4/2/13 Disclosure Information
I have the following financial relationship(s) with
the manufacturers(s) of any commercial
product(s) and/or provider of commercial
service(s) discussed in this CME activity:
Galderma – Paid Consultant
Promius – Research Grant
I do intend to discuss an unapproved/
investigative use of a commercial product/device
in my presentation.
The New Acne Guidelines: What Zit All About? Albert C. Yan, MD, FAAP, FAAD Chief, SecBon of Pediatric Dermatology Children’s Hospital of Philadelphia Associate Professor, Pediatrics and Dermatology Perelman School of Medicine at the University of Pennsylvania Background: Why?
•  Acne is common in the pediatric and adolescent
age group
•  There are no acknowledged specific guidelines
or of care or expert recommendations for
management of acne in the pediatric age group
•  Acne presentations and differential diagnosis
differ at differing ages
The New Acne Guidelines: What Zit All About? As a result of a1ending my lecture, course a1endees will understand how the new AAP-‐endorsed pediatric acne guidelines will impact the clinical management of acne in children and adolescents. Overview •  New acne guidelines? What new acne guidelines? •  Acne through the ages •  Acne pathophysiology in a nutshell •  Acne therapies and recipes •  Anything new on the horizon? How?
•  Unification of efforts from pediatric dermatologists,
dermatologists, pediatricians, the AARS and the
AANA (Acne Alliance of North America)
•  Chairs: Lawrence Eichenfield and Diane Thiboutot
•  Distinguished panel (acneologists, pediatric
dermatologists with acne expertise, pediatricians,
junior expert-reviewers)
•  Desire to increase recognition and improve
management of acne across the spectrum of
primary and specialty care
1 4/2/13 Acne through the Ages Panel Members
Co-Chairs
Diane Thiboutot, MD*
Hilary Baldwin, MD*
Sheila Friedlander, MD
Anne Lucky, MD*
Seth Orlow, MD
Guy Webster, MD, PhD*
Andrea Zaenglein, MD*
Lawrence Eichenfield, MD*
James Del Rosso, DO*
Moise Levy, MD
Anthony Mancini, MD
Keith Vaux, MD
Albert Yan, MD
Andrew Krakowski, MD
Caroline Piggott, MD
Stacey Moore
What is the cause of neonatal acne? 1) Proprionibacterium acnes 2) Malassezia sympodialis 3) Maternal hormones 4) A combinaBon of B & C Malassezia • 
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Seborrheic dermaBBs Tinea (pityriasis) versicolor Pityrosporum folliculiBs Neonatal cephalic pustulosis Neonatal InfanBle Mid-‐childhood Pre-‐adolescent Adolescent Acne Type Age of Onset Neonatal acne 0-‐6 wk InfanBle acne 0-‐1 yr Mid-‐childhood acne 1-‐7 yr Preadolescent acne 7-‐12 yr Adolescent acne 12-‐19 yr Adult Neonatal acne •  Benign, self-‐limited, asymptomaBc erupBon of erythematous papules and pustules; no comedones •  Usually in infants < 6 months of age •  Localized to cheeks, forehead, and scalp •  ConvenBonal Wisdom: maternal hormones Treatment with ketoconazole •  Ketoconazole 2% cream •  Twice daily applicaBon •  1 week Rapelanoro et al. Arch Dermatol. 1996;132(2):190-‐3. 2 4/2/13 • 
