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Clearing Up Treatment for the Primary Care Physician

A review of recent guidelines on the treatment of adolescent acne vulgaris

ABSTRACT Acne vulgaris is a common encountered in family practice and can cause significant distress during ado- lescence. Treatment options discussed include topical benzyl peroxide, topical , oral and topical , hormonal therapy, and . The following review article provides up-to-date recommendations for treating mild to severe pediatric acne.

KEYWORDS: acne vulgaris, adolescence, treatment, pathogenesis

Pathogenesis The pathogenesis of acne involves four steps: (1) and increased sebum production, caused by . (2) alterations in follicular growth and differentiation leading to comedone formation. (3) colonization by Propionibacterium acnes (P acnes), which releases inflammatory mediators. (4) the immune response is mounted and occurs, which when severe can lead to scarring.1

ABOUT THE AUTHORS Darcy Russell, Medical Undergraduate Program, University of British Columbia, Vancouver, BC Joseph M. Lam, MD, FRCPC, Clinical Assistant Professor, Department of Pediatrics and Dermatology, University of British Columbia, BC.  Clearing Up Acne Treatment for the Primary Care Physician

Pathogenesis of Acne 1 Alteration in follicular growth Increased and di erentiation levels Comedone 2

Sebaceous hyperplasia

Increased sebum production Colonization by Propionibacterium acnes (P acnes) 3 Potential scarring Inammation Release of 4 inammatory mediators Increased immune response

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Differential Diagnosis & face area involved.2 Acne morphol- Classification ogy includes closed comedones (whiteheads), open comedones Comedones must be present for a (blackheads), and inflammatory diagnosis of acne. The differential lesions, which include , diagnosis for acne in adolescence nodules, and -like lesions. The includes corticosteroid induced microcomedone is the precursor acne, , , to both comedones and inflamma- papular sarcoidosis, perioral der- tory lesions.3 Secondary changes matitis, pseudofolliculitis barbae, include post inflammatory hyper- and tinea faceie.2 pigmentation, residual erythema, Acne can be categorized accord- and scarring.2 ing to age. occurs up to six weeks of age. Infantile acne 6 Treatment Options is from 6 weeks to one year of age. Acne therapy is targeted at treating Mid-childhood acne occurs from as many pathogenic factors as pos- 1 to 7 years of age. Preadolescent sible. acne is from 7 to 12 years of age or 1. Various over the counter prod- until onset of menarche in girls. ucts are available and are Adolescent acne is between 12 and considered to be somewhat 19 years of age or after menarche in effective, particularly for mild girls.2 acne. Salicyclic acid and benzyl Acne may be classified as peroxide (BP) have been shown mild, moderate or severe based to be efficacious in clinical tri- on the number and type of lesions als. BP is available in concen- involved as well as the total sur- trations ranging from 2.5% to

Comedonal Acne Inflammatory Acne Scarring Acne

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10%, which are all equally effec- noids can be used as monother- tive; however, skin irritation apy or combination therapy for increases with concentration. all types and severities of acne Available formulations include in children and adolescents. ones that can be washed off and They can cause skin irritation, which can be reduced by using a lower strength topical Both topical and oral antibiotics or regular use of a moisturizer.2 work by inhibiting P acnes 3. Both topical and oral antibiot- protein synthesis and decreasing ics work by inhibiting P acnes protein synthesis and decreas- inflammation. ing inflammation. The concern regarding their use to treat acne ones that are left on the skin.2 is the increase in P acnes resist- BP has comedolytic, antibac- ance, which renders antibiotics terial, and anti-inflammatory less effective and may influence properties. It acts at the pilose- commensal bacteria in patients.5 baceous unit by generating free Topical antibiotics (clindamy- radicals that oxidize the cell cin, ) are not rec- wall of P acnes.4 BP can be used ommended as monotherapy, as monotherapy or combina- but instead should be used with tion therapy for all types and topical BP. Their onset of action severities of acne. Common side is slow and there is greater like- effects include dry skin, pho- lihood of developing bacterial tosensitivity, and bleaching of resistance if treatment is greater hair, clothing, and towels that than a few weeks.2 One study come in contact with BP.2 suggests a BP washout period 2. Topical retinoids desquamate after three months of topical the follicular epithelium pre- antibiotics prior to further anti- venting new microcomedone microbial treatment.1 formation and clearing existing Oral antibiotics are appropri- microcomedones. As well, some ate for moderate to severe acne. topical retinoids have anti- The most commonly used oral inflammatory activity. Three antibiotics for children older available topical retinoids are than eight years of age are tet- , , and tazar- racycline, doxycycline, and otene. They can be prescribed minocycline. Patients should be in a variety of formulations and aware of adverse effects of oral concentrations.1 Topical reti- antibiotics. The three previously

