Adolescent Acne: Effective Therapy for a Serious Condition

Transcription

1 BRIDGET M. BRYER GROFF, MD JENNIFER S. TROMBERG, MD BARBARA B. WILSON, MD University of Virginia Adolescent Acne: Effective Therapy for a Serious Condition Dr Bryer Groff and Dr Tromberg are residents in dermatology at the University of Virginia School of Medicine in Charlottesville. Dr Wilson is associate professor of dermatology at the same institution. ABSTRACT: Our understanding of the pathogenesis of acne vulgaris has improved, and many safe and effective treatments are now available. Treatments target the 4 chief mechanisms of acne development: follicular plugging caused by hyperproliferation of the follicular epithelium, increased sebum production, proliferation of Propionibacterium acnes, and an inflammatory response. For mild acne, topical therapies are usually effective. These can include topical retinoids, topical antibiotics, benzoyl peroxide, and other agents. Combinations of topical agents are more effective than monotherapy. Treatments that have proved effective for moderate to severe acne include oral antibiotics, oral contraceptives, spironolactone, isotretinoin, and photodynamic therapy. Adolescent acne can have lasting physical and emotional sequelae. It is important for pediatricians to be sensitive to the psychological impact this disease can have and to work with patients to implement effective treatments. As the most common skin disease affecting adolescents, acne is familiar to all pediatricians. 1 In recent years, acne research has led to a greater understanding of the pathogenesis of this condition, including increased knowledge of the genetic, environmental, and molecular events that contribute to its prevalence and severity. Although often considered to be a rite of passage for adolescents, acne can have lasting physical and emotional sequelae. Fortunately, as a result of our improved understanding of the condition, many effective, safe, and inexpensive treatments are now available. In this article, we review the pathogenesis, epidemiology, and psychosocial impact of acne, and we provide an in-depth discussion of management and treatment options. Recent developments in our understanding of the role of hormones in acne development are also briefly reviewed. PATHOPHYSIOLOGY Four distinct but interrelated factors are widely accepted as the pathogenic mechanisms of acne development: The first clinically apparent lesion is the microcomedo, which results from follicular plugging caused by hyperproliferation of the follicular epithelium. Increased sebum production normally occurs during puberty, and this excess sebum becomes trapped in the occluded follicle (Figure 1). 2 The follicle then becomes colonized with Propionibacterium acnes, an aerotolerant anaerobic bacterium that is a normal inhabitant of the skin surface. 1 The bacterium s cell wall, along with the metabolic by-products of sebum breakdown, initiates an inflammatory response with the attraction of neutrophils to proinflammatory cytokines. 2 Recent interest in the role of toll-like receptors (TLRs), specifical- JUNE 2009 (SUPPLEMENT) CONSULTANT FOR PEDIATRICIANS S5

2 Adolescent Acne: Effective Therapy for a Serious Condition Figure 1 Prominent comedonal acne is evident on the forehead of this 17-year-old boy. ly the increase of TLR2 and TLR4 in the epidermis of acne lesions, has led to new insight into the inflammatory process of acne. TLRs, which are part of the innate immune system, are pattern recognition receptors that influence the release of cytokines, chemokines, and other inflammatory mediators. New therapies that target this cascade are currently in development. 3 A genetic basis for acne? Genetic factors are also being implicated in acne pathogenesis. Twin studies comparing monozygotic and dizygotic twins, which theoretically control for environmental factors, have found evidence of genetic influence on acne severity. 4 However, specific responsible genes have not been confirmed. Hormones and acne. Sebaceous glands and the skin are able to synthesize and metabolize the androgen hormones that influence sebum production, an important factor in the pathogenesis of acne. Dehydroepiandrosterone sulfate (DHEAS), the major precursor of testosterone, and dihydrotestosterone (DHT) interact with androgen receptors on sebaceous glands. Type 1 5 -reductase, found in sebaceous glands, converts testosterone into the more potent DHT. Most acne patients do not have hormonal disorders; however, hormones clearly play a role in acne development. Certain symptoms and physical examination findings may lead the clinician to suspect a hormonal cause of a patient s acne. Such causes include androgensecreting tumors, polycystic ovary syndrome (PCOS), anabolic steroid use (Figure 2), and congenital adrenal hyperplasia. Signs and symptoms of hyperandrogenism include a sudden onset of severe acne, recalcitrant acne, cushingoid features, male-pattern hair loss, increased libido, and deepening of the voice, as well as hirsutism and irregular menses in girls. 5 Insulin resistance is also associated with hyperandrogenism in girls, although data supporting a conclusive link between acne and insulin levels, insulinlike growth factor-1, and dietary glycemic index have yielded conflicting results. 6,7 Screening for hormonal disorders can be done by obtaining blood serum and measuring DHEAS and free and total testosterone. The luteinizing hormone (LH)/follicle stimulating hormone (FSH) ratio can also be checked; this should be done immediately before or after a patient s menstrual period to avoid the physiologic surge in these 2 hormones that occurs with ovulation. Oral contraceptives can interfere with accurate measurement of LH and FSH and should be stopped a month before blood work is done. An elevated DHEAS level suggests an adrenal source of hyperandrogenism; refer any patient with a DHEAS elevation to an endocrinologist to look for congenital adrenal hyperplasia or an adrenal tumor. Elevated testosterone levels are seen when there is an ovarian source of hyperandrogenism, such as PCOS or an ovarian tumor; in patients with a testosterone elevation, referral to a S6 CONSULTANT FOR PEDIATRICIANS JUNE 2009 (SUPPLEMENT)