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InfanKle acne InfanKle acne <1 year of age; may last for up to ~2 years Chronic potenBally scarring condiBon Comedones, papules, pustules, nodules May represent a marker for later-‐onset, more severe acne •  Pa1erns: comedonal (17%), inﬂammatory (59%), mixed (17%), nodular (7%) •  Severity: mild (24%), moderate (62%), severe (14%) •  Family history of severe acne in 56% •  Clearance: 6-‐42 months; average about 22 months •  Scarring: 17-‐56% Chew et al. Clin Exp Dermatol. 1990;15(5):376-‐7. Cunliﬀe et al. Br J Dermatol. 2001;145(3):463-‐6. Hello M et al. Pediatr Dermatol. 2008;25(4):434-‐8. Treatment for infanKle acne •  Similar to adult except for avoidance of tetracycline derivaBves in children <9-‐12 yo •  Topical reBnoids, topical benzoyl peroxides, topical anBbioBcs, combinaBon topical agents •  Oral anBbioBcs (erythromycin derivaBves, trimethoprim, cotrimoxazole) •  Occasionally, isotreBnoin Mid-‐childhood acne •  Acne vulgaris is rare in prepubertal children, beyond infancy •  Those with onset 1-‐7 years of age should be evaluated more closely (especially 3-‐7) •  Bone age; labs: testosterone (F/T), 17-‐hydroxyprogesterone, LH, FSH, DHEA(S), prolacBn, ACTH sBm for those with signs of hirsuBsm or precocious puberty; consultaBon with Endocrinology •  Several case reports highlighBng associaBons: adrenocorBcal tumors, congenital adrenal hyperplasia, elevaBons in testosterone and LH What is idiopathic asepKc facial granuloma? 1)  A clinical mimic of infanBle acne 2)  Probably an inﬂammatory endpoint for a number of diﬀerent disorders 3)  A really inconvenient name for a pediatric disease 4)  All of the above Cunliﬀe et al. Br J Dermatol. 2001;145(3):463-‐6. Hello M et al. Pediatr Dermatol. 2008;25(4):434-‐8. Duke. Br Med J. 1981;282(6272):1275-‐6. [transient increases in LH and testosterone] Mann et al. J Am Acad Dermatol. 2007;56(2 Suppl):S15-‐8. [adrenocorScal tumor] Harde et al. J Dtsch Dermatol Ges. 2006;4(8):654-‐7. [CAH] Tabata et al. J Am Acad Dermatol. 1995;33(4):676-‐8. [high testosterone] Nakagawa et al. Hinyokika Kiyo. 1989;35(10):1731-‐6. [adrenocorScal tumor] Idiopathic facial asepKc granuloma •  IniBal diagnosis: infanBle acne, folliculiBs, pilomatricoma, pyogenic granuloma, atypical Spitz nevus •  Onset: 8 mos – 13 years •  90% solitary lesions but 2 or 3 lesions reported •  3-‐25 mm in size (mean, 10 mm) •  Histology: chronic dermal mixed inﬂammatory granuloma Boralevi et al. Br J Dermatol. 2007;156:705-‐708. 3 4/2/13 Acne Pathophysiology Courtesy of NaBonal CollaboraBve to Control Acne 2003 Comedones Androgen inﬂuences Abnormal desquamaBon Courtesy of NaBonal CollaboraBve to Control Acne 2003 Increased sebum producBon Closed Open Courtesy of NaBonal CollaboraBve to Control Acne 2003 Papule, pustule, and nodule Acne Therapy ProliferaBon of P. acnes and release of inﬂammatory mediators Courtesy of NaBonal CollaboraBve to Control Acne 2003 4 4/2/13 Adolescent: Mild Acne (Comedonal or Inﬂammatory/Mixed Lesions) Initial Treatment
Benzoyl Peroxide (BP) or Topical ReKnoid or Topical CombinaKon Therapy* BP + AnKbioKc or ReKnoid + BP or ReKnoid + AnKbioKc + BP
Inadequate Response**
Add BP or ReKnoid, if not already prescribed or Change Topical ReKnoid ConcentraKon, Type and/or FormulaKon or Change Topical CombinaKon Therapy Topical dapsone may be considered as single therapy or in place of topical antibiotic
Considerations
Previous treatment/
history
Side effects
Financial costs
Psychosocial Impact
Vehicle selection
Active scarring
*Topical fixed-combination prescriptions available
