ACNE VULGARIS Rachel Courtney - December 2004 Epidemiology Affects 80% of people aged 11 to 30 yrs; 79-95% of the adolescent population (peaks between years 14 & 17 in girls and 16 & 19 in boys). Affects 40 to 50 million people in the US Equal incidence in all races Males tend to have more severe acne for a shorter time; females tend to have milder disease for a shorter time. Pathogenesis 1) Androgen induced sebum production – Acne begins in prepubertal period with increase in adrenal androgens, and increases even more in puberty. Androgens (adrenal and gonadal) stimulate enlargement and increased activity of sebaceous glands on face, neck, and upper trunk. Sebaceous glands are androgen-sensitive appendages of the hair follicle that function to secrete lipids to lubricate the skin and hair. Patients with acne have sebaceous glands that are hyperresponsive to androgens compared to other patients. Circulating free testosterone levels are normal in these patients but they may have higher levels of local conversion to dihydrotestosterone in the skin. 2) Abnormal keratinization of sebaceous and follicular epithelium – Normal patterns of epithelial desquamation are altered due to increased sebum levels and decreased linoleic acid concentrations in the skin (both results of increased androgens). Keratinized cells around the hair follicle become more cohesive and begin to accumulate instead of desquamate. This leads to retention hyperkeratosis (plugging), resultant enlargement of the follicle, and microcomedo formation (the precursor of both comedonal and inflammatory acne). 3) Proliferation of Propionibacterium acnes – P. acnes is an anaerobic pleomorphic diptheroid that thrives in the lipid-rich media of sebum within the plugged follicle. This bacteria is a part of normal skin flora but appears to be absent from skin before puberty. 4) Inflammation – P. acnes triggers inflammation by multiple mechanisms. It produces a lipase enzyme which hydrolyzes triglycerides in sebum to produce irritating and comedogenic free fatty acids. P. acnes also releases chemotactic factors (IL-1, IL-8, TNF-α) which attract leukocytes. These leukocytes release hydrolytic enzymes that play a role in the rupture of the follicular wall that leading to inflammation of surrounding tissues. Clinical Disease No standardized system of grading exists. Should classify based on the predominant type of lesion, location, and grade as mild, moderate, or severe. 1) Closed comedo (whitehead) – small, noninflammatory skin-colored or whitish papule, 1-3 mm in diameter with a small central pore. If ruptures, may evolve into #3, 4 or 5. 2) Open comedo (blackhead) – brownish or black noninflammatory papule with central distended pore, 1-3 mm in diameter. 3) Papule – pink or red inflammatory lesion, 2-5 mm in diameter. Resolve in 5-10 days with little scarring. May cause postinflammatory hyperpigmentation in darker-skinned patients. 4) Pustule – superficial papule containing purulent material. 5) Nodule – solid, raised inflammatory lesion >5 mm in diameter that extends deeper into the dermis than a papule. Commonly occur on earlobes, neck and jawline. Therapy MDs must appreciate the significance of this problem to adolescents. Long term psychological consequences such as depression and anxiety have been associated with acne. Must understand the route, timing, and dose of drugs – use only a few and know them well. Make sure that the patient and the parent know how to use the medications. Do not promise instant success: topical therapy may make lesions look worse in the first 3 to 4 weeks, total improvement may take 2-3 months. Explain side effects of all medications. Dispel misconceptions about acne: no evidence relating acne to foods, sex, or uncleanliness. Stress can cause a flare, so can wearing a headband/helmet, or using grease on the scalp. Premenstrual flares can also occur. Topical agents – solutions and gels are drying and nongreasy (good for oily skin), creams and lotions are moisturizing (good for dry skin). Apply to entire face (not spot-treating), not too soon after washing face, more is not better because can get more side effects (pea sized amounts is best). 1. Benzoyl peroxide – bacteriocidal against P. acnes with low potential for resistance, mild comedolytic action, decreases free fatty acids so mild anti-inflammatory effect. available in 2.5%, 3%, 4%, 5%, 6%, 8%, and 10% concentrations comes in gels, lotions, creams, soaps, and washes (gels have better penetration) begin with qOd, advance slowly to BID; slowly advance concentration as tolerated side effects: peeling, irritation, contact dermatitis (1-2%), bleaches hair and fabric examples: Clearasil cream (10%), Neutrogena On-The-Spot lotion/patch (2.5%), Neutrogena acne mask (5%), Oxy lotion (5%, 10%), Oxy 10 wash (10%). 