How To Treat Teenage Acne

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1 New insights into adolescent acne Wynnis L. Tom and Victoria R. Barrio Department of Pediatrics and Medicine (Dermatology), University of California, San Diego, California, USA Correspondence to Victoria R. Barrio, MD, 8010 Frost Street, Suite 602, San Diego, CA 92123, USA Tel: x4825; Current Opinion in Pediatrics 2008, 20: Purpose of review Acne vulgaris remains one of the most common conditions affecting adolescents. The pediatric practitioner is the first to evaluate adolescent acne, making familiarity with the condition and its management essential. This review covers some of the recent literature regarding acne to help practitioners stay current on the issues regarding this topic. Recent findings The pathogenesis of acne is multifactorial and complex, but recent advances in molecular genetics have provided additional information on the actions of Proprionibacterium acnes. Nutritional studies have reevaluated a possible role for diet and lifestyle factors in acne development. Many therapies are available to control acne and to limit associated scarring. Their appropriate use requires an understanding of not only the benefits but also the possible risks and adverse effects involved. Recent concerns regarding the use of antibiotics and isotretinoin will be addressed. Summary This study reviews the recent literature regarding teenage acne, focusing on pathogenesis, associations, and controversies and considerations in therapy. Keywords acne, diet, propionibacterium, therapeutic concerns Curr Opin Pediatr 20: ß 2008 Wolters Kluwer Health Lippincott Williams & Wilkins Introduction Acne vulgaris is the most common skin disease affecting adolescents, with prevalence rates of 70 87% [1]. It can have profound psychosocial consequences and severe disease can leave permanent scarring [2,3]. Smolinski and Yan [4] reviewed mediators of acne and treatments in this journal in This review will discuss molecular studies on Proprionibacterium acnes, effects of diet and lifestyle factors, and updates on therapy that have been published since. Pathogenesis and molecular genetics Clinically, adolescent acne consists of a combination of noninflammatory (open and closed comedones) and inflammatory (papules, pustules, and nodules) lesions. The pathogenesis of acne is thought to involve multiple interrelated factors and events [5]. When puberty comes, an increase in androgen production leads to increased sebum production. Abnormal follicular cornification and desquamation causes occlusion of the pilosebaceous duct. As a result, sebum is trapped, resulting in open and closed comedone formation. P. acnes, a normal anaerobic resident of the skin surface, colonizes the occluded pilosebaceous follicles and breaks down sebum to free fatty acids and peptides. An inflammatory response to the bacterium and these metabolic byproducts leads to formation of papules, pustules, and nodules [5,6]. Recent molecular genetic studies have allowed complete sequencing of the P. acnes genome. The genome includes lipases that give the bacterium the ability to breakdown sebum, heat-shock/stress proteins that lead to cytokine production and inflammation, and enzymes to produce porphyrins that induce neutrophil chemokine production and accelerated oxidation of squalene in sebum for comedogenesis. Genomic sequencing has also suggested additional novel ways in which the bacterium may act in a host with acne, such as expressing genes for polysaccharides and lipoglycan that may provide a protective barrier (biofilm) against host defenses [7,8]. This molecular information also provides a means to design more specific therapies. Investigators in particular are studying the sialidases, surface enzymes that allow the bacterium to adhere to sebocytes and to produce its energy source. Immunization with recombinant sialidase reduced the amount of P. acnes-induced inflammation in a mouse model [9 ]. Further translational research is ß 2008 Wolters Kluwer Health Lippincott Williams & Wilkins