**Assess adherence
Clinical Tips: Benzoyl Peroxide (BP) •  Benzoyl peroxide helps to reduce anBbioBc resistance among P. acnes •  When using BP on the chest and back, a wash is usually preferable to a leave-‐on product •  It is important to warm paBents and their families that benzoyl peroxide can bleach fabrics •  Higher concentraBons above a certain threshold (5-‐6%) conBnue to increase irritancy but provide only modest boosts in eﬃcacy AARS Pediatric Acne Guidelines (AAP Endorsed) Ease of use/regimen
complexity
Acne Rule #1 •  Always make benzoyl peroxide part of your regimen whenever paBents can tolerate it –  Reduces anBbioBc resistance Clinical Tips: Topical reKnoids •  Adapalene and treBnoin are less irritaBng than tazarotene •  CondiBoning period –  IniBal therapy every other night for 1-‐2 weeks may help condiBon those with more sensiBve skin –  Short-‐contact (30-‐60 minutes) nightly may be a reasonable alternaBve for those with more sensiBve skin •  EscalaBons in topical reBnoid concentraBon can reasonably occur within 2-‐4 weeks •  Remind paBents that they can moisturize ad lib when using reBnoids Topical Acne Treatment •  Benzoyl peroxide + something else •  Washes for face + chest + back •  If just treaBng face, leave-‐on products can be more eﬀecBve if somewhat more irritaBng •  What if you can’t tolerate benzoyl peroxide? •  Can subsBtute topical sodium sulfacetamide for sensiBve-‐skin paBents StarKng Topical ReKnoid Treatment •  StarBng agents: –  Adapalene 0.1% loBon, cream, or gel –  TreBnoin 0.025% cream, 0.04% microgel •  Once condiBoned, can increase to next stage reBnoid –  Adapalene 0.3% gel –  TreBnoin 0.05% or 0.1% cream, 0.1% microgel –  Tazarotene 0.1% cream or gel 5 4/2/13 Some Reasonable Generic Regimens •  TreBnoin 0.025% cream or adapalene 0.1% gel •  Consider adding a benzoyl peroxide 5% wash during showers to control face, chest, and back areas Tips for Using ReKnoids with SensiKve Skin PaKents •  Adapalene 0.1% loBon (Diﬀerin) •  TreBnoin 0.04% microgel (ReBn-‐A) •  Tazorac 0.1% short-‐contact •  Short-‐contact regimens may reduce irritaBon: –  Apply for one-‐hour nightly –  Consider increasing to overnight therapy aoer toleraBng treatment for 1-‐2 weeks; if needed Adolescent: Moderate Acne (Comedonal or Inﬂammatory/Mixed) Rule #2 •  You can use topical reBnoids successfully as long as you condiBon paBents to their use –  Short-‐contact or every other day for the ﬁrst 1-‐2 weeks –  Gradually increase concentraBon at each visit unBl desired eﬀect achieved and as long as paBents tolerate Initial Treatment
Inadequate Response**
Topical CombinaKon Therapy* ReKnoid + Benzoyl Peroxide (BP) or ReKnoid + BP + AnKbioKc or ReKnoid + AnKbioKc + BP Change Topical ReKnoid ConcentraKon, Type and/or FormulaKon and/or Change Topical CombinaKon Therapy and/or or Oral AnKbioKc + Topical ReKnoid + BP or Topical ReKnoid + AnKbioKc + BP Add or Change Oral AnKbioKc FEMALES: Consider Hormonal Therapy†
or Consider Oral IsotreKnoin†
Topical dapsone may be considered as single therapy or in place of topical antibiotic
Considerations
Previous treatment/
history
Side effects
Costs
Psychosocial Impact
Vehicle selection
Active scarring
†Consider
AARS Pediatric Acne Guidelines (AAP Endorsed) Ease of use/regimen
complexity
Clinical Tips: CombinaKon Therapy •  CombinaBon therapies involve using 2 or more acBve agents in concert on a daily basis to treat the condiBon –  Individual agents can be used separately –  Agents can be combined in stabilized preparaBons •  Separate agents need be separated in Bme to avoid inacBvaBon of other topicals (e.g., BP + reBnoid) dermatology referral.
