天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生ACNE:Systemic TreatmentAndreas D. KatsambasAthens - Greece16th EADV CongressVienna - Austria16-20 May 2007天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生Acne: TreatmentTopicalSystemicPhysical methodsRetinoids (RA)Antibiotics (OA)Comedo extractions /Electro-cauteryBenzoyl Peroxide(BPO)Isotretinoin(ISO)Chemical peelsTopical Antibiotics(TA)Hormones (HT)PhototherapyAzelaic Acid (AZ)Photodynamictherapy天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生AcneThere is no single anti-acne medicationthat acts against all four pathophysiologicalfactors of acne.(Except Isotretinoin)天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生Systemic Treatment Oral Antibiotics Isotretinoin Hormones天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生Acne: Systemic therapies and their associatedactivities天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生Oral Antibiotics Indications Moderate to severeacne Acne resistant to topicaltreatment Acne covering large partof body surface天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生Oral Antibiotics in Acne Suppress P. Acnes growth Minimize inflammatory mediators synthesized by P. Acnes Tetra and Ery have inherent anti-inflammatory actions (decrease of chemotactic factors and neutrofils recruitment) Reduce comedogenesis by decreasing perifolicular lymphocytic infiltrateMode of ActionJeremy A et al J Inv Derm. 121:20-27; 2003天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生Anti-microbial therapies for acne vulgaris: anti-inflammatory actions of anti-microbial drugs intheir effectivenessAntimicrobial drugs (new quinolones, macrolides,tetracyclines) exert their therapeutic effect both bybacteriocidal actions and anti-inflammatory or anti-immunological actions. Antioxidative action towards neutrophils Inhibition of cytokine/chemokine production and adhesion molecule expression by keratinocytes Suppression of the antigen-presenting ability of Langherans cellsMurata K, Tokura Y. J UOEH. 2007; 29(1): 63-71天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生Oral Antibiotic for AcneFirst Line: Alternatives:Tetracycline ErythromycinDoxycycline TMP/SMXMinocyclineLymecyclineAzithromycin天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生Oral antibiotics for acne: First LineAgentDoseDurationEfficacyAdvantageDisadvantageTetracycline500mg 2x/day2-4 mths+InexpensivePoor absorption withfoodDoxycycline50-100 mg2x/day+OK with foodPhotsensitivityMinocycline50-100 mg2x/day+OK with foodDizziness, rarely benignintracranialhypertension, blue teethand bruises, very rarehepatitis, lupus-likesyndrome2.More expensiveNew AntibioticsLymecycline150-300 mg1x/day+OK with foodAzithromycin250 mg3x/week+OK with food1. A. Katsambas et al. Clinics in Derm. 22: 412-418; 20042. Egger SS et al. Scweiz Runsch Med Prax. 95(35: 1297-303; 2006天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生Oral antibiotics for acne: AlternativesAgentDoseDurationEfficacyAdvantageDisadvantageErythromycin 500 mg2x/day2-5 mths+OK with foodGI upset (not long term)TMP/SMX800 SMX/160TMP+Drug rash, rarelysevere allergicreactionsTMP300 mg2x/day+Drug rashWhite GM. Standard oral antibiotics for acne. 14:29-57; 1999. Modified天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生Sub-antimicrobial doses ofDoxycyline in Moderate AcneDose: 20 mg bd. for several monthsResult: Decrease of comedones and inflammatory lesionsComment: Doxycyline inhibits matrix metalloproteinase and cytokinesSkidmore et al. Arch Derm. 139: 459; 2003天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生Oral Antibiotics: Poor Responders Resistant P. Acnes Gram (-) folliculitis Very high Sebum Excretion Rate Problematic Side EffectsCauses天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生P. Acnes ResistancePrevalence of P. Acnes resistance on theskin of acne patients. 10 year surveillancedate:1991 34,5% to one or more used anti-acne antibiotics1997 55,5% to one or more used anti-acne antibiotics2000 64% to one or more used anti-acne antibioticsCoates P, Cunliffe W et al. Br J Derm. 146 (5): 840 (2002)天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生Propionibacteria Resistance Rates in EuropeJ. Ross, I. Snelling, A Katsambas et al. Br J Derm 148: 467478 (2003)Spain(n=78)Italy(n=116)England(n=103)Sweden(n=116)Hungary(n=65)GreecetetclneryanyResistance% of patients0102030405060708090100天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生Main reason for increasedP. Acnes resistanceThe extensive use of topicalformulations of Erythromycin andClindamycinEady E et al. Dermatology 206(1): 54 (2003)天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生P. Acnes resistance to ErythromycinAddition of zinc salts(zinc gluconate 30mg/24h) reducesresistance of P. Acnes strains toerythromycin.Dreno B et al. Eur J Dermatol. 