Pediatric Annals

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PEDIATRIC DERMATOLOGY 

The Diagnosis and Management of Acne

Robert Sidbury, MD; Amy S Paller, MD

Abstract

Acne affects up to 50 million individuals in the United States,1 including 85% of those between the ages of 12 and 25 years. However, acne is not confined to the adolescent years, as evidenced by comedonal acne in up to 20% of newborns,2 acne that is often cystic and scarring in infants, and the many young adult women who have acne. The cost of acne exceeds 100 million dollars each year, just for nonprescription medications.3 However, the emotional cost is perhaps greater, especially for teenagers, who are going through an important period of psychosocial development. The severity of a patient's concern is not necessarily proportional to the severity of the acne, and patients with mild to moderate acne often describe emotional distress equal to that of patients who are more severely affected.4 Difficulties produced by an individual's reaction to acne can range from mild embarrassment to significant self-esteem impairment, and these effects can last far beyond the last pimple.5 Unfortunately, acne also leaves permanent physical scars, particularly inflammatory nodulocystic acne. Early and aggressive therapy is needed to prevent disfigurement. The therapy for acne should be tailored to the type, severity, and distribution of lesions.

PATHOGENESIS

Acne is a disorder of the sebaceous hair follicles, or pilosebaceous units, which are located primarily on the face and trunk. These structures consist of a sebum-producing gland (sebaceous gland) attached to a keratinocyte-lined follicular duct that opens to the skin surface. Acne is multifactorial, and patterns of clinical expression seen depend on the interplay of four key factors: (1) abnormal shedding of follicular skin cells (ie, dyskeratinization); (2) androgen-driven overproduction of sebum; (3) resident bacterial overgrowth; and (4) host factors.6 The earliest pathologic event is abnormal sloughing of cells lining the pilosebaceous follicles. These cells are shed and renewed as part of the normal keratinocyte life cycle. In acne, desquamated corneocytes (skin cells) are abnormally adherent, possibly due to a deficiency of linoleic acid.7 This leads to clumping that, mixed with excessive sebum, forms a follicular plug or microcomedo. If the follicular opening remains small, the precursor microcomedo slowly enlarges to form a closed comedo (ie, whitehead; Fig. IA). In contrast, if the pressure within the follicle is great enough to dilate the follicular orifice, the contents are exposed to air and the keratinocyte pigment is seen more readily, giving the appearance of a darkly colored plug or open comedo (ie, blackhead; Fig. IB).8

Drug-Induced Acne

Drug-induced acne occurs when certain medications cause acneiform eruptions. Corticosteroids commonly lead to uniform crops of pustules, primarily on the back and the chest. Although oral corticosteroids are the most common cause of drug-induced acne, topical and inhaled forms may also worsen acne. Other medications that may lead to acne or acneiform lesions include androgenic hormones, methotrexate, and anticonvulsants.

REFERRAL TO A DERMATOLOGIST

Many patients with acne vulgaris can be successfully treated by the primary care physician. When adequate responses are not achieved or in patients with moderate to severe inflammatory acne, the comfort level of the individual practitioner and his or her patient should dictate the need for involvement of a dermatologist.

1. White GM. Recent findings in the epidemiologic evidence, classification, and subtypes of acne vulgaris. J Am Acad Dermatol. 1998;39:S34-S37.

2. Jansen T, Burgdorf W, Plewig G. Pathogenesis and treatment of acne in childhood. Pediatr Dermatol. 1997;14:17-21.

3. Bergfeld W. The evaluation and management of acne: economic considerations. J Am Acad Dermatol. 1995;32:S52S56.

4. Niemeier V, Kupfer J, Demmelbauer-Ebner M, et al. Coping with acne vulgaris: evaluation of the chronic skin disorder questionnaire in patients with acne. Dermatology. 1998;196:108-115.

