Azelaic acid

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Acne is a disease of pilosebaceous units in the skin. It is thought to be caused by the interplay of four factors. Excessive sebum production secondary to sebaceous gland hyperplasia is the first abnormality to occur. (1) Subsequent hyperkeratinization of the hair follicle prevents normal shedding of the follicular keratinocytes, which then obstruct the follicle and form an inapparent microcomedo. (2) Lipids and cellular debris soon accumulate within the blocked follicle. This microenvironment encourages colonization of Propionibacterium acnes, which provokes an immune response through the production of numerous inflammatory mediators. Inflammation is further enhanced by follicular rupture and subsequent leakage of lipids, bacteria, and fatty acids into the dermis.

Diagnosis

The diagnosis of acne is based on the history and physical examination. Lesions most commonly develop in areas with the greatest concentration of sebaceous glands, which include the face, neck, chest, upper arms, and back.

Acne vulgaris may be defined as any disorder of the skin whose initial pathology is the microscopic microcomedo. (3) The microcomedo may evolve into visible open comedones ("blackheads") or closed comedones ("whiteheads"). Subsequently, inflammatory papules, pustules, and nodules may develop. Nodulocystic acne consists of pustular lesions larger than 0.5 cm. The presence of excoriations, postinflammatory hyperpigmentation, and scars should be noted.

Acne may be triggered or worsened by external factors such as mechanical obstruction (i.e., helmets, shirt collars), occupational exposures, or medications. Common medications that may cause or affect acne are listed in Table 1. (4) Cosmetics and emollients may occlude follicles and cause an acneiform eruption. Topical corticosteroids may produce perioral dermatitis, a localized erythematous papular or pustular eruption. (5)

[TABLE 1 OMITTED]

Endocrine causes of acne include Cushing's disease or syndrome, polycystic ovary syndrome, and congenital adrenal hyperplasia. (6) Clinical clues to possible hyperandrogenism in women include dysmenorrhea, virilization (i.e., hirsutism, clitoromegaly, temporal balding), and severe acne.

Classification

In 1990, the American Academy of Dermatology developed a classification scheme for primary acne vulgaris. (7) This grading scale delineates three levels of acne: mild, moderate, and severe. Mild acne is characterized by the presence of few to several papules and pustules, but no nodules (Figure 1). Patients with moderate acne have several to many papules and pustules, along with a few to several nodules (Figure 2). With severe acne, patients have numerous or extensive papules and pustules, as well as many nodules (Figure 3).

[FIGURES 1-3 OMITTED]

Acne also is classified by type of lesion--comedonal, papulopustular, and nodulocystic. Pustules and cysts are considered inflammatory acne.

Therapy

TOPICAL AGENTS

Selection of topical therapy should be based on the severity and type of acne. Topical retinoids, benzoyl peroxide, and azelaic acid are effective treatments for mild acne. Topical antibiotics and medications with bacteriostatic and anti-inflammatory properties are effective for treating mild to moderate inflammatory acne. The dosage, approximate cost, and side effects of selected topical medications are summarized in Table 2.

Proper selection of topical formulations may decrease side effects and increase patient compliance. Fortunately, most acne medications are available in several forms. Creams and lotions typically are reserved for dry or sensitive skin, whereas gels are prescribed for oil-prone complexions. During treatment with prescribed medications, patients should use bland facial washes and moisturizers.

Retinoids and Retinoid Analogs. Topical tretinoin (Retin-A) is a comedolytic agent that normalizes desquamation of the epithelial lining, thereby preventing obstruction of the pilosebaceous outlet. (8) This agent also appears to have direct anti-inflammatory effects. (9) A derivative of vitamin A, tretinoin is available in cream, gel, and liquid forms. In tretinoin microsphere (Retin-A Micro), tretinoin is encapsulated in a polymer that slowly releases the active medication, resulting in less irritation than with other tretinoin preparations. (10) With all retinoids, visible improvement occurs after eight to 12 weeks of treatment.

Tretinoin is inactivated by ultraviolet (UV) light and oxidized by benzoyl peroxide. It therefore should be applied only at night and never with benzoyl peroxide. Tretinoin may decrease the amount of native UV protection by thinning the stratum corneum; thus, daily use of sunscreen is recommended. Because the irritation caused by tretinoin is dose-dependent, treatment should be initiated in a low dose. Patients only need a pea-sized amount of product per application.