3 gynecologist or endocrinologist is appropriate. The LH/FSH ratio is also increased in PCOS. Even if androgen hormone levels are normal, many female patients will still benefit from hormone-modulating therapy. 5 EPIDEMIOLOGY AND IMPACT Depending on the ages of the patients studied, the estimated prevalence of acne ranges from 50% to 85%, with some experts asserting that nearly all persons will have acne lesions at some point during their lifetime. 1,2 Although acne has historically been viewed as a cosmetic problem, multiple studies of its psychosocial impact have consistently shown it to have a profound impact on adolescents quality of life, self-esteem, and social functioning. The degree of social and emotional impairment associated with acne has been compared with that seen in patients with arthritis, epilepsy, and other chronic illnesses. 8 Depression, social withdrawal, and anger are often seen in patients with acne; these are hypothesized to be related to the damaging effects of facial appearance on self-concept. 8,9 Most important, improvements in acne after appropriate treatment have been shown to result in enhanced selfesteem, body image, and social functioning. A clinician who is aware of the psychological impact of this disease can often establish a more meaningful therapeutic relationship with the patient through empathy and open communication. products or pomades, presence of nodular or cystic lesions, and irregular menses in girls can help identify any factors that may make the patient s acne more resistant to firstline therapies. On the physical examination, pay special attention to the types and severity of acne lesions (open and closed comedones [see Figure 1], inflammatory papules and pustules [Figure 3], nodules, and cysts); these findings will help guide treatment. The presence of hirsutism and obesity in a girl or cushingoid features in a patient of either sex INITIAL EVALUATION When a patient first presents for acne evaluation, a thorough history and physical examination are warranted. Questions about age at onset, family history of acne or hormonal disorders, medication and steroid use (corticosteroids or anabolic steroids), application of topical Figure 2 The explosive acne on the back of this young athlete resulted from exogenous anabolic steroid use. JUNE 2009 (SUPPLEMENT) CONSULTANT FOR PEDIATRICIANS S7

4 Adolescent Acne: Effective Therapy for a Serious Condition Figure 3 The prominent papular and pustular lesions on this boy s forehead are typical of moderate to severe inflammatory acne. may indicate hormonal causes. Photographs taken before treatment is begun can be helpful in assessing improvement. TREATMENT Treatment regimens for acne vulgaris combine the art and science of medicine. Because acne is a condition with multiple pathophysiological factors, it is important to consider each of these when developing an appropriate therapy. The targets for treatment include sebum overproduction, hormonal influence, inflammation, P acnes colonization, and abnormal follicular differentiation. 10 Current guidelines for treating acne specify options for mild, moderate, and severe disease that target each of the above causative factors. In addition, emerging bacterial resistance and new research on the pathogenesis of acne are leading to novel ideas and treatment possibilities. There is no accepted consensus on how to classify acne severity. The following classification of treatment options is based on the number, type, and size of the acne lesions. Mild acne. Mild acne usually refers to scattered inflammatory papules and predominantly comedonal lesions. The mainstay of treatment for mild acne vulgaris is topical therapy. Agents used include topical retinoids, benzoyl peroxide, topical antibiotics, sulfur-containing products, and azelaic acid. Combinations of various topical medications have been shown repeatedly to be more effective than individual agents used alone. 11 Topical retinoids, such as tretinoin, adapalene, and tazarotene, target follicular differentiation and are useful in the management of both comedonal and inflammatory acne. Decreasing follicular plugging is an important first step in the prevention of new acne lesions. Topical S8 CONSULTANT FOR PEDIATRICIANS JUNE 2009 (SUPPLEMENT)