5. Koo J. The psychosocial impact…

Acne affects up to 50 million individuals in the United States,1 including 85% of those between the ages of 12 and 25 years. However, acne is not confined to the adolescent years, as evidenced by comedonal acne in up to 20% of newborns,2 acne that is often cystic and scarring in infants, and the many young adult women who have acne. The cost of acne exceeds 100 million dollars each year, just for nonprescription medications.3 However, the emotional cost is perhaps greater, especially for teenagers, who are going through an important period of psychosocial development. The severity of a patient's concern is not necessarily proportional to the severity of the acne, and patients with mild to moderate acne often describe emotional distress equal to that of patients who are more severely affected.4 Difficulties produced by an individual's reaction to acne can range from mild embarrassment to significant self-esteem impairment, and these effects can last far beyond the last pimple.5 Unfortunately, acne also leaves permanent physical scars, particularly inflammatory nodulocystic acne. Early and aggressive therapy is needed to prevent disfigurement. The therapy for acne should be tailored to the type, severity, and distribution of lesions.

PATHOGENESIS

Acne is a disorder of the sebaceous hair follicles, or pilosebaceous units, which are located primarily on the face and trunk. These structures consist of a sebum-producing gland (sebaceous gland) attached to a keratinocyte-lined follicular duct that opens to the skin surface. Acne is multifactorial, and patterns of clinical expression seen depend on the interplay of four key factors: (1) abnormal shedding of follicular skin cells (ie, dyskeratinization); (2) androgen-driven overproduction of sebum; (3) resident bacterial overgrowth; and (4) host factors.6 The earliest pathologic event is abnormal sloughing of cells lining the pilosebaceous follicles. These cells are shed and renewed as part of the normal keratinocyte life cycle. In acne, desquamated corneocytes (skin cells) are abnormally adherent, possibly due to a deficiency of linoleic acid.7 This leads to clumping that, mixed with excessive sebum, forms a follicular plug or microcomedo. If the follicular opening remains small, the precursor microcomedo slowly enlarges to form a closed comedo (ie, whitehead; Fig. IA). In contrast, if the pressure within the follicle is great enough to dilate the follicular orifice, the contents are exposed to air and the keratinocyte pigment is seen more readily, giving the appearance of a darkly colored plug or open comedo (ie, blackhead; Fig. IB).8

Figure 1. (A) Closed comedones on the forehead of a boy using occlusive pomade. (B) Numerous open comedones on the nose of an adolescent. (C) Inflammatory papules, pustules, and cysts on the shoulder of an adolescent boy with severe inflammatory nodulocystic acne.

Figure 1. (A) Closed comedones on the forehead of a boy using occlusive pomade. (B) Numerous open comedones on the nose of an adolescent. (C) Inflammatory papules, pustules, and cysts on the shoulder of an adolescent boy with severe inflammatory nodulocystic acne.

The increased production of sebum, the lipidrich product of sebaceous glands, is driven by circulating androgens. Adrenal androgens are the earliest hormones to rise in the prepubertal period and often precede other hormonal and physical changes associated with puberty.9 This can produce typical "teenage" acne lesions as early as 7 to 9 years of age.10 Increased sebum production may also reflect increased end-organ sensitivity.11 In general, the severity of acne correlates with the level of sebum production.12 Earlier age of onset also correlates with increased severity.13

Sebum that accumulates behind a keratotic plug provides an ideal environment for proliferation of a resident skin bacterium, Propionibacterium acnes. P acnes is an anaerobe that metabolizes the sebum to produce free fatty acids and other metabolites. These have both chemotactic and pro-inflammatory properties, and the infiltration of leukocytes that results leads to the hallmark inflammatory papule of acne.14 Ultimately, the expanding sebaceous hair follicle ruptures, triggering an extension of the inflammatory process into the dermis. This results in deeper, sometimes tender, pustules and nodulocysts (Fig. IC).15 Finally, host factors, including end-organ androgen sensitivity, and the immune response to P acnes affect the acne phenotype.