*Topical fixed-combination prescriptions available
**Assess adherence
Fixed CombinaKon Products Brand Components Generic Availability Acanya BP + clindamycin No Benzaclin BP + clindamycin Yes Benzamycin BP + erythromycin Yes Duac BP + clindamycin Yes Epiduo BP + adapalene No VelBn Clindamycin + treBnoin No Ziana Clindamycin + treBnoin No •  Stabilized agents may improve compliance but separated agents may be less expensive; choices should be individualized to the paBent 6 4/2/13 Rule #3 •  CombinaBon products make the your job and the paBent’s life easier, but –  Less ﬂexibility –  More expensive –  Not all insurances will cover Which of the following acne anKbioKcs is most strongly associated with unusual and severe adverse drug reacKon syndromes? 1) 
2) 
3) 
4) 
Erythromycin Tetracycline Doxycycline Minocycline Clinical Tips: Oral anKbioKcs •  Erythromycin resistance is fairly high so in teens and young adults, tetracycline derivaBves are favored •  Tetracycline is taken on an empty stomach and given 2-‐4 Bmes a day; doxycycline and minocycline may be more convenient and more eﬀecBve opBons •  Consider subanBmicrobial dosing where appropriate (limited situaBons): doxycycline 20 mg BID or 40 mg once daily •  AnBcipate duraBon; possible adverse eﬀects; be aware of the rare side eﬀects –  Doxycycline: photosensiBvity –  Minocycline: hyperpigmentaBon, pseudotumor, lupus-‐like reacBons, DRESS Rule #4 •  When using oral anBbioBcs for moderate to severe acne, I prefer: •  For kids > 8 yo Doxycycline > Minocycline > Tetracycline For the combinaSon of compliance and favorable side eﬀect proﬁle (but be careful about the sun in summer!) Adolescent: Severe Acne (Inﬂammatory/Mixed and/or Nodular Lesions) Initial Treatment† CombinaKon Therapy* Oral AnKbioKc + Topical ReKnoid + Benzoyl Peroxide (BP) +/-‐ Topical AnKbioKc Consider Changing Oral AnKbioKc AND Consider Oral IsotreKnoin FEMALES: Consider Hormonal Therapy Topical dapsone may be considered in place of topical antibiotic
Considerations
Previous treatment/
history
Side effects
Costs
Psychosocial Impact
Vehicle selection
Active scarring
Ease of use/regimen
complexity
Clinical ObservaKons: Hormonal Therapy Inadequate Response**† Drug
Ortho Tri-Cyclen®
(norgestimate and
ethinyl estradiol)
Daily Dosage
180-250 ug
norgestimate +
35 ug ethinyl estradiol
Daily Cost
$1.71
Estrostep®
†Consider
dermatology referral.
*Topical fixed-combination prescriptions available
**Assess adherence; consider change of topical retinoid
AARS Pediatric Acne Guidelines (AAP Endorsed) 1 mg norethindrone +
$2.91
20-35 ug ethinyl estradiol
(norethindrone
acetate and ethinyl
estradiol)
Approximately 83% studied show clinical improvement within 3 months Redmond GP. Olson WH. Lippman JS. et al. Obstet Gynecol. 89(4):615-‐22, 1997 Apr. Lucky AW. Henderson TA. Olson WH. Et al. J Amer Acad Dermatol. 37(5 Pt 1):746-‐54, 1997 Nov. 7 4/2/13 Clinical ObservaKons: Hormonal Therapy Drug
Daily Dosage
Clinical Tips: Hormonal Therapy Daily Cost
Yaz (24/4)*
* FDA approval for
acne
3 mg drospirenone + 20
mcg ethinyl estradiol
$2.59
Yasmin (21/7)
3 mg drospirenone + 20
mcg ethinyl estradiol
$2.50
Ocella (21/7)
3 mg drospirenone + 20
mcg ethinyl estradiol
$1.96
Improvement in acne comparable (slightly more favorable) for drospirenone/EE than with convenBonal norgesBmate regimen; elevaBons in SHBG and decreased androgen producBon noted Thorneycroo H et al. CuBs. 2004;74(2):123-‐30. Lucky et al. CuBs. 2008;82(2):143-‐50. Maloney et al. Obstet Gynecol. 2008;112(4):773-‐81.
