A. Introduction

1. Most common skin disease in dermatology
   1. Affects >85% of teenagers
   2. Often cotinues into adulthood
2. Disease of the pilosebaceous unit
3. Normal Pilosebaceous Unit
   1. Large multilobular sebaceous glands
   2. Rudimentary Hair
   3. Follicular canal with stratified squamous epithelium
4. Abnormalities in Acne Vulgaris
   1. Open Comedone (black head) - dark color due to oxidation of melanin
   2. Closed Comedone (white head)
   3. Inflammatory papules and pustules - relatively superficial infected lesions
   4. Cysts and nodules are deeper infected abscesses, fluctuate on palpation
5. Lesions in areas of greatest sebaceous gland density
   1. Face
   2. Neck
   3. Chest
   4. Upper back
   5. Upper arms
6. Scarring and hyperpigmentation are frequent sequellae of untreated acne
7. SAPHO Syndrome
   1. Synovitis
   2. Acne
   3. Pustulosis
   4. Hyperostosis
   5. Osteitis
   6. Skin lesions may be delayed
   7. Unclear etiology of syndrome

B. Pathogenesis

1. Obstruction of specialized (sebaceous) follicles due to:
   1. Excessive production of sebum
   2. Excessive desqaumation of epithelial cells from follicle walls
   3. Normal sebum production is driven by androgenic steroids
   4. Therefore, acne is usually not present before puberty (age 7-9)
2. Sebum is good growth medium for Propionobacterium acnes
   1. P. acnes is a resident anaerobic diphtheroid of the skin
   2. P. acnes colonizes follicular duct and proliferates in teenagers with acne
   3. P. acnes proliferates in sebum-rich microcomedo
   4. Severity of acne is usually proportional to degree of sebum overproduction
   5. Sebum overproduction causes abnormal epithelial differentiation in sebaceous follicles
3. Abnormal Epithelial Differentiation
   1. Abnormally differentiated epithelia within sebaceous follicle will sluff and obstruct
   2. This plug of epithelium causes follicle obstruction, called a microcomedo
   3. Follicular deficiency of linoleic acid may play a role in abnormal cell sluffing
4. Microcomedo may evolve into either comedo or inflammatory lesion
   1. Coallescence of microcomedos leads to a comedone which is non-inflammatory
   2. P. acnes growth in comedone / microcomedo leads to local inflammation
   3. Locally inflamed follicles can rupture into surrounding area
   4. This leads to clinically observable inflammation / infection
5. Papules, pustules and nodules are inflamed, infected comedone
6. P. acnes (or P. granulosum) DNA was found in all Japanese sarcoid specimens [3]

C. Severity [1]

1. Easily diagnosed with detection of comedones
   1. Open comedones: blackheads
   2. Closed comedones: whiteheads
   3. Mild acne is characterized by comedones with minimal or no inflammatory lesions
2. Presence of inflammatory papules or pustules indicates moderate or severe disease
   1. Erythematous papules and pustules limited to the face predominate in moderate acne
   2. Moderately severe acnea with erythematous papules, pustules and nodules on face
3. Severe acne has multiple painful nodules and other lesions, usually on face, back, chest