THERAPY

Management of acne should be based on the type, severity, and localization of lesions. Comedolytics are optimal for treating comedonal lesions, whereas anti-inflammatory agents and antibiotics are most appropriate for treating inflammatory lesions. As the patient ages, acne regimens must be adjusted to the change in the distribution of lesions - from the "T-zone" of the face (ie, forehead, nose, and medial cheeks) to more peripheral sites - and to the shift from largely comedonal lesions to more inflammatory lesions. In addition, resistance to therapy may develop, particularly for antibiotics.

Comedonal Lesions

Topical retinoids (vitamin A derivatives) are most appropriate for the treatment of comedones. They reverse abnormal follicular keratinization, slow desquamation, and decrease adherence of shed cells.16 Tretinoin (all-trans retinoic acid) is available in a variety of formulations, including creams (0.025%, 0.05%, and 0.1%), gels (0.01% and 0.025%), liquid (0.05%), and a microemulsion form. Adapalene is a derivative of naphthoic acid that has retinoid activity, and is available as a 0.1% gel formulation.17 Tazarotene is the newest topical retinoid, and is available in 0.05% and 0.1% gel formulations. Although introduced for the treatment of psoriasis, tazarotene has been found to be helpful for comedonal acne when applied every other night.18 The choice of retinoid depends on the oiliness of the patient's skin (in general, gels and liquids are more drying), the patient's tendency toward irritation, the humidity of the patient's environment, and the patient's history of topical retinoid use. Adapalene gel and the microemulsion form of tretinoin tend to be the least irritating.

These products are generally applied once daily, usually at bedtime. Patients are instructed to allow their faces to dry for 15 to 20 minutes after washing before application to minimize irritation. Dryness and fine scaling is typical after several days of therapy, and may lead to a worsening of clinical appearance during the first 1 to 3 weeks of treatment. Mild irritation from these products can be managed with non-comedogenic emollients. More severe symptoms may require titration of therapy to every other night or, if necessary, discontinuation. In addition to causing xerosis, the products may increase patients' photosensitivity. Although these retinoids are not true photosensitizing agents, they cause thinning of the stratum corneum, or outer, protective layer of the epidermis, increasing overall vulnerability to phototrauma.19 Patients should be warned and instructed to use non-comedogenic sunscreens if exposure to ultraviolet light is anticipated. After several months of therapy, the stratum corneum regains its baseline thickness and tretinoin-induced photosensitivity resolves spontaneously.

Salicylic acid is also useful as a comedolytic agent, and is available in 0.5%, 1.0%, 2.0%, and 5.0% formulations.20 Some patients find that these preparations have a disagreeable odor. However, they provide a useful alternative for patients who are intolerant of topical retinoids. Sulfur products also have mild comedolytic properties, and are available in 2% to 10% creams or lotions.

Inflammatory Lesions

Antibacterial Agents. Mild inflammatory acne may be successfully treated with topical antibacterial agents such as benzoyl peroxide or antibiotics. Moderate to severe inflammatory acne and acne of nonfacial areas is most appropriately managed initially by systemic therapy with antibiotics.

Benzoyl peroxide has long been used as a lipophilic, topical antibacterial agent in acne vulgaris.21 It has been shown to reduce the numbers of P acnes organisms by as much as 95% without leading to the development of resistance. It is available in many forms, including soaps, washes, lotions, gels, and solutions. These range in concentration from 2.5% to 10%. Side effects include irritation and scaling. Benzoyl peroxide can also bleach clothing and hair, so this must be explained to patients. True allergic contact dermatitis is rare. Benzoyl peroxide may be used in concert with a topical retinoid to achieve an increased bacteriocidal effect, because the combination increases penetration. Benzoyl peroxide 5% is also available in a combination with erythromycin.22