•  Screening labs: testosterone (F/T), 17-‐hydroxyprogesterone, LH, FSH, DHEA(S), prolacBn, ACTH sBm for those with signs of hirsuBsm or precocious puberty; consultaBon with Endocrinology •  FDA approval for acne: OrthoTricyclen®, Estrostep®, and Yaz® •  Antagonizes producBon of androgens and increasing SHBG. Almost all oral contracepBves do this. •  Pap smears and rouBne gyn exams should be started within 3 years of sexual acBvity or by age 21 •  Review and explain contraindicaBons with paBent prior to starBng since adolescent habits change over Bme. Consider risk of VTE. •  Spironolactone for appropriate pts who fail convenBonal OCPs Clinical Tips: IsotreKnoin •  Low iniBal doses help minimize adverse eﬀects and allow paBents to adapt to symptoms •  Have paBent take medicaBon with food (without food, up to 40% less medicaBon is bioavailable) •  AnBcipate and explain adverse eﬀects to paBents and their parents •  Overall goal is based on cumulaBve dose rather than on achieving daily target dose (120-‐150 mg/kg total is a be1er predictor than 1 mg/kg/day) •  Most side eﬀects are reversible if idenBﬁed promptly and addressed; excepBons: IBD-‐related issues, teratogenicity Clinical Tips: Severe Acne •  Be aware of severe acne variants •  Acne fulminans –  Fever, arthriBs, severe acne; role of P. acnes •  SAPHO –  SynoviBs, acne, pustulosis, hyperostosis, osteiBs •  PAPA –  pyogenic sterile arthriBs, pyoderma gangrenosum, acne Clinical ObservaKons: Diet Clinical ObservaKons: Diet •  Diet has tradiBonally been thought to have no signiﬁcant eﬀect on acne course or severity •  Some recent studies suggest that some cultures experience less acne that may be a1ributable to a combinaBon of geneBcs and diet; one study suggests an associaBon between acne and skim milk (1.44 OR) as opposed to whole milk (1.00) •  Could high glycemic index diets may induce insulin resistance and therefore hyperandrogenic states in predisposed individuals? Fulton, Plewig, and Kligman. JAMA. 1979;210(11):2071-‐4. Cordain L et al. Arch Dermatol. 2002;138:1584-‐1590. Thiboutot D et al. Arch Dermatol. 2002;138:1591-‐1592 Adebamowo et al. J Am Acad Dermatol. 2005;52(2):207-‐14.
Study PaKents Conclusions Smith et al. JAAD. 2007;57(2):247-‐56. 43 male paBents 12-‐week study Parallel, dietary intervenBon comparing low and high glycemic index diets LGID: -‐21.9 in lesion count HGID: -‐13.8 in lesion count (p=0.01) Drops in wt, free androgen and IGFBP (p=0.001) Smith et al. Am J Clin Nutr. 43 male paBents 2007;86(1):107-‐15. 12-‐week study Parallel, dietary intervenBon comparing LGID/HGID LGID: -‐23.5 HGID: -‐12.0 Drops in wt, BMI, insulin resistance with LGID Smith et al. Mol Nutr Food 12 male paBents Res. 2008;52(6):718-‐26. 7-‐day study HGID: Decreases in SHBG, IGFBP1,3, insulin sensiBvity Smith et al. J Dermatol Sci. 31 male paBents 2008;50(1):41-‐52. 12-‐week study Parallel, dietary intervenBon comparing LGID/HGID Increase in saturated (relaBve to unsaturated) fa1y acids on the skin surface with HGID Kaymak et al. JAAD. 2007;57(5):819-‐23. Measurements of lepBn, IGFBP3, IGF1, insulin glucose did not corelate with glycemic index 49 paBents with acne; 42 controls Self-‐reported diet quesBonnaires 8 4/2/13 Clinical Tips: EducaKng Teens •  Explain why they develop acne and how the medicines work •  Treatments that sound too good to be true usually are; paBence! •  Trial and error •  Control but not cure •  Eﬃcacy with compliance; keep it simple •  AnBcipate side eﬀects before starBng treatment •  Inform them and their parents about rebates What’s New? Yan and Treat. CuSs. 2008;82(2 Suppl 1):18-‐25. Novel ModaliKes •  Photodynamic therapy –  P. acnes produces endogenic porphyrins –  Intense UV-‐free blue light (405-‐420 nm) photoacBvates porphyrins and damages bacterial membranes –  59-‐67% reducBon in inﬂammatory acne –  8-‐15 minute therapeuBc sessions Three treatments of 2.5 minutes at 48°C each over 24 hours Claims to clear 90% of lesions Not “FDA approved” – cleared for markeBng as device $159 cost for device; replacement Bps about $0.42 each OT App for That? There’s aNn Ashkenazi et al. FEMS Immunol Med Microbiol. 