2 New insights into adolescent acne Tom and Barrio 437 needed, but targeted therapies may be available in the future for acne. Dietary and lifestyle factors: relationship to acne The significance of diet in the development of acne is an issue long debated. Parents and their affected children often ask if foods are a culprit; recent surveys of adolescents found that as many as 62 72% believe that diet is a contributing factor [10,11]. Despite strong lay beliefs, the predominant teaching in medicine is that diet plays a minimal role in acne. This is based on small trials conducted in the 1960s and 1970s that found that preparedchocolate bars, peanuts, and other blamed foods did not cause flares of acne [12,13]. These studies have since received criticism for their design and short follow-up. In recent years, the increased emphasis on nutrition and health has prompted investigators to again tackle this difficult subject. Milk and dairy Several studies at the Harvard School of Public Health have focused on the role of dairy intake in acne pathogenesis. Adebamowo et al. [14] retrospectively analyzed questionnaires completed by nurses. They found increased self-reported rates of adolescent acne with increased consumption of milk and milk-containing foods (instant breakfast drink, cottage cheese, and cream cheese) in the teenage years. Skim milk had a stronger association than low-fat or whole milk. The study, however, relied on remote recall by the now-adult individuals. Subsequently, the group prospectively examined the effects of dietary intake in the children of these women (9039 girls and 7843 boys, age 9 15 years). For girls, greater amounts of milk consumption, regardless of fat content, was associated with a higher prevalence of acne. For boys, only skim milk (not whole or low-fat milk) had a positive association [15,16 ]. On the basis of these results, the authors speculate that the nonfat portion of milk contains hormones and bioactive molecules, such as androgens, progesterone, and insulin growth factor-1 (IGF-1), that can have an acnestimulating effect. These cohort studies, however, can only suggest correlation but not causation. Family history of acne and other possible confounding factors such as steroid use were not included in the analysis. In addition, though the children graded their amount of acne on a five-category scale, investigators did not examine if the amount of milk intake correlated with acne severity. Further study is therefore needed via a prospective trial with controlled dairy intake and standardized physician and individual acne assessments. It can be pointed out to adolescents and parents, though, that all three studies found no association of acne with chocolate, soda, french fries, or pizza foods that often are blamed as causative agents. Dietary glycemic load Multiple rural populations have been noted to have little to no acne in childhood and adolescence [17]. Differences in dietary glycemic load have been suggested to account for this difference [18]. High-glycemic-load (HGL) diets, such as Western diets, can elevate blood insulin and IGF- 1 levels acutely and chronically. These hormones stimulate adrenal and gonadal androgen production, leading to increased sebum production and perhaps, to acne. A recent prospective, controlled 12-week trial tested this theory. Forty-three men, years of age and with mild-to-moderate acne were assigned to a low-glycemicload diet (LGL) or a conventional HGL diet. Those on the LGL diet showed a greater decrease in number of acne lesions compared with those on the HGL diet (21.9 vs. 13.8%, P ¼ 0.01). However, the LGL group also had a significant reduction in weight and BMI [19,20]. Weight loss is known to decrease circulating androgen and insulin levels; thus, whether the skin improvements were due to the dietary differences or the concomitant weight reduction is unclear. Other exogenous factors such as hygiene and skin care, sweat/exercise, and psychological stress have also come under scientific scrutiny. Hygiene and skin care practices Patients often believe that acne is caused by dirty skin and some resort to excessive washing. Among medical professionals, it is believed that too much washing may actually worsen acne. Choi et al. [21] examined the role of face washing in an investigator-blinded, randomized, controlled study. Male students with mild-to-moderate acne were randomized to one of three groups: washing once daily, twice daily, or four times a day for 6 weeks with the same mild cleanser. Students who washed their face twice daily fared better, with mild worsening of those who washed once daily, and no aggravation of the acne in those who washed four times a day. Thus, frequent face washing may not be detrimental, but the general twice daily recommendation appears best. Sweating and exercise A small prospective, investigator-blinded study of men with truncal acne assessed the short-term effects of exercise-induced sweating on acne [22 ]. Twenty-three individuals were randomized to one of three groups: no exercise, exercising 5 days per week and showering within 1 h of exercise, and exercising 5 days per week and waiting at least 4 h to shower after exercise. After 2 weeks, no statistically significant differences in acne were noted among or within the three groups, although