Several topical antibiotics are used in inflammatory acne. These localize to the follicular areas and are available in creams, gels, and liquids. The most commonly used are clindamycin and erythromycin, although development of resistance to erythromycin is greater. A topical form of tetracycline is also available. Topical antibiotics are usually applied twice daily, in the morning and in the afternoon. A topical retinoid is also applied at night for the typical patient with a comedonal component. Although some patients object to their odor, topical sulfur products have anti-inflammatory properties as well. Finally, azaleic acid is a dicarboxylic acid that has been effective, as a 20% cream formulation, for inflammatory acne.23 Azelaic acid also inhibits melanin synthesis, so it is most appropriate for patients with inflammatory acne and post-inflammatory hyperpigmentation. However, it should be recognized that postinflammatory hyperpigmentation is a common complication of inflammatory acne in patients with darker skin. As long as further inflammation is prevented by therapy, the increased pigmentation tends to fade with time and does not represent scarring.

Systemic antibiotics are both anti-inflammatory and antibacterial. Tetracycline is prescribed most commonly, usually as 1 g per day in two divided doses. Tetracycline is inexpensive, effective, and safe for long-term use. However, tetracycline must be taken on an empty stomach for optimal absorption. This leads to an increased risk of gastrointestinal disturbance as well as scheduling conflicts, particularly for the morning dose. Other side effects include recurrent candidal infections in female patients and a controversial risk of contraceptive failure if taken concurrently with birth control pills. There is no good evidence that birth control is compromised; however, patients should be advised to alert their physician should breakthrough bleeding occur while they are taking tetracyclines and oral contraceptives simultaneously.24 Finally, benign intracranial hypertension is a rare side effect.

Minocycline, also in the tetracycline family, is usually prescribed in dosages of 150 to 200 mg/ d, divided twice daily. Minocycline is effective and more "user friendly" for teenagers because its increased lipid solubility allows it to be taken with meals. However, it is expensive and has a greater number of potential, but rare, side effects. These include a reversible vestibular disturbance with vertigo and ataxia, charcoal-gray discoloration of the skin (particularly at sites of old acne scars and the mucous membranes), autoimmune hepatitis, vasculitis, and a lupus-like syndrome.25

Doxycycline, another member of the tetracycline class, is inexpensive and lacks the dietary restrictions of tetracycline. Typically prescribed at dosages of 100 mg twice daily, doxycycline is associated with a high incidence of photosensitivity, which restricts its use during summer months. Antibiotics used less commonly for acne include trimethoprim-sulfamethoxazole, erythromycin, and amoxicillin. Although trimethoprim-sulfamethoxazole is effective, the potential for significant side effects, including life-threatening Stevens-Johnson syndrome, makes it less appealing. Erythromycin and amoxicillin are used less now, due to the emergence of resistant P acnes.26

A response to oral antibiotics may be seen in as little as 2 to 4 weeks, but a trial of at least 2 to 4 months should be undertaken before deciding that a drug is not effective. Once an adequate response has been achieved, the dose should be maintained for a minimum of 4 to 6 months. After that time, gradual tapering may be initiated, reducing the dose by half each month to avoid rebound. Although the ultimate goal will be discontinuation of therapy, reducing doses to the lowest effective level is a practical aim. Continuation of an adjunctive topical antibiotic will facilitate this weaning.

A progressive flaring of acne lesions in a patient with previously controlled acne who continues to take antibiotics may signal either the development of antibiotic resistance or a gram-negative folliculitis. The latter is a rare complication of systemic antibiotic use for acne. In this case, superficial pustules or deeper inflammatory lesions will appear, particularly around the nasal area, because of overgrowth of gram-negative organisms related to long-term suppression of normal flora by an antibiotic.27 The systemic antibiotic should be stopped, and either systemic isotretinoin or a systemic antibiotic appropriate for gram-negative organisms should be initiated.

