd. All of the above6) WHICH OF THE FOLLOWING STATEMENTS ABOUTSPIRONOLACTONE IS FALSE?a. Spironolactone is an aldosterone antagonist that bindsthe androgen receptor.b. Spironolactone is often co-administered withoral contraceptives.c. Spironolactone is safe during pregnancy.d. Spironolactone inhibits androgen biosynthesis in thegonads and adrenal gland.7) WHICH OF THE FOLLOWING STATEMENTS ABOUTPHOTODYNAMIC THERAPY (PDT) IS FALSE?a. PDT gives an excellent cosmetic outcome.b. PDT is effective and convenient.c. PDT is not as effective as 5-fluorouracil (5-FU).d. Photosensitivity is a common side effect of PDT8) WHICH OF THE FOLLOWING IS THE MOSTCOMMONLY USED THERAPY FOR AKS?a. Cryotherapyb. PDTc. 5-FU followed by cryotherapy for residual lesionsd. Imiquimod9) WHICH OF THE FOLLOWING STATEMENTS ABOUTCOMBINATION ORAL CONTRACEPTIVE PILLS IS TRUE?a. Combination oral contraceptive pills increaseandrogen production in the ovaries and decreases sexhormone-binding globulin.b. Combination oral contraceptive pills decreaseandrogen production in the ovaries and decreases theamount of circulating androgen by increasing sex hormone-bindingglobulin.c. Combination oral contraceptive pills are used mostsafely in women with a history of migraines.d. Combination oral contraceptive pills are used mostsafely in women older than 35 years.10) WHAT MEASURES HAVE PROVEN TO BE EFFEC-TIVE IN REDUCING THE DEVELOPMENT OF ANTIMI-CROBIAL RESISTANCE DURING ACNE THERAPY?a. Use medications, such as topical retinoids, that do notpromote resistance.b. Limit the duration of topical and systemic antibiotics.c. Add a benzoyl peroxide containing product toprevent and reduce resistant strains of P acnes.d. All of the above18 • NOVEMBER 2007 • SUPPLEMENT TO SKIN & AGING

NOT JUST SKIN DEEP: NEW CONCEPTS & APPROACHES TO ACNE & “ACTINIC KERATOSIS”CONTINUING MEDICAL EDUCATION EVALUATIONPROGRAM EVALUATIONNOT JUST SKIN DEEP: NEW CONCEPTS & APPROACHES TO ACNE & “ACTINIC KERATOSIS”Your evaluation of the CME content is an integral part of this activity. To complete your participation and receive your CME credits,please complete the questionnaire below.Strongly Agree Agree Neutral Disagree Strongly Disagree1. THIS COURSE MET THE OVERALL OBJECTIVES BELOW: ❑ ❑ ❑ ❑ ❑• Recognize the prevalence and pathogenesis of acne to improve treatment outcomes• Summarize the mechanisms of action and discuss the practical applications of the latest acne treatments.• Evaluate various treatment methods, with specific focus on pharmacologic agents to improve patient quality of life for thoseaffected by acne• Discuss the pathogenesis, identification process, and differential diagnoses when diagnosing actinic keratosis (AK)• Describe currently used therapies in the treatment of AK• Analyze the prognosis for the different stages and the efficacy of treatment options2. ARE YOU A PHYSICIAN? ❑ YES ❑ NO3. WILL YOU CHANGE YOUR PRACTICE IN ANY WAY AS A RESULT OF PARTICIPATING IN THIS COURSE? ❑ YES ❑ NO If yes, please specify:_________________________________________________________________________________________________________________4. DO YOU FEEL THE ACTIVITY WAS OBJECTIVE, BALANCED, AND FREE OF COMMERCIAL BIAS? ❑ YES ❑NO If no, please specify:________________________________________________________________________________________________________________5. IF PRESENT, WAS OFF-LABEL DRUG AND/OR DEVICE DISCUSSION PROPERLY DISCLOSED? ❑ YES ❑ NO If no, please specify:_______________________________________________________________________________________________________________6. PLEASE RATE THE FOLLOWING ACTIVITY COMPONENTS:a) Quality of the educational content: ❑ Excellent ❑ Good ❑ Fair ❑ Poorb) Quality of design and organization: ❑ Excellent ❑ Good ❑ Fair ❑ Poorc) Quality of printed/online material: ❑ Excellent ❑ Good ❑ Fair ❑ Poor7. COMPARED WITH OTHER CME ACTIVITIES, THIS ACTIVITY WAS:❑ Better Than Average ❑ Average ❑ Below Average8. PLEASE MARK YOUR PREFERRED MEDIUM FOR CONTINUING EDUCATION (SELECT ONE)❑ Print (Journal/Monograph) ❑ Live Conference ❑ CD-ROM ❑ Audio ❑ Videotape ❑ Online Lessons9. SUGGESTIONS FOR FUTURE ACTIVITIES: ________________________________________________________________________PAYMENT OPTIONS❑ Check (payable to “Advanced Studies in Medicine”)❑ Credit card (please check one): ❑ Mastercard ❑ Visa ❑ American ExpressAccount number: _______________________________________________ Expiration: ____________________________________________Signature: _____________________________________________________ Name on card: ___________________________________________________________________________________________________________________________________________________________NameE-mail (Please provide a valid E-mail for certificate processing)__________________________________________________________________________________________________________________AddressSpecialty Professional Designation__________________________________________________________________________________________________________________City, State, ZipDateSUPPLEMENT TO SKIN & AGING • NOVEMBER 2007 • 19

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