15(3): 152-5; 2005天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生P. Acnes ResistanceErythromycin HighClindamycin .HighTetracycline .MediumDoxycycline .MediumTrimethoprin .MediumResistance to Minocycline .Very rareManagement: Isotretinoin MinocyclineJ. Ross, I. Snelling, A Katsambas et al. Br J Derm 148: 467478 (2003)天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生Guidelines to avoid P. Acnes Resistance Oral antibiotic should not be used as monotherapy2 Oral antibiotics should not be used for more than 4 months Antibiotics should be combined with Topical Retinoids to enhance efficacy against comedones and inflammatory lesions Topical BPO or Azelaic Acid may be added to oral antibiotics to reduce the development of P. Acnes resistance.1. Thielitz H, Gollnick H. Hautarzt 56(11): 1040; 20052. Ochsendorf F. J Dtsch Dermatol Ges. 4(10): 828-41; 2006天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生Topical Retinoids (TR) andOral Antibiotics (OA) TR increases follicular cell turnover More OA is transported into the follicular canal where P. Acnes resides Increased tissue concentration of OA Reduced potential for low-concentration induced OA resistanceKatsambas A et al. Clin Derm 22:439-444; 2004天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生Future CombinationsA comparison of the efficacy and safetyof lymecycline plus adapalen gel 0.1%vs. lymecycline plus gel vehicle inmoderate inflammatory acneCunliffe W et al. JAAD 49(3): S218; 2003天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生Future CombinationsResults: Combination therapy (lymecycline 300mg/d + adapalen gel 0.1%)was faster and significantly more effective than oral lymecycline300mg/d + vehicle in clearing both inflammatory lesions andcomedones. Irritation was milder in Lym. + vehicle but not S.S.Cunliffe W et al. JAAD 49(3): S218; 2003Baseline1 week4 week8 week12 weekLymecycline 300 mg/d +Adapalene gel 0.1% (n=118)Oral Antibiotic 300 mg/d+vehicle (n=124)Mean % Reduction(N=242)P=0.013P=0.00030-10-20-30-40-50-60-70天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生Poor Responders: CauseGram (-) Folliculitis Sudden onset of many pustules Sudden deterioration of acneManagement:Isotretinoin (1mg/kgr)Ampicilin天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生Poor Responders: CauseVery High Sebum Excretion Rate (S.E.R)The excess of sebum dilute the antibiotic andproduce lower and ineffective concentration ofthe antibiotic in the pilosebaceous unit.Management: Double dose of antibiotic (Minocycline 200mg/d) (Doxycyclin 200mg/d) Isotretinoin Estrogen + Anti-androgens天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生Poor Responders Cause Management Resistant P. Acnes Isotretinoin-Minocycline Gram (-) folliculitis Isotretinoin Ampicilin Very high Sebum Isotretinoin Excretion Rate Cypr. Acetate + Estrogens Minocylcin 200 mg/d Doxycycline 200 mg/dAntibiotics天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生IsotretinoinThe only agent that displays activityagainst all pathogenetic factors ofacne Oral Isotretinoin Reduces sebum production Normalizes follicular desquamation Reduces P acnes indirectly Reduces inflammation天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生Consensus: Oral Isotretinoin is theMainstay of Therapy for Severe Acne Targets all pathophysiologic factors in acne May achieve dramatic results even in severe disease Now used more frequently in moderate, non-responsive acne Side effect are common, but usually manageable Education is vital (side effects, teratogenicity, adverse psychiatric events, monitoring) Variable rate of recurrence; re-treatment may be necessaryGollnick et al. J Am Acad Dermatol. Vol 49 (1): 2003天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生An expert view on the treatment of acne withsystemic antibiotics and/or oral isotretinoin in thelight of the new European recommendationsOral isotretinoin should be administered as 2nd line therapyin those cases of severe acne, which were resistant to orwhich did not respond successfully to an initial combinationregimen with systemic antibiotics and topical treatments(topical retinoids +/- benzoyl peroxide). However, anumber of prognostic factors, as well as psychosocialmorbidity should be taken into account when choosing theuse of oral isotretinoin as first line therapy.Dreno B et al. Eur J Dermatol. 