The long-term goal of antibiotic therapy is suppression of lesions until the patient "outgrows" his or her propensity toward potentially disfiguring lesions. Patients and parents need reassurance that long-term use of these antibiotics is safe. Concerns about the development of drug resistance due to long-term antibiotic use are unfounded in this situation. The organisms that have developed resistance to acne antibiotics are P. acnes and coagulase-negative staphylococcus. Neither of these is responsible for significant illness in healthy populations. Moreover, resistance is to tetracycline and erythromycin, agents that are rarely used to treat systemic infections and for which resistance does not cross-react with most antibiotics used for serious infections.28

Hormonal Therapy. Androgenic hormones govern the exocrine activity of the sebaceous glands. In males, the testes are the primary source of testosterone. In females, the most important source of circulating androgens is the adrenal gland, which produces dehydroepiandrosterone. Although the mechanism is unclear, androgens clearly increase sebum production, and men without functional androgen receptors (androgen insensitivity) do not have acne.29 Most patients with acne do not have abnormal androgen levels, so recalcitrant acne in the absence of other signs of hormonal excess is not an indication for an endocrinologie workup. Clinical clues of a significant hormonal role in acne include poor response to standard therapies, acne flares with menstruation, and a beard distribution for acne lesions.

Spironolactone is the most commonly used antiandrogenic medication for acne. It is typically dosed at 25 to 200 mg/d, and patients should have potassium levels monitored. Menstrual irregularity and mastalgia are occasional side effects of spironolactone therapy.30

Estrogen-containing oral contraceptives are also effective at suppressing serum androgen levels. In contrast, androgenic oral contraceptives can exacerbate acne. An oral contraceptive with norgestimate and ethinyl estradiol was approved as a treatment for acne in 1997 by the Food and Drug Administration. This agent is most effective for inflammatory acne, but should be administered only with guidance from a gynecologist skilled at caring for adolescent female patients. Effects can be seen as early as 1 month after initiation, but 6 months may be required to achieve suppression of inflammatory acne.31

Systemic corticosteroids also suppress androgen production, and thus may be effective in acne. However, they also can trigger acneiform lesions and unacceptable side effects with continued use. A more practical approach is to inject intralesional corticosteroids (usually 2.5 to 5 mg/mL of triamcinolone acetonide) into isolated, bothersome cysts and nodules to hasten resolution and prevent scarring.

Systemic Retinoid Therapy. The most potent weapon in the arsenal against inflammatory acne is systemic isotretinoin. Isotretinoin, a vitamin A derivative, acts by decreasing the amount of sebum production while simultaneously normalizing follicular keratinization. Although there is no direct effect on the bacteria, these factors lead to a reduction in the number of P. acnes organisms and usually a dramatic improvement in severe acne. Unlike with systemic antibiotics, improvement often persists following discontinuation of treatment. This is, in a sense, the only treatment that can result in a true acne "cure," and probably relates to an atrophy of the sebaceous glands.32

Isotretinoin is dosed at 1 mg/kg/d for a 4- to 5-month course. However, this treatment can have a wide range of side effects. Dryness of the skin and mucous membranes is the most common dose-dependent side effect. It leads to frequent cheilitis, epistaxis, and eye irritation in contact lens wearers. Less common but important side effects include reversible alopecia, depression, musculoskeletal discomfort with an elevation of creatine Phosphokinase, hypertriglyceridemia, increased sun sensitivity, and asymptomatic skeletal changes called hyperostoses.33 Surgery should not be undertaken while isotretinoin is being administered because of the risk of abnormal wound healing and increased skin fragility. The most significant side effect is severe teratogenicity, mandating contraception and monthly pregnancy testing in female patients of childbearing age. Contraception should be continued for one menstrual cycle after stopping therapy. There is no known teratogenic risk to a fetus because a father is taking isotretinoin. Patients receiving isotretinoin must have counseling regarding the risks of these side effects. Baseline and monthly laboratory testing, including complete blood counts, liver and renal studies, cholesterol, and triglycerides, should be performed in all patients.