D. Treatments [1,4,5]

1. Topical Agents
   1. For mild to moderate acne, particularly with uninflamed lesions (comedones) [6]
   2. Benzoyl peroxide (5% and 10%) - apply qd only (may irritate when more frequent)
   3. Topical retinoids also very effective
   4. Topical Antibiotics - Clindamycin and Erythromycin are most effective
   5. Combinations of benzoyl peroxide and topical antibacterials very effective
   6. Azelaic Acid (Azelex®) [7] - 20% cream, apply bid, less irritating (and effective) than topical retinoids or benzoyl peroxide
   7. Azelaic Acid (Finacea®) [8] - 15% gel, apply bid, similar to cream (approved for rosacea)
   8. Retinoids (Vitamin A Derivatives): tretinoin, adapalene, tazarotene
   9. Benzoyl peroxide 5% ± topical erythromycin was more effective than oral tetracyclines [6]
   10. Effects are generally seen within first 6 weeks of treatment
2. Topical Antibiotics [5]
   1. Kill P. acnes (and staphylococci) with little systemic absorption
   2. Generally effective and well tolerated for reduction of inflammatory lesions
   3. Clindamycin (Cleocin T) - 1% gel, solution or lotion; apply qd - bid
   4. Erythromycin (Emgel®, Erycett®, T-Stat) - 2% gel or solution
   5. Tetracycline - cream or oral treatment (500mg bid)
   6. Azelaic acid also has antimicrobial activity
   7. Combinations with retinoids or benzoyl peroxide more effective than either agent alone
   8. Erythromycin + benzoyl peroxide (Benzamycin®) - 3%/5% gel; apply bid
   9. Topical benzamycin® more effective than oral tetracyclines in mild/moderate acne [6]
   10. Antibiotic resistance of P. acnes can reduce efficacy of oral antibiotics [6]
3. Topical Retinoids
   1. For treatment of inflammatory lesions and comedones
   2. Effective in 4-70% of cases
   3. Tretinoin, Adapalene, Tazarotene
   4. Adapalene is best tolerated
   5. Tazarotene is most effective but most irritating
4. Adapalene (Differin®) [5]
   1. Synthetic retinoid analog (derivative of naphthoic acid)
   2. Decreases formation of comedones and inflammatory skin lesions
   3. Appears to be as effective as, and better tolerated than, tretinoin
   4. Apply 0.1% gel once daily in evening after washing affected areas
   5. Can cause erythema, dryness, scaling, burning
5. Tazarotene (Tazorac®) [9]
   1. Acetylinic retinoid, 0.1% gel and cream now approved for acne
   2. As effective as tretinoin or adapalene for treatment of acne vulgaris
   3. Gel is more irritating than tretinoin or adapalene
   4. Cream may be better tolerated but degree of efficacy is not well documented
6. Tretinoin (Retin-A®, Renova®)
   1. Generally well tolerated topical vitamin A derivative with excellent activity
   2. May cause erythema, dryness, scaling, irritation in skin
   3. Gel supplied as 0.01% and 0.025% strengths
   4. Creams as 0.025%, 0.05%, and 0.1%
   5. Also as a 0.05% liquid for more diffuse application
   6. May help prevent photodamage and "aging" effects on skin
7. Systemic Therapy
   1. Generally reserved for moderately severe and severe acne
   2. Tetracyclines - kill P. acnes and inhibits neutrophil migration (~60% response)
   3. Low dose doxycycline 40mg po qd (Oracea®) is FDA approved for rosacea [16]
   4. Minocycline immediate (Dynacin®, Minocin®, 100mg bid) or extended release (Solodyne®, 45-135mg qd) are generally preferred over other tetracyclines [15]
   5. Systemic retinoid - isotretinoin (13-cis-retinoic acid, see below)
   6. Hormonal therapy - anti-androgens ± estrogens
   7. Several oral contaceptives (OCP) are labelled for acne prevention/improvement
   8. OCP may be combined with spironolactone (antiandrogen) may be effective
   9. Low dose glucocorticoids may be effective in hormonal therapy resistant cases
   10. Antibiotic resistance of P. acnes can reduce efficacy of oral antibiotics [6]
   11. Topical benzoyl peroxide is as effective in antibiotic resistant or sensitive P. acnes [6]
   12. At least one month of therapy usually required for full benefit
8. Isotretinoin (Accutane®) [10]
   1. Synthetic vitamin A (cis-13-retinoic acid) derivative for severe acne
   2. Dramatic clearing with prolonged periods of remission in severe acne
   3. Reduction of sebum, anti-inflammatory, and corrects altered keratinization
   4. Side Effects: dry skin and mucous membranes, decreased night vision, hair loss
   5. Other Effects: liver function abnormalities, dyslipidemia, vertebral hyperostoses
   6. Lipid Anomalies: hypertriglyceridemia, hypercholesterolemia, reduced HDL [11]
   7. Patients with initial >89 mg/dL increase in triglycerides are at highest risk for developing hyperlipidemia and insulin resistance syndromes [11]
   8. Psychiatric problems - depression, psychosis, suicide
   9. Major Teratogen - full contraception is absolutely required; no effects on sperm
   10. Serum ßHCG must be done to rule out pregnancy before prescribing
   11. Informed consent required and adequate contraception must be used
   12. In women, isotretinoin is then started during menses
   13. Most side effects of isotretinoin are similar to hypervitaminosis A
9. Hormonal Agents
   1. Hormonal treatments only tolerated by women, reduce androgen production
   2. Oral contraceptives (OCs), spironolactone, flutamide, cyproterone
   3. Several OCs approved for use in acne, contain 35µg estrogen or less
   4. About 50-60% reduction in inflammatory lesions with OCs
   5. Spironolactone in doses 50-200mg divided daily as adjunct, reduces lesions ~60%
   6. Significant side effects with spironolactone
   7. Flutamide 250mg/day very effective
   8. Cyproterone high dose 100mg/day effective, but usually used at low dose (2mg/d)
10. Blue Light (Clearlight®) [12]
    1. High intensity narrow band blue light (without ultraviolet light) FDA approved
    2. Elicits photoreaction in which porphyrins react with oxygen to create reactive oxygen species (ROS)
    3. ROS may damage lipid rich cell membranes of P. acnes causing bacterial death
    4. Treatment twice a week
    5. Dry skin and ild sensation of warmth main adverse effects
    6. Unclear how efficacy compares with other treatments
11. Pulsed-Dye Laser [13,14]
    1. Emit visible light that, at low energy density, can stimulate procollagen production
    2. Due to local, non-lethal heating of dermal perivascular tissues
    3. One or 2 treatments with pulsed dye laser lead to sustained significant improvement at 12 weeks in one study [13] but no improvement in another study [14]
    4. Well tolerated an effective in mild to moderate inflammatory acne
12. Thermal Devices [17]
    1. Three devices approved by FDA to treat individual acne lesions with local heat application
    2. ThermaClear®, Zeno®, Radiancy Clear Touch®
    3. Burst of heat from these devices thought to accelerate lesion healing without causing burn
    4. Generally well tolerated
    5. May be useful for treatment of individual lesions
    6. Unclear how compares with other treatments
13. Surgical (plastic) treatments may be used in highly resistant or scarred cases