There is no strong evidence for the teratogenicity of tretinoin, which remains pregnancy category C. A study (11) published in 1998 focused on the transdermal absorption of topical tretinoin and found the absorbed concentration to be below endogenous retinoid levels. However, no definitive consensus has been reached on the use of topical tretinoin in pregnancy. It may be wise to avoid use of topical retinoids or retinoid analogs in women who may become pregnant during treatment.

Adapalene (Differin) is a topical synthetic retinoid analog that normalizes differentiation of follicular epithelial cells and demonstrates direct anti-inflammatory properties. Double-blind studies have shown 0.1 percent adapalene gel to be as effective as 0.025 percent tretinoin gel. (12) [Evidence level A, meta-analysis] Adapalene is superior to 0.025 percent tretinoin gel in both tolerability and speed of efficacy, (12) and is equivalent in efficacy to 0.1 percent tretinoin microsphere. (13) [Reference 13--Evidence level A, randomized controlled trial (RCT)] Adapalene is a reasonable choice as a first-line topical retinoid; this agent may be especially useful in patients who are unable to tolerate the irritation caused by tretinoin.

Tazarotene (Tazorac) is available in 0.05 and 0.1 percent gel and cream formulations. It is a pregnancy category X agent. Tazarotene may be more irritating than other retinoids. Dose-related erythema and burning are the most common adverse effects. Studies have indicated that tazarotene gel is a more efficacious keratolytic than tretinoin 0.025 percent gel (14) and tretinoin 0.1 percent microsphere gel. (15) Because tazarotene may increase irritation, it usually is considered a second-line retinoid option in patients who have not responded to topical tretinoin or adapalene therapy.

Topical Antibiotics. These agents are another mainstay of acne treatment. Topical antibiotics commonly are used in conjunction with retinoids or benzoyl peroxide in patients with any degree of inflammatory acne. The most frequently used topical antibiotics are clindamycin and erythromycin. These drugs normally are applied once or twice daily.

Benzoyl Peroxide and Benzoyl Peroxide Combinations. Benzoyl peroxide is inexpensive and available over the counter. It has a stronger effect on papules than tretinoin, but a weaker effect on comedones. (16) Combinations of topical antibiotics and benzoyl peroxide increase efficacy and reduce antibiotic resistance in patients with P. acnes colonization. The preparations are available in gel form, and include 1 percent clindamycin with 5 percent benzoyl peroxide (BenzaClin) and 3 percent erythromycin with 5 percent benzoyl peroxide (Benzamycin). The preparations are equally effective in the treatment of acne. (17) [Evidence level B, single blinded RCT] One study18 comparing combined 1 percent clindamycin and 5 percent benzoyl peroxide with 1 percent clindamycin alone found the combination product to be more efficacious, with less P. acnes resistance. [Evidence level A, RCT]

Azelaic Acid. This agent is a dicarboxylic acid that has bacteriostatic and keratolytic properties. Azelaic acid (Azelex) may be particularly effective in the treatment of acne with postinflammatory hyperpigmentation. (19)

Other Topical Agents. Over-the-counter products may be used as primary or adjunctive treatments. Additional prescription topical agents include sulfacetamide (Klaron) and 10 percent sulfacetamide with 5 percent sulfur (Sulfacet-R). Sulfacetamide products are available in cream, gel, and wash formulations. These products generally are not considered first-line therapies, but they may be used in patients who cannot tolerate other topical agents.

SYSTEMIC AGENTS

Oral Antibiotics. When acne is resistant to topical therapies, oral antibiotics may be used. Oral antibiotics commonly are initial therapy in patients with moderate to severe inflammatory acne. Systemic antibiotics decrease P. acnes colonization and have intrinsic anti-inflammatory effects. First-line oral antibiotics have included tetracycline and erythromycin. Because P. acnes resistance to erythromycin is increasing, this antibiotic is becoming a second-line agent that is used when treatment with tetracycline or other macrolide antibiotics fails or is not tolerated. (20)

Tetracycline must be taken on an empty stomach. Iron supplements and milk products decrease systemic absorption of the antibiotic. Because of the risk of tooth discoloration and inhibited skeletal growth, tetracycline should not be used in pregnant women or children younger than nine years. Moderate to severe phototoxicity and gastrointestinal intolerance also may limit the use of tetracycline.

Doxycycline (e.g., Vibramycin, Doryx) frequently is used to treat moderate to severe acne vulgaris. However, associated photosensitivity may limit its usefulness.

