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1、ACNE: Systemic Treatment,Andreas D. Katsambas Athens - Greece,16th EADV Congress Vienna - Austria 16-20 May 2007,Acne: Treatment,Acne,There is no single anti-acne medication that acts against all four pathophysiological factors of acne. (Except Isotretinoin),Systemic Treatment, Oral Antibiotics Isot
2、retinoin Hormones,Acne: Systemic therapies and their associated activities,Oral Antibiotics,Indications Moderate to severe acne Acne resistant to topical treatment Acne covering large part of body surface,Oral Antibiotics in Acne, Suppress P. Acnes growth Minimize inflammatory mediators synthesized
3、by P. Acnes Tetra and Ery have inherent anti-inflammatory actions (decrease of chemotactic factors and neutrofils recruitment) Reduce comedogenesis by decreasing perifolicular lymphocytic infiltrate,Mode of Action,Jeremy A et al J Inv Derm. 121:20-27; 2003,Anti-microbial therapies for acne vulgaris:
4、 anti-inflammatory actions of anti-microbial drugs in their effectiveness,Antimicrobial drugs (new quinolones, macrolides, tetracyclines) exert their therapeutic effect both by bacteriocidal actions and anti-inflammatory or anti-immunological actions. Antioxidative action towards neutrophils Inhibit
5、ion of cytokine/chemokine production and adhesion molecule expression by keratinocytes Suppression of the antigen-presenting ability of Langherans cells,Murata K, Tokura Y. J UOEH. 2007; 29(1): 63-71,Oral Antibiotic for Acne,First Line: Alternatives: Tetracycline Erythromycin Doxycycline TMP/SMX Min
6、ocycline Lymecycline Azithromycin,Oral antibiotics for acne: First Line,1. A. Katsambas et al. Clinics in Derm. 22: 412-418; 2004 2. Egger SS et al. Scweiz Runsch Med Prax. 95(35: 1297-303; 2006,Oral antibiotics for acne: Alternatives,White GM. Standard oral antibiotics for acne. 14:29-57; 1999. Mod
7、ified,Sub-antimicrobial doses of Doxycyline in Moderate Acne,Dose: 20 mg bd. for several months Result: Decrease of comedones and inflammatory lesions Comment: Doxycyline inhibits matrix metalloproteinase and cytokines,Skidmore et al. Arch Derm. 139: 459; 2003,Oral Antibiotics: Poor Responders, Resi
8、stant P. Acnes Gram (-) folliculitis Very high Sebum Excretion Rate Problematic Side Effects,Causes,P. Acnes Resistance,Prevalence of P. Acnes resistance on the skin of acne patients. 10 year surveillance date: 1991 34,5% to one or more used anti-acne antibiotics 1997 55,5% to one or more used anti-
9、acne antibiotics 2000 64% to one or more used anti-acne antibiotics,Coates P, Cunliffe W et al. Br J Derm. 146 (5): 840 (2002),Propionibacteria Resistance Rates in Europe,J. Ross, I. Snelling, A Katsambas et al. Br J Derm 148: 467478 (2003),Main reason for increased P. Acnes resistance,The extensive
10、 use of topical formulations of Erythromycin and Clindamycin,Eady E et al. Dermatology 206(1): 54 (2003),P. Acnes resistance to Erythromycin,Addition of zinc salts (zinc gluconate 30mg/24h) reduces resistance of P. Acnes strains to erythromycin.,Dreno B et al. Eur J Dermatol. 15(3): 152-5; 2005,P. A
11、cnes Resistance,Erythromycin High Clindamycin .High Tetracycline Medium Doxycycline Medium Trimethoprin .Medium Resistance to Minocycline Very rare Management: Isotretinoin Minocycline,J. Ross, I. Snelling, A Katsambas et al. Br J Derm 148: 467478 (2003),Guidelines to avoid P. Acnes Resistance, Oral
12、 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 de
13、velopment of P. Acnes resistance.,1. Thielitz H, Gollnick H. Hautarzt 56(11): 1040; 2005 2. Ochsendorf F. J Dtsch Dermatol Ges. 4(10): 828-41; 2006,Topical Retinoids (TR) and Oral Antibiotics (OA), TR increases follicular cell turnover More OA is transported into the follicular canal where P. Acnes
14、resides Increased tissue concentration of OA Reduced potential for low-concentration induced OA resistance,Katsambas A et al. Clin Derm 22:439-444; 2004,Future Combinations,A comparison of the efficacy and safety of lymecycline plus adapalen gel 0.1% vs. lymecycline plus gel vehicle in moderate infl
15、ammatory acne,Cunliffe W et al. JAAD 49(3): S218; 2003,Future Combinations,Results: Combination therapy (lymecycline 300mg/d + adapalen gel 0.1%) was faster and significantly more effective than oral lymecycline 300mg/d + vehicle in clearing both inflammatory lesions and comedones. Irritation was mi
16、lder in Lym. + vehicle but not S.S.,Cunliffe W et al. JAAD 49(3): S218; 2003,Poor Responders: Cause Gram (-) Folliculitis, Sudden onset of many pustules Sudden deterioration of acne Management: Isotretinoin (1mg/kgr) Ampicilin,Poor Responders: Cause Very High Sebum Excretion Rate (S.E.R),The excess