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mentioned can cause stain- increase in liver enzymes and tri- ing of forming teeth enamel if glycerides. Monthly lab work has given at less than eight years traditionally been recommended of age. Tetracycline may cause for patients on the standard GI upset and a fixed drug erup- dose; however, current best evi- dence does not support this.11 A Topical fixed-dose combination major adverse effect is terato- genic potential. Female patients therapies can be used for all types should have monthly pregnancy and severities of acne in children 9 tests and be counselled to use years of age and older. two forms of birth control while on isotretinoin. Other more con- troversial adverse effects include tion.2 Common side effects of skeletal issues, development of doxycycline are photosensitivity inflammatory bowel disease, and and pill esophagitis.6,7 Rare side mood changes.12 effects of minocycline include 5. Topical fixed-dose combina- drug hypersensitivity syndrome, tion therapies can be used for Stevens-Johnson syndrome, all types and severities of acne and lupus-like syndrome.2,8,9 For in children 9 years of age and oral antibiotics, the maximal older. Examples include pair- response may take three to six ing BP with a topical months. Prescribers should con- or a topical retinoid, or pairing sider stopping oral antibiotics a topical retinoid with a topical and maintaining topical ther- antibiotic.2 Fixed combinations apy once inflammatory lesions may be more expensive than are markedly decreased.1 Ide- each agent prescribed sepa- ally therapy should be limited rately; however, they may be to three to four months or the more convenient and thus have shortest possible duration to see better adherence.13 a satisfactory response.10 6. Hormonal therapy targets sup- 4. Oral isotretinoin is used for pression of ovarian androgen severe acne. It targets all four production and blocks andro- factors in acne pathogenesis.1 gen effects on . Common side effects include Ortho Tri Cyclen, Estrostep, dry, chapped skin and lips, and Yaz are currently FDA dry eyes, and myalgias. Some approved for the treatment of patients may experience a dose acne, though others are effi- dependent and asymptomatic cacious and commonly used.

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Common side effects include Pediatric Acne Action Plan nausea/ vomiting, breast ten- Note that any acne treatment takes derness, headache, weight gain, four to eight weeks before notice- and breakthrough bleeding. An able results are achieved. uncommon but serious adverse effect is the risk of thromboem- Mild Acne bolism; prescribers should ask – characteristics: comedonal or about family history and smok- mixed comedonal and inflam- ing.2 Specific to the pediatric matory population is the concern over – initial treatment: whether low doses of estrogen (1) BP OR topical retinoid allow for enough estrogen for (2) topical combination therapy bone accrual given that peak using BP AND antibiotic OR bone mass accrual occurs dur- retinoid AND BP OR ing adolescence.14 retinoid AND antibiotic Pediatric Acne Action Plan

MILD MODERATESEVERE

Characteristics: Comedonal or mixed Comedonal or mixed In ammatory/mixed and/ comedonal and in ammatory comedonal and in ammatory or nodular lesions Initial (1) BP or topical retinoid (1) Topical combination therapy Combination therapy using Treatment: (2) Topical combination therapy using retinoid and BP or retinoid oral antibiotic and topical using BP and antibiotic or and BP/antibiotic or retinoid/ retinoid and BP and/or retinoid and BP or retinoid antibiotic + BP topical antibiotic and antibiotic and BP (2) Oral antibiotic + topical retinoid and BP or topical retinoid and antibiotic and BP

If Inadequate First check adherence, then: First check adherence, then: First check adherence, then: Response: (1) Add retinoid or BP if not (1) Change topical retinoid concentration, (1) Consider changing oral already prescribed type, and/or formulation, and/or antibiotic (2) Change topical retinoid change topical combination therapy (2) Consider oral isotretinoin concentration, type and/or (2) Add or change oral antibiotic (3) Consider hormonal therapy formulation (3) Consider hormonal therapy in females in females (3) Change topical combination (4) Consider isotretinoin (4) Consider dermatology therapy (5) Consider dermatology referral referral

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SUMMARY OF KEY POINTS The differential diagnosis for acne in adolescence includes Acne therapy is targeted at treating as many pathogenic corticosteroid induced acne, folliculitis, keratosis pilaris, factors as possible. papular sarcoidosis, , pseudofolliculitis barbae, and tinea faceie. Topical fixed-dose combination therapies can be used for all types and severities of acne in children 9 years of age and older. Acne may be classified as mild, moderate or severe based on the number and type of lesions involved as well as the total Both topical and oral antibiotics work by inhibiting P acnes surface area involved. protein synthesis and decreasing inflammation.