Minocycline (Minocin) is a potent acne medication, but treatment with this antibiotic generally is reserved for patients who do not respond to or cannot tolerate aforementioned treatment options. (21) Rare but serious side effects are more common in patients taking minocycline than in patients treated with tetracycline or doxycycline. (22)

Oral antibiotics must be taken for six to eight weeks before results are evident, and treatment should be given for six months to prevent the development of microbial resistance. (23) Oral antibiotics may be discontinued after inflammation has resolved. Topical antibiotics may be continued for further treatment. Some patients may require long-term oral antibiotic therapy to control their acne and prevent scarring. The dosing, approximate cost, and side effects of systemic medication for the treatment of acne are summarized in Table 3.

Oral Antibiotics and Oral Contraceptive Pills (OCPs). A decrease in the effectiveness of OCPs is a concern with coadministration of oral antibiotics. Although this concern has not been supported by research, some package inserts contain a warning about decreased OCP efficacy with concomitant ampicillin or tetracycline therapy. A review of pharmokinetic data showed a reduction of contraceptive steroid hormones only with concomitant use of rifampin (Rifadin). (24) [Evidence level B, nonquantitative systematic review] Nonetheless, it may be wise to inform patients receiving oral antibiotic therapy about the possibility of OCP failure, and to recommend the use of a second method of contraception.

OCPs. These contraceptives may be a valuable adjunct in the treatment of acne in female patients. OCPs decrease circulating androgens, thereby decreasing sebum production. (25) The estrogen in OCPs increases the amount of sex hormone-binding globulin, which, in turn, decreases the free testosterone level. The estrogen also decreases secretion of gonadotropins by the anterior pituitary, with a consequent decrease in the amount of androgens produced by the ovaries. When an OCP is used to treat acne, the physician should prescribe a formulation that contains progestins with low androgenic possibility. (25) Appropriate progestins include norethindrone (Norlutin), norethindrone acetate (Aygestin), ethynodiol diacetate (Zovia), and norgestimate (Ortho-Cyclen). Ultimately, the choice of OCP should be based on tolerability and compliance.

Isotretinoin. This vitamin A derivative is used to treat severe, often nodulocystic and inflammatory acne. Isotretinoin (Accutane) acts against the four pathogenic factors that contribute to acne. It is the only medication with the potential to suppress acne over the long term. To be able to prescribe this medication, the physician must be a registered member of the manufacturer's System to Manage Accutane-Related Teratogenicity (SMART) program. The SMART program was developed in conjunction with the U.S. Food and Drug Administration (FDA) to minimize unwanted pregnancies and educate patients about the possible severe adverse effects and teratogenicity of isotretinoin, which is a pregnancy category X drug. (26)

Hepatitis, hypertriglyceridemia, intracranial hypertension, arthralgia, myalgias, night blindness, and hyperostoses are rare side effects of isotretinoin therapy. (27) Serum liver function tests and triglyceride levels must be monitored monthly in patients receiving isotretinoin. When isotretinoin is present in the gestational period, it can result in severe fetal abnormalities involving several systems. (27) Therefore, two forms of contraception must be used during isotretinoin therapy and for one month after treatment has ended. To ensure that female patients are not pregnant when treatment is initiated, two negative urine pregnancy tests are required before isotretinoin is prescribed. Pregnancy status is rechecked at monthly visits. (26)

The link between isotretinoin and depression is controversial. A meta-analysis published in 2000 reviewed the purported risk of depression, suicide, or psychiatric disorders in patients taking isotretinoin and found no evidence that the drug was associated with an increased risk for depression, suicide, or other psychiatric disorders. (28) [Evidence level B, systematic review of cohort studies] However, several case reports (28) and case series (28) have described situations in which depression began on initiation of isotretinoin therapy.

Goals of Therapy and Treatment of Complications

The goals of acne therapy include controlling acne lesions, preventing scarring, and minimizing morbidity. The family physician should be sensitive to issues related to medication compliance, the patient's personal goals for acne treatment, and psychologic problems related to acne (e.g., anxiety). Lack of compliance, the most important cause of treatment failure, can be minimized by patient education and the establishment of realistic treatment goals. (29) The patient needs to know that the goal of treatment is to prevent new lesions. Current lesions must heal on their own. Visible improvement occurs after eight to 12 weeks of treatment.