17、of sebum dilute the antibiotic and produce lower and ineffective concentration of the antibiotic in the pilosebaceous unit. Management: Double dose of antibiotic (Minocycline 200mg/d) (Doxycyclin 200mg/d) Isotretinoin Estrogen + Anti-androgens,Poor Responders,Cause Management Resistant P. Acnes Isot
18、retinoin-Minocycline Gram (-) folliculitis Isotretinoin Ampicilin Very high Sebum Isotretinoin Excretion Rate Cypr. Acetate + Estrogens Minocylcin 200 mg/d Doxycycline 200 mg/d,Antibiotics,Isotretinoin,The only agent that displays activity against all pathogenetic factors of acne,Oral Isotretinoin R
19、educes sebum production Normalizes follicular desquamation Reduces P acnes indirectly Reduces inflammation,Consensus: Oral Isotretinoin is the Mainstay of Therapy for Severe Acne, Targets all pathophysiologic factors in acne May achieve dramatic results even in severe disease Now used more frequentl
20、y 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 necessary,Gollnick et al. J Am Acad Dermatol. Vol 49 (1): 2003,An expert view o
21、n the treatment of acne with systemic antibiotics and/or oral isotretinoin in the light of the new European recommendations,Oral isotretinoin should be administered as 2nd line therapy in those cases of severe acne, which were resistant to or which did not respond successfully to an initial combinat
22、ion regimen with systemic antibiotics and topical treatments (topical retinoids +/- benzoyl peroxide). However, a number of prognostic factors, as well as psychosocial morbidity should be taken into account when choosing the use of oral isotretinoin as first line therapy.,Dreno B et al. Eur J Dermat
23、ol. 2006; 16(5): 565-71,Isotretinoin,Dose: 0.5 1 mg/kg (with food) (Better start with lower dose and increase according to tolerability) Duration: 16-30 weeks Cumulative dose: 120-150 mg/kg (CD lower than 120mg/kg Increases rate of relapse) Patient counseling : Crucial,Isotretinoin : Poor responders
24、, Patients with many macrocomedones microcysts Women with endocrine problems - Polycystic Ovarian Syndrome - Late onset adrenal hyperplasia,Causes,Treatment of Acne : Poor responders Isotretinoin,Management: Gentle excision or cautery under topical anesthesia before ISO treatment,Patients with many
25、macrocomedones microcysts,Cunliffe W et al. Dermatology 206 (1) 11:6 (2003),Treatment of Acne: Poor responders Isotretinoin, Women with endocrine problems Women with SAHA syndrome Women with late onset acne,Treatment of Acne : Poor responders,Management: Oral estrogens alone or with antiandrogens gi
26、ven together or after ISO treatment E.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/d,Isotretinoin: Women with endocrine problems,Carmine E et al.
27、Clin Endocrin 57(2) 213:2002 Leyden J et al JAAD 47 (3) 399: 2002,Treatment of Acne : Poor responders Isotretinoin,Side effects: Management: Dermatitis Cheilitis Moisturizers HC Cream Arthralgia Myalgia Lower doses NSAID S. Aureous Boils Erythromycin Depression (Idiosyncratic) Discontinuation,Patien
28、ts with problematic side effects,The association between depression and Isotretinoin in acne,Isotretinoin (ISO) has a positive psychological impact for the majority of patients who benefit from treatment. However, it is important to recognize that depression can occur as an idiosyncratic side effect
29、 that requires immediate discontinuation and urgent, appropriate treatment,Hersom K et al. JAAD 49(3):424;2003,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
30、component of combination therapy in women with or without endocrine abnormalities Sometimes used in women with late-onset acne,Gollnick et al. J Am Acad Dermatol. Vol 49 (1): 2003,Recommended hormonal testing in female patients with acne,*Tests should be obtained in the luteal phase of cycle (Within
31、 two weeks before onset of menses),Hormonal treatment in acne,New development in Systemic Treatment of Acne, Lipoxygenas inhibitors (zileuton)1 Micronized Isotretinoin1 RM58662,1. Zouboulis C. Arch Dermatol. 130: 668-71; 2003 2. Verfaille CJ et al. Br J Dermatol. (in press) 2007,Oral R115866 in the
32、treatment of moderate to severe facial acne vulgaris: an exploratory study,Background: 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/
33、 24 for 12 weeks followed by a 4-week treatment free follow-up,Verfaille CJ et al. Br J Dermatol 2007 (in print),Oral R115866 in the treatment of moderate to severe facial acne vulgaris: an exploratory study,Results: Total lesion count : 76% reduction (P0.001) - Mild side effects Conclusion: R115866
34、 1mg/24 for 12 weeks in pts with moderate to severe facial acne is efficacious and well tolerated and merits further investigation,Verfaille CJ et al. Br J Dermatol 2007 (in print),FINAL REMARKS,All acne cases can be adequately controlled if the relationship between doctor and patient has been built on trust and confidence,