The response rate to isotretinoin is as high as 90%. Patients should be advised that their acne may worsen during the initial 2 to 3 months of therapy, and that up to 25% may require a second course of treatment. The universal cheilitis should be treated by vigorous application of thick emollients, and moisturizers should be used for the intranasal areas, skin, and eyes as needed. Patients should be instructed to apply non-comedogenic sunscreens before exposure to ultraviolet light to minimize the propensity to photosensitivity. Finally, prior to the initiation of therapy, patients and their parents should be made aware of the significant time and expense involved with a course of isotretinoin. Pediatricians often refer patients who need this treatment to dermatologists or use this in concert with one because of the potential side effects.

Figure 2. Acne excoriee is most commonly seen in adolescent girls, and evidence of a psychiatric disturbance, especially obsessive-compulsive disorder, should be considered. Acne excoriee usually occurs with otherwise mild acne, but the trauma from picking may cause scanning.

Figure 2. Acne excoriee is most commonly seen in adolescent girls, and evidence of a psychiatric disturbance, especially obsessive-compulsive disorder, should be considered. Acne excoriee usually occurs with otherwise mild acne, but the trauma from picking may cause scanning.

NONPHARMACOLOGIC THERAPY

Most teenagers attempt various methods of self-treatment, including "popping," "buffing," and the increasingly popular "stripping" for comedone removal. By and large, these efforts are far less effective than prescription therapies and they may lead to scarring. Once scarring has occurred, definitive interventions should not be undertaken to improve this aspect of appearance until acne has remitted. At that time, several options can be presented for scar revision, including chemical peels, dermabrasion, and the newer carbon dioxide resurfacing lasers. Patients who have elevated firm scars (ie, keloids) can be treated with intralesional corticosteroid injection (up to 40 mg/mL), silicone sheeting, or both. In most cases, these treatments would mandate referral so that they could be done by a dermatologist or a plastic surgeon. In addition to allowing active acne to clear, at least 6 months should pass between discontinuation of oral isotretinoin therapy and any physical scar revision. This is due to potential isotretinoin-induced skin fragility and a risk of increased vascularization of healing tissue.

Avoidance of the triggers of acne is also important for patients. If makeup is necessary for maintaining self-esteem, oil-free or water-based products should be used instead of oil-based products. Sunscreens and emollients that are applied to the face and trunk should be non-comedogenic. Because hands carry oils, it is important to avoid touching the face. Wearing hats or gear that causes mechanical friction and occlusion may also be problematic. This often occurs because of sports or during the summer. Finally, one of the most frequently asked about issues is the role of food in triggering acne. There is currently no evidence that ingestion of any food increases the tendency for acne to develop. However, greasy foods may leave residual oils on the face and hands that can be occlusive.

ACNE VARIANTS

The practitioner should be aware of several distinctive variants of acne.

Pomade Acne

Defined by closed comedonal lesions of the upper forehead and lateral cheeks, pomade acne results from oily skin and the use of hair care products (Fig. IA). Education regarding the causative role played by these products, limiting the use of pomades, and washing hands after application often resolve this problem.

Acne Excoriee

This is a potentially disfiguring condition seen more commonly in females. It results when manipulation of acne lesions leads to multiple, linear, angulated excoriations at sites of acne lesions (Fig. 2). This is difficult to manage because the picking becomes both habitual and impossible to resist. Psychiatric intervention can be extremely useful for this, particularly in patients who demonstrate other indications of obsessive-compulsive behavior.34

Neonatal Acne

This variant of acne is seen during the first months of life and is a common, benign condition. It is thought that neonatal acne is triggered by the transiently increased production of androgenic hormones by the infant, and that this is also why neonatal acne resolves spontaneously (Fig. 3).

Figure 3. Neonatal acne tends to resolve within months and relates to increased hormonal levels generated by the infant.

Figure 3. Neonatal acne tends to resolve within months and relates to increased hormonal levels generated by the infant.