5 retinoids have a comedolytic effect on mature comedones, reduce the formation of new ones, and have anti-inflammatory properties. 12 Retinoids can cause a flare of acne in the first few weeks of use, and this should be explained to the patient. Other potential adverse effects include excessive dryness, erythema, peeling, and itching; these effects can be mitigated by titrating up to daily use over several weeks time, as well as by the adjunctive use of moisturizers. Retinoids are classified as category C medications, and studies are conflicting regarding their use in pregnant women. When known safe alternatives are available, these agents are generally avoided in females who are pregnant or who wish to become pregnant. Topical antibiotics, such as clindamycin and erythromycin, are also used to treat mild and moderate acne. Antibiotic resistance is a concern, and studies show that combining the use of an antibiotic with a benzoyl peroxide product is critical in preventing resistance of P acnes. Benzoyl peroxide has direct antimicrobial activity through its generation of oxygen radicals, in addition to other keratolytic and antiinflammatory properties. P acnes has not developed resistance to the bactericidal effects of benzoyl peroxide; this agent may thus prevent or eliminate overall resistance when used in combination with other topical antimicrobials. 11 Other topical agents include azelaic acid, sulfur, and sulfacetamide. Azelaic acid has comedolytic and anti-inflammatory properties and is safe during pregnancy. Sulfur has been used historically with some success and is currently gaining new momentum as an acne treatment; however, its efficacy is disputed. Sulfur also has antimicrobial, antifungal, and keratolytic properties and can work well alone or when combined with sodium sulfacetamide. Sulfacetamide is contraindicated in patients with sulfa allergies. Sulfur, however, is safely tolerated by sulfa-allergic patients. 13 Vehicles and regimens. All of the above topicals are available in a variety of vehicles: creams, gels, lotions, washes, and suspensions. The patient s unique skin type, as well as ease of use, helps with the decision of which to choose when developing a treatment plan. A typical topical regimen might include benzoyl peroxide gel or wash followed by clindamycin 1% lotion in the morning and by clindamycin along with a topical retinoid before bedtime. Such a regimen addresses the issues of sebum production, inflammation, bacterial proliferation, and plugged pores that are involved in comedonal and inflammatory acne. However, there are many ways to combine the treatments, and often the best regimen for a particular patient is arrived at by trial and error. Moderate and severe acne. If acne is unresponsive to topical therapy alone or if a patient presents with cysts or scarring, more aggres- Figure 4 The jawline involvement seen in this young woman s acne is characteristic of adult female acne. JUNE 2009 (SUPPLEMENT) CONSULTANT FOR PEDIATRICIANS S9

6 Adolescent Acne: Effective Therapy for a Serious Condition Figure 5 This photograph shows a patient with severe nodulocystic acne before initiation of treatment with isotretinoin. sive treatment is warranted. Treatment options for moderate and severe acne include oral antibiotics, oral contraceptives, spironolactone, isotretinoin, and photodynamic therapy. These therapies are usually used in addition to topical agents. Oral antibiotics. The most common drugs used are tetracyclines (tetracycline chloride, doxycycline, minocycline), trimethoprim/sulfamethoxazole (TMP/SMX), and erythromycin. Cephalexin is sometimes used, with one recent study supporting its efficacy. 14 Of note, the potential for vaginal candidiasis exists with any oral antibiotic therapy and should be considered when contemplating this treatment option, especially given the long-term nature of acne therapy. Doxycycline is often the firstline drug for systemic antibiotic therapy. Minocycline has been shown to be more effective at reducing P acnes on the skin than doxycycline; however, it also has the potential for more severe adverse effects. 11 Doxy- Figure 6 Here, the same patient pictured in Figure 5 is shown after a 6-month course of isotretinoin. S10 CONSULTANT FOR PEDIATRICIANS JUNE 2009 (SUPPLEMENT)