2006; 16(5): 565-71天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生IsotretinoinDose: 0.5 1 mg/kg (with food) (Better start with lower dose and increase according to tolerability)Duration: 16-30 weeksCumulative dose: 120-150 mg/kg (CD lower than 120mg/kg Increases rate of relapse) Patient counseling : Crucial天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生Isotretinoin : Poor responders Patients with many macrocomedones microcysts Women with endocrine problems - Polycystic Ovarian Syndrome - Late onset adrenal hyperplasiaCauses天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生Treatment of Acne : Poor respondersIsotretinoinManagement: Gentle excision or cauteryunder topical anesthesia before ISOtreatmentPatients with many macrocomedones microcystsCunliffe W et al. Dermatology 206 (1) 11:6 (2003)天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生Treatment of Acne: Poor respondersIsotretinoin Women with endocrine problems Women with SAHA syndrome Women with late onset acne天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生Treatment of Acne : Poor respondersManagement: Oral estrogens alone or with antiandrogens given together or after ISO treatmentE.g. Ethinylestradiol (EE) 35mg + Cyproterone Acetate (CPA) 2mg EE 25mg + CPA 50mg EE 25mg + 100mg Levonogestrel Spironolactone 25-50 mg/d Prednisone 2.5-5 mg/d Indefinitely Dexamethasone 0.125 0.5 mg/dIsotretinoin: Women with endocrine problemsCarmine E et al. Clin Endocrin 57(2) 213:2002Leyden J et al JAAD 47 (3) 399: 2002天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生Treatment of Acne : Poor respondersIsotretinoinSide effects: Management:Dermatitis Cheilitis Moisturizers HC CreamArthralgia Myalgia Lower doses NSAIDS. Aureous Boils ErythromycinDepression (Idiosyncratic) DiscontinuationPatients with problematic side effects天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生The association between depressionand Isotretinoin in acneIsotretinoin (ISO) has a positivepsychological impact for the majority ofpatients who benefit from treatment.However, it is important to recognize thatdepression can occur as anidiosyncratic side effect that requiresimmediate discontinuation and urgent,appropriate treatmentHersom K et al. JAAD 49(3):424;2003天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生Hormonal Therapy Excellent choice for women who need oral contraception for gynecologic reasons Use early in female patients with moderate to severe acne or with SAHA syndrome Useful as a component of combination therapy in women with or without endocrine abnormalities Sometimes used in women with late-onset acneGollnick et al. J Am Acad Dermatol. Vol 49 (1): 2003天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生Recommended hormonal testing in femalepatients with acneTest*Interpretation of elevated valuesLH/FSH ratioPolycystic ovary syndromeFree testosteroneOvarian tumorPolycystic ovary syndromeDHEA-SCongenital adrenal hyperplasiaAdrenal tumour17-hydroxyprogesteroneCongenital adrenal hyperplasia*Tests should be obtained in the luteal phase of cycle(Within two weeks before onset of menses)天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生Hormonal treatment in acneAgentDoseDurationDrawbacksOral contraceptives + OestrogensCyproterone acetate/Ethinyl Estradiol2 mg / 10-50 g35 mg 6 monthsVascular thrombosisMelasmaWeight gainNorgestimate/EthinylEstradiol (tricyclic)(0.18/0.215/0.25) /35 g 6 monthsVascular thrombosisMelasmaWeight gainLevonorgestrel/EthinylEstradiol100 g / 20 g 6 monthsVascular thrombosisMelasmaWeight gainOthersPrednisone2.5-5 mg dailyindefinitelyAdrenal suppressionDexamethasone0.125-0.5 mg dailyindefinitelyAdrenal suppressionSpironolactone25-100 mg twicedaily 6 monthsMenstrual irregularitiesContraindicated inpregnancy天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生New development in SystemicTreatment of Acne Lipoxygenas inhibitors (zileuton)1 Micronized Isotretinoin1 RM586621. Zouboulis C. Arch Dermatol. 130: 668-71; 20032. Verfaille CJ et al. Br J Dermatol. (in press) 2007天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生Oral R115866 in the treatment of moderateto severe facial acne vulgaris:an exploratory studyBackground: R115866 is a new generation retinoic acid (RA) metabolsim-blocking agent, - (nonretinoid) enhancing endogenous levels of all-trans RA by blocking its metabolism.Method: 17 pts with severe facial acne 1mg R115866/ 24 for 12 weeks followed by a 4-week treatment free follow-upVerfaille CJ et al. Br J Dermatol 2007 (in print)天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生Oral R115866 in the treatment of moderate tosevere facial acne vulgaris:an exploratory studyResults: Total lesion count : 76% reduction (P0.001) - Mild side effectsConclusion: R115866 1mg/24 for 12 weeks in pts with moderate to severe facial acne is efficacious and well tolerated and merits further investigationVerfaille CJ et al. Br J Dermatol 2007 (in print)天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生天堂医生FINAL REMARKSAll acne cases can be adequatelycontrolled if the relationship betweendoctor and patient has been built on trustand confidence