Infantile Acne

In contrast to neonatal acne, infantile acne begins after the first months of life and may continue until 2 to 3 years of age. Affected infants are most commonly male and may exhibit acne lesions ranging from comedones to cysts (Fig. 4). In fact, some infants have primarily cystic acne and are thus difficult to treat.35 The cause of infantile acne is unknown. Most infants with acne have no evidence of precocious puberty or androgenization, and their hormone levels are normal. Treatment should be appropriate for the type of lesions, but systemic therapy may be required for patients with a significant inflammatory component because scarring may occur. Systemic erythromycin is the initial treatment of choice if moderate to severe inflammation is present, particularly because tetracyclines can produce dental staining. Patients with inflammatory cysts may require systemic isotretinoin, or systemic corticosteroid administration, intralesional corticosteroid administration, or both.

Figure 4. Infantile acne is more commonly seen in male infants, and may range in severity from comedonal acne to severe cystic acne, as shown.

Figure 4. Infantile acne is more commonly seen in male infants, and may range in severity from comedonal acne to severe cystic acne, as shown.

Drug-Induced Acne

Drug-induced acne occurs when certain medications cause acneiform eruptions. Corticosteroids commonly lead to uniform crops of pustules, primarily on the back and the chest. Although oral corticosteroids are the most common cause of drug-induced acne, topical and inhaled forms may also worsen acne. Other medications that may lead to acne or acneiform lesions include androgenic hormones, methotrexate, and anticonvulsants.

REFERRAL TO A DERMATOLOGIST

Many patients with acne vulgaris can be successfully treated by the primary care physician. When adequate responses are not achieved or in patients with moderate to severe inflammatory acne, the comfort level of the individual practitioner and his or her patient should dictate the need for involvement of a dermatologist.

REFERENCES

1. White GM. Recent findings in the epidemiologic evidence, classification, and subtypes of acne vulgaris. J Am Acad Dermatol. 1998;39:S34-S37.

2. Jansen T, Burgdorf W, Plewig G. Pathogenesis and treatment of acne in childhood. Pediatr Dermatol. 1997;14:17-21.

3. Bergfeld W. The evaluation and management of acne: economic considerations. J Am Acad Dermatol. 1995;32:S52S56.

4. Niemeier V, Kupfer J, Demmelbauer-Ebner M, et al. Coping with acne vulgaris: evaluation of the chronic skin disorder questionnaire in patients with acne. Dermatology. 1998;196:108-115.

5. Koo J. The psychosocial impact of acne: patient's perceptions. J Am Acad Dermatol. 1995;32:S26-S30.

6. Brown SK, Shalita AR. Acne vulgaris. Lancet. 1998; 351:1871-1876.

7. Morello AM, Downing DT, Strauss JS. Octadecanoic acids in the skin surface: lipids of acne patients and normal subjects. J Invest Dermatol. 1976;66:319-322.

8. Strauss JS, Kligman AM. The pathologic dynamics of acne vulgaris. Arch Dermatol. 1960;82:779-790.

9. Sizonenko PC, Paumier L. Hormonal changes in puberty: III. Correlation of plasma dehydroepiandrosterone, testosterone, FSH, and LH with stages of puberty and bone age in normal boys and girls and in patients with Addison's disease or hypogonadism or with premature or late adrenarche. J Clin Endocrinol Metab. 1975,41:894-904.

10. Rothman KF, Lucky AW. Acne vulgaris. Adv Dermatol. 1993;8:347-374.

11. Ley den JJ. Therapy for acne vulgaris. N Engl J Med. 1997; 336:1156-1162.

12. Pochi PE, Strauss JS. Endocrinologie control of the development and activity of the human sebaceous gland. J Invest Dermatol. 1964;43:383-388.

13. Lucky AW, Biro FM, Simbarti LA, et al. Predictors of severity of acne vulgaris in young adolescent girls: results of a five-year longitudinal study. J Pediatr. 1997,130:30-39.