AND BP (2) oral antibiotic + topical – if inadequate response: first retinoid AND BP OR topical check adherence, then retinoid AND antibiotic (1) add retinoid or BP if not AND BP already prescribed – if inadequate response: first (2) change topical retinoid check adherence, then concentration, type and/or (1) change topical retinoid formulation concentration, type, and/ (3) change topical combination or formulation, and/or therapy2 change topical combination therapy Moderate Acne (2) add or change oral antibiotic – characteristics: comedonal or (3) consider hormonal therapy mixed comedonal and inflam- in females matory (4) consider isotretinoin – initial treatment: (5) consider dermatology referral2 (1) topical combination therapy using retinoid AND BP OR Severe Acne retinoid AND BP/antibiotic – characteristics: inflammatory/ OR retinoid/antibiotic + BP mixed and/or nodular lesions + CLINICAL PEARLS Do not be afraid of isotretinoin. It can be used first line in patients with severe nodular and/or inflammatory acne, , and recalcitrant acne.12 It is the only treatment that targets all four pathogenic factors implicated in acne vulgaris  and can permanently decrease acne.

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DID YOU KNOW?

Just Acne?

Adolescents with acne reported social, psychological, and emotional symptoms similar to people with chronic medical conditions including asthma, epilepsy, diabetes, back pain and arthritis.15

Venereol. 2007; 21(6): 747-753. – initial treatment: combination 4. Krakowski A, Stendardo S, Eichenfield L. Practical con- therapy using oral antibiotic siderations in acne treatment and the clinical impact of topical combination therapy. Pediatr Dermatol. AND topical retinoid AND BP 2008; 25 (suppl 1): 1-14. AND/OR topical antibiotic 5. Patel M, Bowe W, Heughebaert C, Shalita A. The devel- opment of due to antibiotic – if inadequate response: first treatment of acne vulgaris: a review. J Drugs Derma- check adherence, then tol. 2010; 9(6): 655-664. 6. Kadayifci A, Gulsen M, Koruk M, Savas M. Doxycycline- (1) consider changing oral induced pill esophagitis. Dis Esophagus. 2004; 17(2): antibiotic 168-171. 7. Bjellerup M, Ljunggren B. Double blind cross-over (2) consider oral isotretinoin studies on phototoxicity to three tetracycline deriva- (3) consider hormonal therapy tives in human volunteers. Photo-dermatology. 1987; 4(6): 281-287. in females 8. Knowles S, Shear N. Recognition and management of (4) consider dermatology severe cutaneous drug reactions. Dermatol Clin. 2007; 2 25(2): 245-253. referral 9. Shapiro L, Knowles S, Shear N. Comparative safety of tetracycline, minocycline, and doxycycline. Arch Conclusion Dematol. 1997; 133(10): 1224-1230. 10. Zaenglein A, Pathy A, Schlosser, et al. Guidelines of The pathogenesis of acne vulgaris care for the management of acne vulgaris. J Am Acad Dermatol. 2016; 74(5): 945-973.ß appears to be similar across the 11. Lee Y, Schamitz T, Muscat J, et al. Laboratory monitor- ages. The above pediatric treat- ing during isotretinoin therapy for acne: a systematic review and meta-analysis. JAMA Dermatol. 2016; ment approaches serve as a guide 152(1): 35-44. for the family physician to comfort- 12. Accutane [product monograph]. Hoffman-Roche Canada. Mississauga, ON; 2016. [updated Novem- ably and successfully manage acne ber 29, 2016; cited June 29th, 2017]. Available from: vulgaris. http://www.rochecanada.com/ 13. Yentzer B, Ade R, Fountain J et al. Simplifying regi- mens promotes greater adherence and outcomes References with topical acne medications: a randomized con- 1. Gollnick H, Cuniffe W, Berson D, et al. Management of trolled trial. Cutis. 2010; 86(2): 103-108. acne: a report from a global alliance to improve out- 14. Sabatier J, Guaydier-Souquieres G, Benmalek A, come in acne. J Am Acad Dermatol. 2003; 49(suppl 1): Marcelli C. Evolution of lumbar bone mineral content S1-S37. during adolescence and adulthood: a longitudinal 2. Eichenfield L, Krakowski A, Piggott C, et al. Evidence- study in 395 healthy females 10-24 years of age and based recommendations for the diagnosis and treat- 206 premenopausal women. Osteoporos Int. 1999; ment of pediatric acne. Pediatrics. 2013; 131(suppl 3): 9(6): 476-482. S163-S186. 15. Mallon E, Newton J, Klassen A, et al. The quality of life 3. Thieltz A, Sidou F, Gollnick H. Control of microcome- in acne: a comparison with general medical condi- done formation throughout a maintenance treat- tions using generic questionnaires. Br J Dermatol. ment with adapalene gel, 0.1%. J Eur Acad Dermatol 1999; 140(4): 672-676.

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