Acne vulgaris: A practical approach John C. Selby, M.D., Ph.D. Department of Dermatology University of Iowa Hospitals and Clinics Iowa City VA Health Care System

Objectives (1) Understand the pathophysiology of acne vulgaris (2) Recognize common clinical variants of acne (3) Appreciate practical management principles based on clinical variant and disease severity

Pathophysiology Acne vulgaris classically involves the face, upper back, and upper chest, all areas of the body where sebaceous glands are found in high density. Acne originates with a comedone, a non-inflammatory papule consisting of a follicular opening filled with keratin and excess sebum, commonly referred to as a “plugged pore”. Dysmaturation and abnormal cohesion of keratinocytes near the neck of the follicular opening create the “plug”. Excess sebum builds up behind the plug, due to androgen- mediated stimulation of the sebaceous gland. Cutibacterium acnes (formerly Propionibacterium acnes) in the resident flora of the follicle now trapped within this “plug” release lipases that breakdown sebum as well as trigger innate immune responses through activation of Toll-like receptors. If left unchecked, auto-amplification of the innate immune response leads to the development of an inflammatory papule or pustule. Ultimately, rupture of the follicle can lead to the formation of a deep inflammatory nodule. Depending on the magnitude of the inflammatory response, permanent scarring can occur, often accompanied by benign postinflammatory hyperpigmentation.

Clinical Variants (a) Comedonal acne: patients who have open/closed comedones and only a few or no inflammatory lesions. (b) Inflammatory acne: patients who have predominantly inflammatory papules and pustules with some background open/closed comedones. (c) Nodulocystic acne: patients who have a preponderance of large deep inflammatory nodules together with background papules, pustules, and open/closed comedones. (d) Hormonal acne: women aged ~25-45 years who present with papules, pustules, and small nodules localized around the chin and jawline, often with background open/closed comedones.

Differential diagnosis: • Drug-induced acne (anabolic steroids, lithium, EGFR-inhibitors, corticosteroids, isoniazid, phenytoin) • Rosacea • Periorificial dermatitis • Folliculitis • Pseudofolliculitis -1- Practical Management Note: Recommendations that follow assume that female patients are not pregnant nor are they attempting to conceive.

Comedonal acne: 1. General skin care measures: (a) Wash face with a gentle skin cleanser once or twice daily. Over-the-counter Cetaphil Gentle Skin Cleanser is typically what is recommended in the Dermatology clinic (non-soap cleanser). (b) Check to ensure that all products applied to the skin, including make-up, moisturizers, and sunscreens, are labeled as oil-free and/or non-comedogenic. (c) Recommend avoidance of harsh “exfoliating” washes and scrub brushes and cleansers marketed for “oily skin.” In general, these products remove too much oil from the skin and lead to paradoxical stimulation of oil gland activity (seborrhea). 2. Topical retinoids: (a) Start all patients on tretinoin 0.025% cream [20g/month] applied daily at bedtime 3 nights per week for the first 2 weeks, then increase to nightly application as tolerated. -Nightly application is required because most retinoids are photolabile. (b) For patients who report intolerance of tretinoin, recommend use of over-the-counter adapalene 0.1% gel. (c) For patients who complain of oily skin, recommend starting with tretinoin 0.01% gel. (d) Retinoid tips: -Wash face, then wait ~20 minutes before applying a pea-sized amount of retinoid (tretinoin or adapalene) to the entire face. -Counsel patient that use of a topical retinoid will cause some degree of dryness and irritation, and this is a normal response. In the morning and/or at night, the patient may apply a topical over-the- counter non-comedogenic moisturizer to help offset this irritation (Cetaphil or CeraVe lotion). -Counsel patient that if they cannot tolerate nightly application, that is okay. However, if they can tolerate retinoid application 3 nights per week (scheduled), treatment will confer a clinical benefit. -Counsel patient that a topical retinoid is the most important medication for acne treatment because it is the only medication that treats comedone formation. However, the clinical response is slow and it can take 3-4 months of scheduled use to appreciate a clinical benefit. (d) At follow-up visits, if patient is tolerating nightly retinoid application, consider increasing the strength of the retinoid (using the same cream or gel vehicle). -For any new retinoid prescription, have the patient alternate application with their existing retinoid for 2 or 3 weeks before using the higher-strength retinoid on a nightly basis.

-2- Inflammatory acne: 1. General skin care measures as per treatment of comedonal acne. 2. Topical retinoids as per treatment of comedonal acne. 3. Male patients: Identify and eliminate or minimize all prescription and over-the-counter testosterone-based treatments/supplements. 4. Anti-inflammatory medications: Mild disease (a) Start a benzoyl peroxide 2% to 5% (not 10%) wash (sometimes called a creamy wash) daily with each shower or bath (e.g., PanOxyl wash). Let the medicated wash sit on areas of skin affected with acne for several minutes prior to rinsing off. Use daily if tolerated. Otherwise, use only 2 or 3 days per week (scheduled). -Counsel the patient that benzoyl peroxide wash can bleach towels used for application of the wash, but it will not bleach clothes if thoroughly rinsed off the skin. -If inflammatory lesions are only present on the face, one can alternatively use a benzoyl peroxide 2% to 5% cream, gel, or lotion applied to active inflammatory lesions daily every morning. -Benzoyl peroxide products should not be used at the same time as topical retinoids because peroxides can degrade most retinoids and render them ineffective.

Mild to moderate disease (a) Start a benzoyl peroxide product as noted for mild disease above. (b) Start clindamycin 1% gel or lotion applied to all areas of typical acne flare twice daily. -Okay to apply clindamycin together with a topical retinoid. (c) Counsel patient that it is important to maintain use of the benzoyl peroxide product while using topical clindamycin to help prevent the development of antibiotic resistance.

Moderate to severe disease (a) Start a benzoyl peroxide product as noted for mild disease above. (b) Start doxycycline monohydrate (preferred) or doxycycline hyclate 100 mg oral twice daily for ~12 weeks (until next clinic follow-up visit). -Instruct the patient to take this medication with food to avoid causing dyspepsia. -Additionally, counsel the patient that this medication can also cause a photosensitivity reaction similar to a sunburn. Patients on doxycycline should wear a broad-spectrum sunscreen SPF>30 during periods of significant outdoor ultraviolet light exposure. -If patients complain of dyspepsia with doxycycline, recommend minocycline 100 mg twice daily. (c) Counsel patient that it is important to maintain use of the benzoyl peroxide product while using oral doxycycline or minocycline to help prevent the development of antibiotic resistance.

Nodulocystic acne: 1. Refer to Dermatology for isotretinoin treatment (Accutane). 2. While patient is waiting for this appointment, initiate empiric treatment measures as described for inflammatory acne, moderate to severe disease.

-3- Hormonal Acne: 1. General skin care measures as per treatment of comedonal acne. 2. Topical retinoids as per treatment of comedonal acne. 3. Initiate a benzoyl peroxide product as per treatment of inflammatory acne, mild disease. 4. After review of relevant risk factors, recommend combination oral contraceptive pills containing ethinyl estradiol and a third or fourth generation progestin like norgestimate or drospirenone (OrthoTri-Cyclen or Yaz; both are FDA-approved for acne vulgaris). 5. If acne remains sub-optimally controlled or if the patient is already on some other form of birth control (IUD, progestin monotherapy), start spironolactone 50 mg twice daily. -Counsel patient on possible side-effects including diuresis, menstrual irregularities, and breast tenderness. -In general monitoring of potassium levels in an otherwise healthy patient is not indicated. -Consider monitoring of potassium levels only in patients with significant cardiac disease, renal insufficiency, and/or or patients who are taking medications that can affect potassium levels (ACE inhibitors). -If spironolactone at a dose of 50 mg twice daily confers benefit but acne remains sub-optimally controlled, okay to increase dose to a maximum of 100 mg twice daily.

After initiating the above measures, have the patient return to clinic in 3 or 4 months for re- evaluation. If acne remains sub-optimally controlled, advance therapy and/or consider placing a regular outpatient Dermatology Consult.

Other clinical scenarios in which you might consider placing a regular outpatient Dermatology Consult: • Uncertain diagnosis of acne • Transgender patients • Pregnant females or patients attempting to conceive • Oncology patients undergoing systemic chemotherapy

References [1] Wolff, K., and R.A. Johnson. Fitzpatrick’s Color Atlas and Synopsis of Clinical Dermatology, Sixth Edition. New York: McGraw-Hill, 2009. With excellent photographs and diagrams of various common skin diseases, accompanied by brief descriptions of the pathophysiology, laboratory evaluation, and management plan for each disease, this small color textbook is a useful reference for any primary care provider. [2] Zaenglein, A.L. and D.M. Thiboutot. “Acne vulgaris” in Dermatology, Third Edition, Bolognia JL, Jorizzo JL, Schaffer JV, Eds. Elsevier Saunders, 2012. An expansive two-volume reference text, this work is used in the didactic curriculum of most dermatology resident training programs. [2] Zaenglein, A., et al. “Guidelines of care for the management of acne vulgaris.” Journal of the American Academy of Dermatology 2016; 74:945-973. [3] Titus, Stephen and J. Hodge. “Diagnosis and treatment of acne.” American Family Physician 2012; 86(8):734-740. [4] Russell, J.J. “Topical therapy for acne.” American Family Physician 2000; 61(2):357-365.

-4- [5] Kamangar, F., and K. Shinkai. “Acne in the adult female patient: a practical approach.” International Journal of Dermatology 2012; 51:1162-1174. [6] Husein-ElAhmed, H. “Management of acne vulgaris with hormonal therapies in adult female patients.” Dermatologic Therapy 2015; 28:166–172. [7] Koos, E.B., T.D. Petersen, and A.B. Kimball. “Meta-analysis comparing efficacy of antibiotics versus oral contraceptives in acne vulgaris.” Journal of the American Academy of Dermatology 2014; 71:450-459. [8] J.S. Barbieri, N. Spaccarelli, D.J. Margolis, and W.D. James. “Approaches to limit systemic antibiotic use in acne: Systemic alternatives, emerging topical therapies, dietary modification, and laser and light-based treatments.” Journal of the American Academy of Dermatology 2019; 80:538-549.

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