2003;35:17-‐24. Elman et al. J Cosmet Laser Ther. 2003;5:111-‐7. –  Red light photodynamic phototherapy may be signiﬁcantly more eﬀecBve but also much more irritaBng Topical Therapy: Novel Vehicles •  Microsphere technologies -‐ deliver medicaBon more slowly at higher concentraBons (treBnoin, benzoyl peroxide) •  Hydrogel formulaBon -‐ less drying, greater eﬃcacy (treBnoin/clindamycin) (aka, Ziana) h1p://artooheiphone.com/ 9 4/2/13 Newer Vehicles Topical Therapy: Novel Molecules •  Dapsone 5% in a solvent microparBculate (SMP) vehicle gel •  Foam vehicles – easy to spread (clindamycin) (aka, Evoclin) •  Emollient bases – benzoyl peroxide; benzoyl peroxide/clindamycin (aka, Duac, Acanya) •  Stabilized benzoyl peroxide + adapalene combinaBon product (aka, Epiduo) –  FDA approved July 2005; indicaBon for 12 yo and older; Category C –  Mechanism unknown – anBmicrobial, anB-‐
inﬂammatory –  CombinaKon with benzoyl peroxide can cause yellow or orange discoloraBon of skin or facial hair (7.4%); can also be seen with sulfacetamides and reBnoids –  Vehicle irritaBon rate 20% Systemic Therapy: Novel Dosing Surgical ModaliKes •  SubanBmicrobial dosing of doxycycline –  20 mg po BID dosing (oﬀ-‐label) –  40 mg po QD dosing (extended-‐release formulaBon) – oﬀ-‐
label •  Scarring –  Rolling or thumbprint scarring: subcision to lyse scars Skidmore et al. Arch Dermatol. 2003;139:459-‐64. •  Pulsed dosing of isotreBnoin Alam et al. Dermatol Surg;31(3):310-‐7. –  ConvenBonal: 120-‐150 mg/kg over 5-‐6 mos –  Novel: 0.5 mg/kg/day x 1 wk out of every 4 wks x 6 mos •  Remission: 88% iniBal; 56% ﬁnal due to 40% relapse •  Best for milder cases of nodulocysBc acne Goulden et al. Br J Dermatol. 1997;137(1):106-‐8. Surgical ModaliKes Surgical ModaliKes –  CombinaBon subcision and 1320 nm Nd:YAG Fulchiero et al. Dermatol Surg. 2004;30(10):1356-‐60. –  TradiBonal: Dermabrasion or CO2 laser –  Novel: 1320 nm Nd:YAG laser and radiofrequency ablaBon Rogachefsky et al. Dermatol Surg. 2003;29:904-‐8. Bellew et al. Dermatol Surg. 2005;31(9Pt2):1218-‐21. 10 4/2/13 FracKonal Laser Resurfacing FracKonal Laser Resurfacing ChrasBl et al. Dermatologic Surgery. 2008;34(10):1327-‐1332. ChrasBl et al. Dermatologic Surgery. 2008;34(10):1327-‐1332. On the Horizon •  5α-‐reductase type 1-‐inhibitors –  Sebum producBon a key step in acne pathogenesis –  Conversion of testosterone to dehydrotestosterone (DHT) by 5α-‐reductase type 1 in the skin –  MK-‐386 reduces DHT but has no clinical eﬀect for acne either alone or with minocycline Leyden et al. J Am Acad Dermatol. 2004;50(3):443-‐7. –  BRL-‐7660 reduces sebum producBon and acne lesions in one preliminary study Bowring. SKINmed: Dermatology for the Clinician. 2005;4(4):211-‐3. On the Horizon Leukotrienes Prostaglandins Interleukins 6 and 8 Peroxisome proliferators-‐acBvated receptors (PPARs) Toll-‐like receptors (P. acnes and bacterial pepBdoglycans) •  Botulinum toxin (topical) 240 acBve clinical trials registered in clinicaltrials.gov • 
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Summary • 
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Pediatric acne guidelines forthcoming Acne through the ages Acne pathophysiology in a nutshell Acne therapies and recipes Keep an eye out for new treatments on the horizon 11