3 438 Dermatology there was a trend toward increase in acne lesion counts with the two exercise groups. Larger studies are needed to clarify if exercise-induced sweating causes any aggravation of acne. Stress As mentioned earlier, acne can cause significant psychological distress. Psychological stress is also thought to exacerbate acne but few objective data have been available until recently. Two independent groups of researchers studied high-school and university students and found that increased stress levels during examination periods, as measured by validated scales, correlated with increased acne severity [23,24 ]. The mechanism by which stress negatively impacts on acne remains to be elucidated, but could include increased hormone levels or inflammation-inducing neuropeptide production. Yosipovitch et al. [24 ] had postulated that increased sebum production could be a factor. However, although they found a correlation between stress and acne, there was no association with increased sebum production during times of increased stress. Updates on treatment An armamentarium of therapies is available for the treatment of acne. Smolinski and Yan [4] reviewed the major classes of medications and their mechanisms of action in this journal. Evidence-based guidelines are also available to help the clinician, such as those established by the Global Alliance to Improve Outcomes in Acne and more recently, by the American Academy of Dermatology [25,26 ]. Table 1 summarizes therapy utilizing these recommendations [27]. Treatment is primarily based on the type of skin lesions present and the severity of the condition. In addition, patient preferences and likelihood of compliance also influence the selection of particular therapies. Not yet in these algorithms are novel agents. These include new classes of combined topical therapies, such as clindamycin-tretinoin and adapalene-benzoyl peroxide. Simpler treatment regimens may allow increased compliance in adolescents. Another newly approved agent is dapsone gel. Oral dapsone is a sulfone with antimicrobial and anti-inflammatory properties, and a topical formulation has been found to help particularly with inflammatory acne lesions [28 ]. This may be an alternative to topical antibiotic therapies, for which there is growing bacterial resistance. Using the topical and oral therapies in Table 1, the majority of cases of acne can be well controlled. For refractory cases, individuals seeking alternative methods, or for treatment of acne-related scarring, laser therapies and cosmetic measures can be considered. Gold [29 ] provided a recent update on lasers, light sources, and photodynamic therapy for acne. A newly published evidence-based review of these techniques found that they can give short-term improvement, with photodynamic therapy currently having the most consistent outcomes (up to 68% improvement) [30 ]. In addition to understanding the benefits of each treatment, knowledge of side effects and risks is also key to their use. Several adverse effects with systemic therapies have been proposed in the last few years and they warrant investigation and understanding. Oral antibiotic risks The tetracycline class of antibiotics is most often used in acne therapy. Choosing the proper tetracycline involves weighing the risks and benefits for each patient. A recent study showed tetracycline to be associated with an increased risk of hepatotoxicity with current use [odds ratio (OR) 3.70, 95% confidence interval (CI) ] and past use (OR 2.72, 95% CI ), whereas doxycycline did not [31 ]. Drug-induced lupus erythematosus from antibiotics is very rare, but it is an Table 1 Therapeutic options for acne Mild Comedonal papular/pustular Moderate papular/pustular Moderate nodular Severe nodular/cystic First-line therapies Topical retinoid Topical retinoid BPO or topical antibiotic/bpo Alternatives Salicylic acid Sulfur/sodium sulfacetamide Alternatives for female patients BPO Azelaic acid Azelaic acid Topical retinoid þ oral antibiotic þ BPO or Hormonal therapy þ topical retinoid BPO or Topical retinoid þ oral antibiotic þ BPO or Oral isotretinoin Hormonal therapy þ topical retinoid BPO or topical antibiotic/bpo; oral isotretinoin if refractory Oral isotretinoin Oral antibiotic þ topical retinoid þ BPO or Hormonal therapy þ topical retinoid BPO or Maintenance therapy (all degrees of severity) ¼ topical retinoid BPO or. BPO, benzoyl peroxide. Adapted from [27].