7 Figure 7 Extensive scarring, along with nodulocystic acne lesions, is evident on this patient s back. cycline can cause photosensitivity or nausea and vomiting if not taken with food but is otherwise well tolerated. Minocycline can cause pseudotumor cerebri, blue-gray hyperpigmentation of skin and teeth (with long-term use), lupus, autoimmune hepatitis, and a serum sickness like reaction. Erythromycin is effective in treating acne, but this agent is being used less often because of resistance and the GI sensitivity it induces. It is helpful for patients who cannot tolerate tetracyclines, such as pregnant women or children younger than 8 years. TMP/SMX is usually very effective in the treatment of acne, especially nodulocystic acne but is generally not used as a first-line drug because of the increased risk of severe allergic reactions, including toxic epidermal necrolysis. As with topical antibiotics, bacterial resistance is becoming a serious concern with oral antibiotics. New formulations of antibiotics and the use of low, anti-inflammatory doses may help to curb this growing problem. Antibiotics for acne that are currently in development include azithromycin, lymecycline, and an extended-release minocycline. 10 Systemic treatments for girls only. Spironolactone, a diuretic with antiandrogen effects, is especially useful in girls who have PCOS or acne flares with menses, as well as in the treatment of adult female acne. 15 The latter is seen in young women who may or may not have had acne as a teenager but in whom inflammatory papules and nodules develop along the jaw line, chin, and upper neck in their young adult years (Figure 4). Use of spironolactone must be avoided in patients who are considering becoming pregnant because it can feminize a male fetus. At higher doses, it may also cause hyperkale- JUNE 2009 (SUPPLEMENT) CONSULTANT FOR PEDIATRICIANS S11

8 Adolescent Acne: Effective Therapy for a Serious Condition mia. Typically, the diuretic effects disappear after a few weeks of use. Oral contraceptives may also be used to treat acne in girls. Isotretinoin, a high-dose vitamin A derivative, is recommended for patients with severe, nodular acne, or any level of acne that is recalcitrant and/or physically or emotionally scarring (Figures 5 and 6). 11 Isotretinoin is highly teratogenic; consequently, its use is strictly monitored by the FDA through an online program called ipledge. Other adverse effects of isotretinoin can include dry skin and lips, hair loss, headaches, mood changes, decreased night vision, and musculoskeletal pain. These effects usually resolve after the drug is discontinued. Isotretinoin can elevate levels of triglycerides, total cholesterol, and transaminases, all of which should be monitored during treatment. The typical course of isotretinoin therapy is 5 to 6 months; occasionally, a second course is necessary. Photodynamic therapy is another tool in the anti-acne arsenal. It takes advantage of the photosensitivity of naturally endogenous porphyrins produced by P acnes. Visible light activates the photosensitive porphyrins, which destroy the bacteria. 16 Alternatively, an exogenous porphyrin, aminolevulinic acid (ALA), which is available in a cream formulation, can be applied to the skin before light therapy. ALA is taken up by the pilosebaceous units and, when exposed to blue and red light, it has a phototoxic effect on the follicles. This results in a reduction in sebum production and in the size of the sebaceous glands. 17 Role of diet and natural therapies. At this time, there is little or conflicting evidence about the impact of diet, chemical peels, herbal or alternative therapies on acne. For further information on the role of diet and alternative treatments in acne as well as information on acne medications please refer to the Guidelines of Care for Acne Vulgaris Management established by the American Academy of Dermatology in Management tips to optimize outcomes. In caring for patients with acne, it is important to establish a trusting therapeutic relationship, recognize clues to underlying causes, and initiate prompt treatment to prevent scarring (Figure 7). Writing down an acne treatment plan for each patient encourages adherence. Providing open communication and follow-up appointments helps establish a team approach in which the clinician and the patient work together. If initial treatment is not successful, it is important to validate the patient s feeling of frustration by demonstrating awareness of the psychosocial implications of this disease and by encouraging the use of more potent medications or referring the patient to a dermatologist. REFERENCES: 1. 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