14. Puhvel SM Sakamoto M. The chemoattractant properties of comedonal components. J Invest Dermatol. 1978;71:324329.

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16. Leyden JJ, Shalita AR. Rational therapies for acne vulgaris: an update on topical treatment. J Am Acad Dermatol. 1986,15:907-914.

17. Shalita AR, Weiss JS, Chaucer DK, et al. A comparison of the efficacy and safety of adapalene gel 0.1% and tretinoin gel 0.025% in the treatment of acne vulgaris: a multicenter trial. J Am Acad Dermatol. 1996;34:482-485.

18. Shalita AR, Chalker DK, Griffith RF, et al. Tazarotene gel is safe and effective in the treatment of acne vulgaris: a multicenter, double-blind, vehicle-controlled study. Cutis. 1999;63:349-354.

19. Leyden JJ. Topical treatment of acne vulgaris: retinoids and cutaneous irritation. J Am Acad Dermatol. 1998;38:S1S4.

20. Shalita AR. Treatment of mild and moderate acne vulgaris with salicylic acid in an alcohol-detergent vehicle. Cutis. 1981;28:556-558, 561.

21. Cunliffe WJ, Holland KT. The effect of benzoyl peroxide on acne. Acta Dermatol Venereal (Stockh). 1980;61:267-269.

22. Chalker DK, Shalita AR, Smith JG, et al. A double-blind study of the effectiveness of a 3% erythromycin and 5% benzoyl peroxide combination in the treatment of acne vulgaris. J Am Acad Dermatol. 1983;9:933-936.

23. Cunliffe WJ, Holland KT. Clinical and laboratory studies on treatment with 20% azelaic acid cream for acne. Acta Dermatol Venereol (Stockh). 1989;133(suppl):31-34.

24. Helms SE, Bredle DL, Zajic J, et al. Oral contraceptive failure rates and oral antibiotics. J Am Acad Dermatol. 1997;36:705-710.

25. Sturkenboom MCJM, Meier CR Jick H, et al. Minocycline and lupuslike syndrome in acne patients. Arch Intern Med. 1999;159:493-497.

26. Eady EA, Cove JH, Holland KT, et al. Erythromyrin-resistant proprionibacteria in antibiotic treated patients: association with treatment failure. Br J Dermatol. 1989;121:5157.

27. Neubert U, Jansen T, Plewig G. Bacteriologie and immunologic aspects of gram-negative folliculitis: a study of 46 patients. Int J Dermatol. 1999;38:270-274.

28. Boiognia JL, Edelson RL. Spread of antibiotic-resistant bacteria from acne patients to personal contacts: a problem beyond the skin? Lancet. 1997;350:972-973.

29. Imperato-McGinley J, Gautier T, Cal LQ, et al. The androgen control of sebum production: studies of subjects with dihydrotestosterone deficiency and complete androgen insensitivity. J Clin Endocrinol Metab. 1993;76:524-528.

30. Shaw JC. Anti-androgen and hormonal treatment of acne. Dermatol Clin. 1996;14:803-811.

31. Lucky AW, Henderson TA, Olson WH, et al. Effectiveness of norgestimate and ethinyl estradiol in treating moderate acne vulgaris. J Am Acad Dermatol. 1997;37:746-754.

32. Strauss JS, Rapini RP, Shalita AR, et al. Isotretinoin therapy of acne: results of a multicenter dose-response study. J Am Acad Dermatol. 1984;10:490-496.

33. Bershad S, Rubenstein A, Paterniti JR Jr, et al. Changes in plasma lipids and lipoproteins during isotretinoin therapy for acne. N Eng J Med. 1985,313:981.

34. Koo JY, Smith LL. Psychologic aspects of acne. Pediatr Dermatol. 1991;8:185-188.

35. Mengesha YM, Hansen RC. Toddler-age nodulocystic acne. J Pediatr 1999;134:644-648.

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