4 New insights into adolescent acne Tom and Barrio 439 association of which to be aware when treating adolescents for acne. In a large retrospective cohort of patients using tetracyclines for acne, minocycline was found to have a hazard ratio of 3.11 (95% CI ), whereas the other tetracyclines did not have an association. This risk increased with longer treatment duration but even 6 months or less of exposure was associated with lupus [32 ]. A few years ago concern was raised for an association of systemic antibiotic use with an increased risk of breast cancer in women. A case control study by Velicer et al. [33] showed that increased cumulative days of antibiotic use were associated with an increased cancer risk (OR 2.07 if >1001 days of use). Class of antibiotic did not matter in this study. The association persisted after adjusting for factors known to increase breast cancer risk (older age, earlier age of menarche, family history, etc.). The study, however, did not control for medications other than hormone use that could potentially affect cancer risk. Other studies have found no or weaker associations. Friedman et al. [34] looked at 2.1 million women, age 20 and older, and found a much smaller hazard ratio (1.14, 95% CI ) with antibiotic use and no dosedependent effect was seen. The tetracyclines were the only antibiotic group that was associated weakly (95% CI ). Overall, the data show that there may be a small association between antibiotic use and breast cancer risk but whether it is a direct cause is unknown at this time. It is possible that it is the underlying disease requiring antibiotics that are associated with this risk. In the interim, systemic antibiotics should not be eliminated from the acne treatment regimen but limited courses are advised for the other well documented reasons discussed earlier, that is, bacterial resistance and adverse effects with continued use. Once improvement is achieved after several months of therapy, oral antibiotics should be stopped and maintenance with topical retinoids with or without topical antibiotics should ensue. Concerns regarding isotretinoin Isotretinoin is a systemic retinoid indicated for the treatment for severe, nodulocystic acne and additionally, offlabel is used for acne that is scarring or refractory to conventional therapy. It affects all of the causative factors involved in acne pathogenesis (sebum production, comedogenesis, colonization with P. acnes, inflammatory response). Because of its side effect profile and need for pregnancy monitoring, it is mainly prescribed by dermatologists. Yet given the number of adolescents who receive this treatment, familiarity on the part of the pediatrician is needed. Isotretinoin administration requires laboratory monitoring. A large retrospective cohort study found that associated abnormalities are mainly triglycerides (44% became elevated), total cholesterol level (31%), and transaminase level (11%). These changes were generally transient and reversible. Hematologic abnormalities were uncommon [35]. A frequent concern that parents have is the association with depression. Studies to date, including a large metaanalysis, have not found a significant correlation of isotretinoin with depressive symptoms or mood changes [36,37]. Many experts still recommend close monitoring for any signs or symptoms of mood alteration. Long-term, several-year use of isotretinoin in individuals with disorders of cornification has been reported to cause bony abnormalities, including diffuse hyperostosis of the spine. The effects of short-term courses are less clear. A multicenter, prospective, open-label trial assessed the effect of a single standard course of isotretinoin for severe, recalcitrant acne in 217 adolescents. No significant change in bone mineral density at the lumbar spine or hip and no cases of bony hyperostosis were seen [38]. Thus, the standard 5 6 month treatment course used for severe acne does not appear to have detrimental effects on the bone of adolescents. Another recent concern is a possible association of isotretinoin with inflammatory bowel disease. Evaluation of adverse events filed to the Food and Drug Administration from 1997 to 2002 showed 85 associated cases, with four cases considered highly probable and 58 probable [39]. Whether isotretinoin is causative or unmasking disease is unclear, but gastrointestinal symptoms should raise the need for further workup. Conclusion Research in the field of acne continues on many fronts. Molecular and translational studies may allow targeted therapies in the future in the form of vaccines. Despite improved clinical trials assessing the relationship of dietary components and acne, a direct effect has not been confirmed. Carefully controlled studies are needed to determine the independent effects of milk/dairy, LGL diets, and weight loss. Both a substantial amount of benefit and an ability to comply with a particular diet need to be demonstrated in order to justify such a change. Particularly with foods that provide important nutrients (i.e. milk), supplemental sources would be needed for growing adolescents. Larger studies will help to further determine the interplay of lifestyle factors and acne. Finally, old and new acne therapies not only have demonstrated efficacy but also adverse effects of which to be aware.