2. Retinoids – derivatives of vitamin A, mainstay for acne treatment for >25 years, most effective comedolytic agents by reducing hyperkeratosis and cohesiveness of follicular epithelial cells, lesser anti-inflammatory effects. o Tretinoin (Retin-A, Avita, generics): available in cream 0.025%, 0.05%, 0.1% or gel 0.01%, 0.025% or microsphere 0.04%, 0.1%. Cream is least irritating. begin with lower concentrations of cream or micro gel every other night, apply small amount to skin 20-30 minutes after washing face. Increase to nightly, increase concentration for effect (0.05% cream < 0.025% gel < 0.1% cream) in 2-3 weeks, irritation is expected, in 3-4 weeks will have pustular eruption indicating dislodging of microcomedos do not use in AM because irritation is compounded by sun exposure. Avoid use in dark-skinned patients as pigment changes can occur. side effects: peeling, drying, irritation, pigment changes, sun sensitivity, ? teratogenicity o Adapalene (Differin): available in gel, cream, pledgets, and solution 0.1% derivative of naphothoic acid – more photostable than retinoid and causes less irritation, has moderate to potent anti-inflammatory effect apply daily, may take 8-16 weeks for results o Tazarotene (Tazorac): available in gel and cream, both 0.05% and 0.1% concentrations synthetic actylenic retinoid that rapidly penetrates skin where converted to its active metabolite, tazarotenic acid. photostable, has anti-inflammatory effects, can also be used for psoriasis apply overnight or as short contact therapy for 5 minutes (wash away with mild soap) side effects: erythema, pruritis, burning, stinging 3. Azelaic Acid (Azelex 20% cream) – dicarboxylic acid first developed for benign hyperpigmentation disorders; used for mild to moderate inflammatory acne, has bacteriostatic properties against P. acnes, normalizes keratinization. apply BID to clean, dry skin similar to 5% BP or 0.05% tretinoin side effects: uncommon – pruritis, burning, stinging, rash, hypopigmentation 4. Topical Antibiotics – reduce counts of P. acnes, decrease percentage of free fatty acids in surface lipids. Used in mild to moderate inflammatory acne. resistance is frequently seen apply BID to clean, dry skin erythromycin 2% solution, gel, pads, ointment (A/T/S solution, T-Stat solution, Erygel, Emgel, Aknemycin) clindamycin 1% solution, lotion, gel, pledget (Cleocin T solution, C/T/S, Clindets, Clinagel 1%) ****combination preparations of BP plus antibiotics include: BP 5% + erythro 3% (Benzamycin gel) and BP 5% + clinda 1% (benzaclin topical gel) – BEST BECAUSE THERE IS NO BACTERIAL RESISTANCE**** Systemic Agents – for use with moderate to severe acne 1. Antibiotics – Tetracycline, Doxycycline, Minocycline, Erythromycin available for use (not approved by FDA) not for use in noninflammatory acne, can use in combination with topical therapies don’t use for >8-12 weeks and always use with BP to avoid resistance. side effects: multiple (see formulary) 2. Isotretinoin (Accutane) – 13-cis-retinoic acid, vitamin A derivative; acts by suppressing sebum production and diminishing growth of P. acnes length of therapy is 15-24 weeks, less likely to relapse if total cumulative dose is 120mg/kg lab monitoring: baseline - CBC, LFTs, cholesterol, TG, UA, HCG (week before and day of initiation); 2 weeks into treatment – cholesterol, TG; monthly and at end of therapy repeat baseline tests side effects: cheilitis (90%), xerosis (78%), dry mouth (70%), epistaxis (46%), conjunctivitis (40%), desquamation, hair loss, arthralgias/myalgias, decreased night vision, HA, depression (may be at higher risk of depression and suicide with personal or FH of depression), photosensitivity, elevated LFTs, proteinuria, hematuria, elevated ESR (40%), leukopenia, high platelets, staph infections, pseudotumor cerebri. 3. Combined Oral Contraceptives – reduces ovarian androgen production and circulating levels of free testosterone which suppresses sebaceous gland activity. options are third generation OCPs with less androgenic progestins (Ortho-Cyclen, Ortho Tri-Cyclen, OrthoCept, Desogen). ALGORITHM FOR ACNE TREATMENT Lesion Type ┌-- Comedonal ---------│ ├-- Inflammatory/ -----│ Mixed └-- Comedonal ------------- Initial Treatment Benzoyl peroxide (BP) OR BP/topical abx combo OR Topical retinoid MILD If Inadequate Response Add topical retinoid or topical abx or substitute BP/topical abx combo Add topical retinoid Add BP or BP/topical abx combo Increase strength or change type of topical retinoid; add BP or BP/topical abx combo Add topical retinoid or oral abx. Consider OCP for female patients. Consider referral to derm. Increase strength or change type of topical retinoid. Consider adding OCPs. Add BP or BP/topical abx combo. Consider referral to derm. MODERATE ┌--- Inflammatory/-----│ Mixed │ └--- Topical retinoid ± BP or BP/topical abx combo BP or BP/topical abx combo ± topical retinoid ± oral abx OR Oral abx and topical retinoid SEVERE ┌ --- │ Comedonal --------│--- Inflammatory/-----│--- Mixed │ └ --- Consider referral Oral abx and topical retinoid ± BP or BP/topical abx combo ± OCP Refer to dermatologist References: Neinstein LS, Pakula AS. Adolescent Health Care: A Practical Guide. 4th edition, 2002 Leyden JJ. Therapy for Acne Vulgaris. NEJM; 1997.