E. Treatment by Type of Acne

1. Noniflammatory Comedonal Acne
   1. "Blackheads" and "Whiteheads"
   2. Topical retinoid therapy alone usually sufficient
   3. Salicylic acid can be used second line
2. Papular Inflammatory Acne
   1. Erythematous, oily lesions, pustular, raised
   2. Topical antibiotic alone is usually effective
   3. Additional topical therapy could be added
   4. Systemic antibiotics may be considered in resistant disease
3. Widespread Comedones and Inflammatory Lesions
   1. Combinations of the above two syndromes
   2. Systemic antibiotic with topical retinoid recommended
4. Severe Nodular and Cystic Acne
   1. Topical or systemic antibiotic therapy usually ineffective
   2. Systemic isotretinoin is treatment of choice
5. Explosive Inflammatory Acne (Acne Fulminans)
   1. Often associated with ulcerative lesions
   2. Fever, leukocytosis, arthralgia may occur
   3. Systemic glucocorticoid therapy (with antibiotic) required

References

1. James WD. 2005. NEJM. 352(14):1463
2. Brown SK and Shalita AR. 1998. Lancet. 351(9119):1871
3. Shige I, Usui Y, Takemura T, Eishi Y. 1999. Lancet. 354(9173):120
4. Haider A and Shaw JC. 2004. JAMA. 292(6):726
5. Treatment of Acne. 1997. Med Let. 39(995):19
6. Ozolins M, Eady EA, Avery AJ, et al. 2004. Lancet. 364(9452):2188
7. Azelex. 1996. Med Let. 38(976):52
8. Azelaic Acid. 2003. Med Let. 45(1165):76
9. Tazarotene. 2002. Med Let. 44(1132):52
10. Accutane Review. 2002. Med Let. 44(1139):82
11. Rodondi N, Darioli R, Ramelet AA, et al. 2002. Ann Intern Med. 136(8):582
12. Blue Light for Acne Vulgaris. 2003. Med Let. 45(1159):50
13. Seaton ED, Charakida A, Mouser PE, et al. 2003. Lancet. 362(9393):1347
14. Orringer JS, Kang S, Hamilton T, et al. 2004. JAMA. 291(23):2834
15. Extended Release Minocycline. 2006. Med Let. 48(1248):95
16. Doxycycline Low Dose. 2007. Med Let. 49(1252):5
17. ThermaClear for Acne. 2007. Med Let. 49(1263):51