5 440 Dermatology References and recommended reading Papers of particular interest, published within the annual period of review, have been highlighted as: of special interest of outstanding interest Additional references related to this topic can also be found in the Current World Literature section in this issue (p. 508). 1 Dreno B, Poli F. Epidemiology of acne. Dermatology 2003; 206: Pearl A, Arroll B, Lello J, Birchall NM. The impact of acne: a study of adolescents attitudes, perception and knowledge. N Z Med J 1998; 111: Kilkenny M, Merlin K, Plunkett A, Marks R. The prevalence of common skin conditions in Australian school students: 3. Acne vulgaris. Br J Dermatol 1998; 139: Smolinski KN, Yan AC. Acne update: Curr Opin Pediatr 2004; 16: Webster GF. The pathophysiology of acne. Cutis 2005; 76 (Suppl): Bergfeld WF. The pathophysiology of acne vulgaris in children and adolescents, Part 1. Cutis 2004; 74: Rosen T. The Propionibacterium acne genome: from the laboratory to the clinic. J Drugs Dermatol 2007; 6: This study describes the relevance of the Propionibacterium genome to the patient with acne. 8 Bruggemann H, Henne A, Hoster F, et al. The complete genome sequence of Propionibacterium acnes, commensal of the skin. Science 2004; 305: Nakatsuji T, Liu YT, Huang CP, et al. Vaccination targeting a surface sialidase of P. acnes: implications for new treatment of acne vulgaris. PLoS ONE 2008; 3:e1551. This paper describes a mouse model for what may be a new treatment to prevent the development of acne. 10 Al-Hoqail IA. Knowledge, beliefs and perception of youth toward acne vulgaris. Saudi Med J 2003; 24: Rigopoulos D, Gregoriou S, Ifandi A, et al. Coping with acne: beliefs and perceptions in a sample of secondary school Greek pupils. J Eur Acad Dermatol Venereol 2007; 21: Fulton JE Jr, Plewig G, Kligman AM. Effect of chocolate on acne vulgaris. JAMA 1969; 210: Anderson PC. Foods as the cause of acne. Am Fam Phys 1971; 3: Adebamowo CA, Spiegelman D, Danby F, et al. High school dietary dairy intake and teenage acne. J Am Acad Dermatol 2005; 52: Adebamowo CA, Spiegelman D, Berkey CS, et al. Milk consumption and acne in adolescent girls. Dermatol Online J 2006; 12:1. 16 Adebamowo CA, Spiegelman D, Berkey CS, et al. Milk consumption and acne in teenaged boys. J Am Acad Dermatol 2008; 58: This study looks at the relationship of milk consumption and development of acne in a male teenage population. This is one of the more recent attempts to answer the question of whether diet is related to the development of acne. 17 Cordain L. Implications for the role of diet in acne. Semin Cutan Med Surg 2005; 24: Cordain L, Lindeberg S, Hurtado M, et al. Acne vulgaris: a disease of Western civilization. Arch Dermatol 2002; 138: Smith RN, Man NJ, Braue A, et al. The effect of a high-protein, low glycemicload diet versus a conventional, high-glycemic-load diet on biochemical parameters associated with acne vulgaris: a randomized, investigatormasked, controlled trial. J Am Acad Dermatol 2007; 57: This is the first randomized, controlled trial of the effects of dietary glycemic load on acne. 20 Smith RN, Mann NJ, Braue A, et al. A low-glycemic-load diet improves symptoms in acne vulgaris patients: a randomized controlled trial. Am J Clin Nutr 2007; 86: Choi JM, Lew VK, Kimbal AB. A single-blinded, randomized, controlled clinical trial evaluating the effect of face washing on acne vulgaris. Pediatr Dermatol 2006; 23: Short RW, Agredano YZ, Choi JM, Kimball AB. A single blinded, randomized pilot study o evaluate the