Scarring always is a potential risk in inflammatory acne. The method of scar treatment depends largely on the morphology of the scar. Common treatments include resurfacing with ablative or nonablative lasers, dermabrasion, and chemical peels, although there is little evidence to support these options. (30) Soft tissue augmentation, undermining, and punch biopsy excision are additional alternatives. (31)

Referral

The patient who has not responded to treatment as expected may need to be referred to a dermatologist. Gram-negative folliculitis should be suspected if inflammatory acne worsens after several months of oral antibiotic therapy. Acne fulminans is the rapid onset of severe, inflammatory acne, often accompanied by fever, arthralgia, and bone diathesis. The triad of severe acne, hidradenitis suppurativa, and dissecting cellulitis of the scalp may require aggressive treatment. Intralesional corticosteroid injections may benefit nodulocystic disease. If treatment with isotretinoin is indicated, the prescribing physician must be enrolled in the manufacturer's SMART program.

Referral also may be required because of treatment complications or for correction of scarring. In the future, treatment with blue or blue-red lasers may be readily available, and referral to the facilities that have these lasers may benefit patients with acne that does not improve with standard treatments.

The authors indicate that they do not have any conflicts of interest. Sources of funding: Dr. Feldman has received grant support from Roche Dermatology and is a speaker on the use of Roche's acitretin (Soriatane) in the treatment of psoriasis. He notes that he has not received funds for publishing articles on, or in promotion of, isotretinoin. Dr. Feldman also has received grant support from Galderma Laboratories, manufacturer of adapalene (Differin), and from Ortho Dermatological, manufacturer of tretinoin (Retin-A).

Figures 1 through 3 provided by Steven Feldman, M.D., Ph.D.

REFERENCES

(1.) Gollnick HP, Zouboulis CC, Akamatsu H, Kurokawa I, Schulte A. Pathogenesis and pathogenesis related treatment of acne. J Dermatol 1991;18:489-99.

(2.) Holmes RL, Williams M, Cunliffe WJ. Pilo-sebaceous duct obstruction and acne. Br J Dermatol 1972;87:327-32.

(3.) White GM. Acne therapy. Adv Dermatol 1999;14: 29-59.

(4.) Zaenglein AL, Thiboutot DM. Acne vulgaris. In: Bolognia JL, Jorizzo JL, Rapini RP, eds. Dermatology. New York: Mosby, 2003:533-4.

(5.) Mengesha YM, Bennett ML. Pustular skin disorders: diagnosis and treatment. Am J Clin Dermatol 2002;3:389-400.

(6.) Jabbour SA. Cutaneous manifestations of endocrine disorders: a guide for dermatologists. Am J Clin Dermatol 2003;4:315-31.

(7.) Pochi PE, Shalita AR, Strauss JS, Webster SB, Cunliffe WJ, Katz HI, et al. Report of the Consensus Conference on Acne Classification. Washington, D.C., March 24 and 25, 1990. J Am Acad Dermatol 1991;24:495-500.

(8.) Gollnick H, Schramm M. Topical drug treatment in acne. Dermatology 1998;196:119-25.

(9.) Millikan LE. The rationale for using a topical retinoid for inflammatory acne. Am J Clin Dermatol 2003;4:75-80.

(10.) Embil K, Nacht S. The microsponge delivery system (MDS): a topical delivery system with reduced irritancy incorporating multiple triggering mechanisms for the release of actives. J Microencapsul 1996;13:575-88.

(11.) Van Hoogdalem EJ. Transdermal absorption of topical anti-acne agents in man; review of clinical pharmacokinetic data. J Eur Acad Dermatol Venereol 1998;11(suppl 1):S13-9.

(12.) Cunliffe WJ, Poncet M, Loesche C, Verschoore M. A comparison of the efficacy and tolerability of adapalene 0.1% gel versus tretinoin 0.025% gel in patients with acne vulgaris: a meta-analysis of five randomized trials. Br J Dermatol 1998;139(suppl 52):48-56.

(13.) Thiboutot D, Gold MH, Jarratt MT, Kang S, Kaplan DL, Millikan L, et al. Randomized controlled trial of the tolerability, safety, and efficacy of adapalene gel 0.1% and tretinoin microsphere gel 0.1% for the treatment of acne vulgaris. Cutis 2001;68(4 suppl):10-9.

(14.) Webster GF, Berson D, Stein LF, Fivenson DP, Tanghetti EA, Ling M. Efficacy and tolerability of once-daily tazarotene 0.1% gel versus once-daily tretinoin 0.025% gel in the treatment of facial acne vulgaris: a randomized trial. Cutis 2001;67(6 suppl):4-9.

(15.) Leyden JJ, Tanghetti EA, Miller B, Ung M, Berson D, Lee J. Once-daily tazarotene 0.1% gel versus once-daily tretinoin 0.1% microsponge gel for the treatment of facial acne vulgaris: a double-blind randomized trial. Cutis 2002;69(2 suppl):12-9.

(16.) Liao DC. Management of acne. J Fam Pract 2003; 52:43-51.

(17.) Leyden JJ, Hickman JG, Jarratt MT, Stewart DM, Levy SF. The efficacy and safety of a combination benzoyl peroxide/clindamycin topical gel compared with benzoyl peroxide alone and a benzoyl peroxide/ erythromycin combination product. J Cutan Med Surg 2001;5:37-42.

(18.) Cunliffe WJ, Holland KT, Bojar R, Levy SF. A randomized, double-blind comparison of a clindamycin phosphate/benzoyl peroxide gel formulation and a matching clindamycin gel with respect to microbiologic activity and clinical efficacy in the topical treatment of acne vulgaris. Clin Ther 2002;24:1117-33.

(19.) Lowe NJ, Rizk D, Grimes P, Billips M, Pincus S. Azelaic acid 20% cream in the treatment of facial hyperpigmentation in darker-skinned patients. Clin Ther 1998;20:945-59.

(20.) Eady EA, Gloor M, Leyden JJ. Propionibacterium acnes resistance: a worldwide problem. Dermatology 2003;206:54-6.

(21.) Garner SE, Eady EA, Popescu C, Newton J, Li Wan Po A. Minocycline for acne vulgaris: efficacy and safety. Cochrane Database Syst Rev 2003;(1): CD002086.

(22.) Shapiro LE, Knowles SR, Shear NH. Comparative safety of tetracycline, minocycline, and doxycycline. Arch Dermatol 1997;133:1224-30.

(23.) Tan HH. Antibacterial therapy for acne: a guide to selection and use of systemic agents. Am J Clin Dermatol 2003;4:307-14.

(24.) Archer JS, Archer DF. Oral contraceptive efficacy and antibiotic interaction: a myth debunked. J Am Acad Dermatol 2002;46:917-23.

(25.) Shaw JC. Acne: effect of hormones on pathogenesis and management. Am J Clin Dermatol 2002; 3:571-8.

(26.) Lowenstein EJ. Isotretinoin made S.M.A.R.T. and simple. Cutis 2002;70:115-20.

(27.) Ellis CN, Krach, KJ. Uses and complications of isotretinoin therapy. J Am Acad Dermatol 2001;45: S150-7.

(28.) Jick SS, Kremers HM, Vasilakis-Scaramozza C. Isotretinoin use and risk of depression, psychotic symptoms, suicide, and attempted suicide. Arch Dermatol 2000;136:1231-6.

(29.) Katsambas AD. Why and when the treatment of acne fails. What to do. Dermatology 1998;196:158-61. 30. Jordan RE, Cummins CL, Burls AJ, Seukeran DC. Laser resurfacing for facial acne scars. Cochrane Database Syst Rev 2004;(1):CD001866.

(31.) Goodman G. Post acne scarring: a review. J Cosmet Laser Ther 2003;5:77-95.

STEVEN FELDMAN, M.D., PH.D., is professor of dermatology, pathology, and public health sciences at Wake Forest University School of Medicine, Winston-Salem, N.C. Dr. Feldman received his medical and doctoral degrees from Duke University, Durham, N.C. He completed a residency in dermatology at the University of North Carolina at Chapel Hill, and a residency in dermatopathology at the Medical University of South Carolina, Charleston.

RACHEL E. CARECCIA, M.D., is a second-year dermatology resident at Wake Forest University School of Medicine. Dr. Careccia is a graduate of the University of Miami (Fla.) School of Medicine.

KELLY L. BARHAM, M.D., is completing an internal medicine internship at Moses H. Cone Memorial Hospital, Greensboro, N.C. She received her medical degree from Wake Forest University School of Medicine.

JOHN HANCOX, M.D., is a second-year dermatology resident at Wake Forest University School of Medicine. Dr. Hancox is a graduate of West Virginia University School of Medicine, Morgantown.

Address correspondence to Steven Feldman, M.D., Ph.D., Wake Forest University School of Medicine, Department of Dermatology, Medical Center Boulevard, Winston-Salem, NC 27157-1071 (e-mail: sfeldman@wfubmc.edu). Reprints are not available from the authors.

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