effect of exercise-induced sweat on truncal acne. Pediatr Dermatol 2008; 25: This small pilot study is one of the first to address the issue of the effect of sweat on severity of truncal acne. 23 Chiu A, Chon SY, Kimball AB. The response of skin disease to stress: changes in the severity of acne vulgaris as affected by examination stress. Arch Dermatol 2003; 139: Yosipovitch G, Tang M, Dawn AG, et al. Study of psychological stress, sebum production and acne vulgaris in adolescents. Acta Derm Venereol 2007; 87: This study looks at the correlation of stress and acne. This negative study excludes sebum production as a cause. 25 Gollnick H, Cunliffe W, Berson D, et al. Management of acne: a report from a Global Alliance to Improve Outcomes in Acne. J Am Acad Dermatol 2003; 49 (Suppl):S1 S Strauss JS, Krowchuk DP, Leyen JJ, et al. Guidelines of care for acne vulgaris management. J Am Acad Dermatol 2007; 56: An up-to-date consensus statement and review of acne management. 27 Zaenglein AL, Thiboutot DM. Expert committee recommendations for acne management. Pediatrics 2006; 118: Lucky AW, Maloney JM, Roberts J, et al. Dapsone gel 5% for the treatment of acne vulgaris: safety and efficacy of long-term (1 year) treatment. J Drugs Dermatol 2007; 6: The results of this study show long-term safety for a novel treatment for acne. 29 Gold MH. Acne vulgaris: lasers, light sources and photodynamic therapy: an update Expert Rev Anti Infect Ther 2007; 5: This review summarizes information on alternatives to traditional medication-based treatment of acne. 30 Haedersdal M, Togsverd-Bo K, Wulf HC. Evidence-based review of lasers, light sources and photodynamic therapy in the treatment of acne vulgaris. J Eur Acad Dermatol Venereol 2008; 22: This is a comprehensive evidence-based review of light and laser therapy for acne treatment. 31 Heaton PC, Fenwick SR, Brewer DE. Association between tetracycline or doxycycline and hepatotoxicity: a population based case-control study. J Clin Pharm Ther 2007; 32: Case control study looking at risk of hepatotoxicity with current and former tetracycline use. 32 Margolis DJ, Hoffstad O, Bilker W. Association or lack of association between tetracycline class antibiotics used for acne vulgaris and lupus erythematosus. Br J Dermatol 2007; 157: This retrospective cohort study teased out the hazard ratio of different antibiotics for the development of drug-associated lupus. 33 Velicer CM, Heckbert SR, Lampe JW, et al. Antibiotic use in relation to the risk of breast cancer. JAMA 2004; 291: Friedman GD, Oestreicher N, Chan J, et al. Antibiotics and risk of breast cancer: up to 9 years of follow-up of 2.1 million women. Cancer Epidemiol Biomarkers Prev 2006; 15: Zane LT, Leyden WA, Marqueling AL, Manos MM. A population-based analysis of laboratory abnormalities during isotretinoin therapy of acne vulgaris. Arch Dermatol 2006; 142: Marqueling AL, Zane LT. Depression and suicidal behavior in acne patients treated with isotretinoin: a systematic review. Semin Cutan Med Surg 2005; 24: Jick SS, Kremers HM, Vasilakis-Scaramozza C. Isotretinoin use and risk of depression, psychotic symptoms, suicide, and attempted suicide. 1. Arch Dermatol 2000; 136: DiGiovanna JJ, Langman CB, Tschen EH, et al. Effect of a single course of isotretinoin therapy on bone mineral density in adolescent patients with severe, recalcitrant, nodular acne. J Am Acad Dermatol 2004; 51: Reddy D, Siegel CA, Sands BE, Kane S. Possible association between isotretinoin and inflammatory bowel disease. Am J Gastroenterol 2006; 101: