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Therapeutics for the Clinician

Safe and Effective Treatment of Seborrheic

Boni E. Elewski, MD

Seborrheic dermatitis is a common chronic inflam- eborrheic dermatitis, a common skin disorder matory skin disorder that can vary in presentation that typically presents as erythematous plaques from mild to dense, diffuse, adherent S or patches, can vary from mild dandruff to dense, scale. The disorder occurs throughout the world diffuse, adherent scale affecting areas of the head and without racial or geographic predominance; it is trunk where sebaceous glands are prominent, includ- more common in males than females. Its precise ing the , nasolabial folds, chest, , and etiology remains unknown, but the condition is ears. A chronic inflammatory disorder, its precise eti- strongly associated with lipophilic ology remains unknown, though it is associated with yeasts found among the normal skin flora and genetic, environmental, and general factors, as represents a cofactor linked to several risk well as lipophilic Malassezia yeasts.1,2 factors, including T-cell depression, increased In seborrheic dermatitis, plaques typically appear sebum levels, and activation of the alternative as red, flaky, greasy-looking patches of skin; the complement pathway. The goal of treatment amount of flaking and varies from patient is symptom control, with an emphasis on the to patient. Seborrheic dermatitis typically presents as importance of maintaining patient adherence to a condition of the scalp, which is a unique environ- therapy to achieve low rates of recurrence. Avail- ment in humans—warm and dark, and particularly able therapies include , hospitable to infections and infestations introduced agents, immunomodulators, and medicated kera- by fingers, hats, combs, or styling implements.3 Dis- tolytic . Although corticosteroids are tribution is symmetric, commonly presenting in hairy associated with recurrence, they sometimes may areas of the head (ie, scalp, scalp margin, eyebrows, be recommended in combination with antifungal eyelashes, beard, mustache) but also on the forehead agents. Antifungal therapy is considered primary, and in external ear canals; nasolabial folds; and body but some agents are more effective than others folds, including the axillae, navel, groin, and infra- because of their favorable pharmacokinetic pro- mammary and anogenital areas.2 Lesions typically files, high rates of absorption, anti-inflammatory worsen during the winter, while sun exposure during and properties, and vehicle. the warmer months appears to improve the clinical Cutis. 2009;83:333-338. appearance of the disease.4 Scratching and emotional tend to aggravate the condition.5,6

Epidemiology of Seborrheic Dermatitis Accepted for publication April 17, 2009. To emphasize the widespread prevalence of seborrheic From the University of Alabama, Birmingham. dermatitis, some authors have noted that dandruff, Supported by an educational grant from Ortho Dermatologics, the mildest form of seborrheic dermatitis,7 occurs in a division of Ortho-McNeil-Janssen Pharmaceuticals, Inc. 15% to 20% of the population, though it is important Dr. Elewski owns shares of Johnson & Johnson and is a consultant to differentiate between seborrheic dermatitis of the for Ortho Dermatologics. The University of Alabama received a 1 research grant from Ortho Dermatologics. scalp and any scalp flaking, regardless of etiology. In Correspondence: Boni E. Elewski, MD, The Eye Foundation general, the prevalence of seborrheic dermatitis ranges Professional Building, 700 18th St S, EFH 414, Birmingham, AL 35233. from 1% to 3% in the immunocompetent population7

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and greatly increases in the immunocompromised The epidemiology of dermatologic disease rarely population, particularly patients with AIDS.6 has been studied in populations with skin of color, Seborrheic dermatitis is more common in males though the report of one US survey comparing the than females, probably because stimulate most commonly treated dermatologic conditions in sebum production. In general, the condition ini- black and white patients found seborrheic dermatitis tially appears during the teenaged years or 20s, with to be among the top 5 diagnoses in black patients a waxing and waning course throughout adulthood.2 but not white patients.9 Adolescents, young adults, and adults older than 50 years are most commonly affected; however, an Etiology of Seborrheic Dermatitis Australian survey of 1116 children aged 11 days to Dawson10 emphasized that seborrheic dermatitis must 5 years 11 months found the overall prevalence of be viewed as more than a superficial disorder of the seborrheic dermatitis to be 10.0% in boys and 9.5% . It is a condition in which the epi- in girls, suggesting that the condition also is com- dermis is substantially altered by hyperproliferation, mon in early childhood.8 excess intercellular and intracellular lipids, interdigi- Seborrheic dermatitis occurs throughout the tation of the corneal envelope, and . The world in patients of various ethnicities and races. etiology of seborrheic dermatitis appears to depend

Table 1. Seborrheic Dermatitis Risk Factors1,6

Risk Factor Description Lipids and hormones Distribution of lesions on the body corresponds to the distribution of sebaceous glands, with excess sebum found on the scalp, nasolabial folds, chest, eyebrows, and ears

Most common in adolescents and young adults (when sebaceous glands are most active) and adults older than 50 years

Comorbid conditions Parkinson disease

Cranial nerve palsies

Truncal paralyses

Mood disorders

HIV/AIDS

Some cancers

Alcoholic pancreatitis

Down syndrome

Immunologic factors Depressed levels of helper T cells

Reduced phytohemagglutinin, concanavalin A stimulation

Lower antibody titers

Lifestyle factors Poor nutrition

Inadequate hygiene practices

Abbreviation: HIV, human immunodeficiency .

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on 3 factors: secretions, microfloral Treatment of Seborrheic Dermatitis metabolism, and individual susceptibility.10 Many Seborrheic dermatitis is a chronic disease and factors have been cited as possible contributors to the patients should be informed about the risk for relapse, development of seborrheic dermatitis (Table 1). predisposing factors, and the lifetime need for special attention to hygiene. To remove oils and generally Role of Malassezia Species improve the skin, patients should be encouraged to Yeasts of the genus Malassezia (formerly Pityrosporum) cleanse the affected skin often with soap and water. are a normal part of the skin flora yet are associated Patients should engage in outdoor recreation, particu- with many common dermatologic disorders, including larly in the summer, with the goal of improving the tinea (or ) versicolor and Malassezia folliculi- condition through exposure to sunlight, providing tis. Following some debate in the literature evaluating precautions are taken against sun damage.2 if yeasts are of primary pathogenic significance or a secondary phenomenon, it has become clear that Pharmacologic Options lipid-dependent Malassezia yeasts are causal factors The primary goal of therapy for seborrheic dermatitis in the development of seborrheic dermatitis, most is symptom control because, at this time, there is no commonly Malassezia globosa, with its high cure for the disease. Various treatments are used for activity, and Malassezia restricta. These 2 organisms seborrheic dermatitis, including mild corticosteroids, predominate on the scalp of individuals with sebor- antifungal agents, immunomodulators, and medicated rheic dermatitis or dandruff.7,10 Because the disease shampoos.11 Although mild corticosteroids used alone responds to antifungal and Malassezia can be effective in managing symptoms, the disease is counts diminish as the condition improves, it has likely to recur quickly once therapy is stopped. been strongly suggested that yeasts play a role in the Antifungal agents should therefore be considered pathogenesis of seborrheic dermatitis. Genetic and primary therapy.5,12 environmental factors as well as comorbid conditions Because seborrheic dermatitis is a chronic recur- may predispose certain populations to the develop- ring skin disorder, the goal of treatment is the devel- ment of seborrheic dermatitis.2 In general, patients opment of a safe and effective regimen associated with seborrheic dermatitis are thought to have higher with low rates of recurrence.12 Accordingly, treat- Malassezia counts than healthy controls, though some ment should incorporate an antifungal agent that is experts dispute this assumption.1 effective and tolerable to the patient, both to reduce relapse and to promote patient adherence. An opti- Other Risk Factors mal topical agent is one with good penetration that It also has been observed that individuals with central stays on the skin; has anti-inflammatory properties; nervous system disorders appear to be prone to developing and is delivered via a vehicle that enhances penetra- extensive seborrheic dermatitis that often is refractory to tion, provides a healing environment, and sustains treatment. In these cases, it has been hypothesized that the infection results from excessive pooling of sebum caused by immobility, which permits increased growth Table 2. 2 of yeasts. Another confounding factor in the develop- Recommended Treatment Approach ment of seborrheic dermatitis is a compromised immune system. Medications that can induce seborrheic derma- • Start patient on a topical antifungal agent with good titis or cause it to flare include buspirone hydrochloride, minimum inhibitory concentrations against the yeast. chlorpromazine, cimetidine, gold, , halo- peridol, interferon alfa, , methyldopa, , • Additional antifungal assets should include good 6 and thiothixene. penetration and absorption, anti-inflammatory prop- erties, and a vehicle that is able to promote efficacy Diagnosis of Seborrheic Dermatitis by enhancing penetration. Seborrheic dermatitis usually is diagnosed based on a history of waxing and waning severity and the • If the condition has not resolved or improved, add a distribution of involvement on examination. A skin appropriate for the body area infected. biopsy specimen may be needed in patients with exfoliative erythroderma, and fungal culture may be • Using topical as monotherapy is not recom- used to rule out .6 However, the result of mended because steroids do not kill pathogens, so a fungal culture is not always useful in the diagnosis symptoms will recur when steroids are stopped. of seborrheic dermatitis because the pathogen is part of normal skin flora.

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a reservoir of active agent for extended delivery derivatives and , in (Table 2). addition to the , also are available and may be able to reduce the number of Topical Agents Malassezia organisms that colonize treated areas, Among the currently available topical antifun- though the minimum inhibitory concentra- gal agents that have been studied in the treatment of tions (MICs) associated with these drugs are inferior seborrheic dermatitis are , , to other agents discussed here. None of these agents , , , and sertacon- currently is indicated for seborrheic dermatitis.1 azole; of these agents, only ketoconazole, formulated creams such as , which as a , gel, and foam, currently is indicated for is formulated as a cream, gel, ointment, , seborrheic dermatitis. Fluconazole 2% has and foam, and cream, ointment, or been found to be effective in patients with seborrheic lotion are popular therapies for seborrheic derma- dermatitis of the , though this product currently titis, sometimes in combination with .1 is not available in the United States1; ketoconazole Steroids, which target , may be useful also is formulated as a shampoo but is indicated for ancillary therapies if topical antifungal agents have caused by . Because not eradicated the disease. However, high-potency it can reduce the number of Malassezia yeasts on the formulations have been associated with a number of scalp, miconazole may be effective against seborrheic adverse events, including effects on the adrenal cor- dermatitis, either as monotherapy or in combination tex as well as the skin, though low-potency topical with hydrocortisone. formulations can provide quick control of flare-ups A number of comparative studies have evaluated and relief of pruritus.11 the antifungal activity of several azole antifun- Because of their ability to reduce the inflamma- gal agents against Malassezia yeasts. In one study, tory response by inhibiting T lymphocyte activation, 55 strains of 7 Malassezia species were investigated immunomodulators have been used to treat sebor- for in vitro susceptibility to ketoconazole, voricon- rheic dermatitis, though they are indicated only for azole, and itraconazole, as well as terbinafine.13 The . These agents, which are classified as study found that all strains of the Malassezia species topical inhibitors, have been considered were susceptible to the 3 at low concentra- safer than corticosteroids for long-term use6,17; the tions, though with variations depending on the US Food and Drug Administration had mandated a species involved. Strains of M furfur tested with black box warning because of safety concerns rela- terbinafine ranged from highly susceptible to rela- tive to long-term malignancy risk caused by systemic tively resistant.13 Similar results have been reported immunosuppression.17,18 Examples of topical calcineu- by researchers who studied 95 Malassezia isolates to rin inhibitors include ointments 0.03% assess the antifungal activity of ketoconazole, vori- and 0.1% and cream 1%, both indicated conazole, itraconazole, and fluconazole14 and a group as second-line therapy for atopic dermatitis only.6 who studied the antifungal activity of ketoconazole, itraconazole, and fluconazole against 28 strains Other Medications: Shampoos of M furfur.15 Both concluded that all strains of Seborrheic dermatitis commonly is treated with non- M furfur studied were susceptible to all drugs stud- specific agents, some with activity. Chiefly ied, though with some variations.14,15 formulated as shampoos, keratolytic agents include olamine, which has broad-spectrum and . Neither has antifungal antifungal activity as well as an anti-inflammatory activity; they work by causing cornified epithelium effect, has been found to be effective in the treatment to swell, soften, macerate, and desquamate. Avail- of seborrheic dermatitis as a cream with a 1% concen- able as over-the-counter products, such as Denorex®, tration, gel, and shampoo with a 1% concentration, Neutrogena T/Gel®, and P&S® shampoos, these prod- though only the shampoo is indicated for the treat- ucts are widely available and are likely to have been tried ment of seborrheic dermatitis of the scalp.1 However, by most patients before consulting a dermatologist. meta-analyses of clinical trials comparing various Other over-the-counter shampoos, including agents commonly used to treat fungal infections of and sulfide, do have antifun- the foot have shown that ciclopirox is less effective gal activity.1,6 Many of these products are available than azoles or and its cure rates are low.16 over-the-counter, including Head & ® and Another antifungal agent studied for its efficacy Denorex (both ) and Dandrex® and in the treatment of seborrheic dermatitis is metroni- Selsun blue® (both selenium sulfide), and are likely dazole gel, which is indicated for topical treatment to have been used by most patients prior to visiting of inflammatory lesions of rosacea.1 The synthetic a dermatologist. Other antifungal shampoos include

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ciclopirox shampoo 1%, which is indicated for sebor- 180 yeast strains, with MIC values that were con- rheic dermatitis of the scalp, and ketoconazole sham- siderably lower against a variety of strains poo 2%, which is indicated for tinea versicolor. than either comparator agent.21 Other reports have found the in vitro activity of against Sertaconazole: Effective Treatment of many causative organisms associated with fungal Seborrheic Dermatitis infections to be higher than or comparable with Sertaconazole nitrate cream 2%, indicated for the other azoles, including ketoconazole, , treatment of tinea pedis in the United States, is an miconazole, , and clotrimazole.22,23 available option for the treatment of seborrheic der- Clinical Studies—Two European studies evaluated matitis. A broad-spectrum antifungal agent with anti- the efficacy and safety of sertaconazole in the treat- inflammatory and antipruritic properties, sertaconazole ment of seborrheic dermatitis.19,24 In a 1994 double- has been shown in controlled studies in Europe to be a blind randomized trial, sertaconazole gel 2% applied safe and effective treatment of seborrheic dermatitis.19 once daily every 3 days for 4 weeks was used to treat Study—In a study of the phar- seborrheic dermatitis of the scalp in 15 men and macokinetics and tolerance of sertaconazole after women and was compared with placebo.19 Results repeated administration, researchers determined that showed sertaconazole had a substantial decrease in the drug is well-tolerated both locally and systemi- the severity of the clinical signs of pruritus and des- cally.20 The absorption rate of the drug was both quamation as well as an overall decrease in derma- rapid and long lasting, reaching values of 50% titis. In addition, of participants with severe disease between 2 and 4 hours after administration with at baseline, those treated with sertaconazole showed high absorption (72%) in the stratum corneum considerable improvement, whereas those treated 24 hours after administration. Percutaneous absorp- with placebo showed no clinical improvement.19 tion following topical administration was low, with In a 1997 double-blind, randomized, parallel- no trace of drug detected in blood or urine samples.20 group study of sertaconazole gel 2% versus keto- In Vitro Studies—A comparative study of the conazole gel 2% used every 3 days for 28 days in antifungal activity of the azoles sertaconazole and 60 males and females with seborrheic dermatitis of bifonazole and the allylamine terbinafine mea- the scalp, 28-day therapy with sertaconazole resulted sured MIC values for all 3 agents against a variety in considerable improvement in the symptoms of of yeasts and . The results demon- desquamation and pruritus and was clinically supe- strated that sertaconazole was statistically more rior to ketoconazole, an established reference drug. active than bifonazole and terbinafine against No patients withdrew from the trial because of

Not Available Online

Improvement in symp- toms of desquama- tion and pruritus after treatment with serta- conazole gel 2% or ketoconazole gel 2%. Reprinted with permis- sion from Ferrer Group Research Centre.25

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adverse events, and the researchers concluded that 12. Gupta AK, Kogan N. : current sertaconazole may be considered an effective treat- treatment practices. Expert Opin Pharmacother. 2004;5: ment of seborrheic dermatitis.24 The Figure provides 1755-1765. a graphic illustration of symptomatic findings.25 13. Gupta AK, Kohli Y, Li A, et al. In vitro susceptibility of the seven Malassezia species to ketoconazole, vori- Conclusion conazole, itraconazole, and terbinafine. Br J Dermatol. Seborrheic dermatitis is an extremely common and 2000;142:758-765. recurrent dermatitis presenting in individuals of var- 14. Miranda KC, de Araujo CR, Costa CR, et al. Antifungal ied ages and ethnicities. Treatment traditionally has activities of azole agents against the Malassezia species. Int involved antifungal agents, alone or in combination J Antimicrob Agents. 2007;29:281-284. with corticosteroids, but there has been a continu- 15. Zissova LG, Kantarjiev TB, Kuzmanov AH. Drug suscep- ing need for additional effective nonsteroidal topical tibility testing of Malassezia furfur strains to antifungal therapies. Because of its demonstrated broad-spectrum agents. Folia Med (Plovdiv). 2001;43:10-12. antifungal activity against yeasts and dermatophytes, 16. Crawford F, Hollis S. Topical treatments for fungal infec- including Malassezia species, as well as its anti- tions of the skin and nails of the foot. Cochrane Database inflammatory and antipruritic properties, sertaconazole Syst Rev. 2007;(3):CD001434. can be considered a promising nonsteroidal agent for 17. Spergel JM, Leung DY. Safety of topical calcineurin the topical treatment of seborrheic dermatitis. inhibitors in atopic dermatitis: evaluation of the evidence. Curr Rep. 2006;6:270-274. Acknowledgment—Editorial services provided by 18. Ring J, Möhrenschlager M, Henkel V. The US FDA ‘black Ann Braden Johnson, PhD, and Medisys Health box’ warning for topical calcineurin inhibitors: an ongo- Communications, LLC. ing controversy. Drug Saf. 2008;31:185-198. 19. Alsina M, Zemba C. Sertaconazol en la dermatitis sebor- References reica del cuero cabelludo. Med Cut I L A. 1994;22:111-115. 1. Gupta AK, Bluhm R. Seborrheic dermatitis. J Eur Acad Cited by: Torres J, Márquez M, Camps F. Sertaconazole in Dermatol Venereol. 2004;18:13-26. the treatment of mycoses: from to gynecol- 2. Johnson BA, Nunley JR. Treatment of seborrheic derma- ogy. Int J Gynaecol Obstet. 2000;71(suppl 1):S3-S20. titis. Am Fam Physician. 2000;61:2703-2710, 2713-2714. 20. Farré M, Ugena B, Badenas JM, et al. Pharmacokinetics 3. Grimalt R. A practical guide to scalp disorders. J Investig and tolerance of sertaconazole in man after repeated Dermatol Symp Proc. 2007;12:10-14. percutaneous administration. Arzneimittelforschung. 4. Gupta AK, Madzia SE, Batra R. Etiology and management 1992;42:752-754. of seborrheic dermatitis. Dermatology. 2004;208:89-93. 21. Carillo-Muñoz AJ, Tur-Tur C. Comparative study of 5. Faergemann J. Management of seborrheic dermatitis and antifungal activity of sertaconazole, terbinafine, and pityriasis versicolor. Am J Clin Dermatol. 2000;1:75-80. bifonazole against clinical isolates of Candida spp, 6. Selden S. Seborrheic dermatitis. Emedicine [serial online]. Cryptococcus neoformans and dermatophytes. Chemotherapy. http://www.emedicine.com/derm/topic396.htm. Updated 1997;43:387-392. March 10, 2009. Accessed May 12, 2009. 22. Carrillo-Muñoz AJ, Torres-Rodriguez JM. In-vitro anti- 7. Gupta AK, Batra R, Bluhm R, et al. Skin diseases asso- fungal activity of sertaconazole, econazole, and bifonazole ciated with Malassezia species. J Am Acad Dermatol. against Candida spp. J Antimicrob Chemother. 1995;36: 2004;51:785-798. 713-716. 8. Foley P, Zuo Y, Plunkett A, et al. The frequency of 23. Palacin C, Sacristán A, Ortiz JA. In vitro comparative common skin conditions in preschool-aged children in study of the fungistatic and fungicidal activity of serta- Australia: seborrheic dermatitis and pityriasis capitis conazole and other against . (). Arch Dermatol. 2003;139:318-322. Arzneimittelforschung. 1992;42:711-714. 9. Alexis AF, Sergay AB, Taylor SC. Common dermatologic 24. Szlachcic A, Fillat O, Herrero E, et al. Eficacia y seguridad disorders in skin of color: a comparative practice survey. de Sertaconazol gel al 2% vs Ketoconazol gel al 2% en el Cutis. 2007;80:387-394. tratamiento de la dermatitis seborreica del cuero cabel- 10. Dawson TL Jr. Malassezia globosa and restricta: break- ludo. XXVI Congreso Nacional de Dermatología. 29-31 through understanding of the etiology and treatment of mayo 1997. Benalmádena, Málaga. Cited by: Torres J, dandruff and seborrheic dermatitis through whole-genome Márquez M, Camps F. Sertaconazole in the treatment of analysis. J Investig Dermatol Symp Proc. 2007;12:15-19. mycoses: from dermatology to gynecology. Int J Gynaecol 11. Elewski BE, Abramovits W, Kempers S, et al. A novel Obstet. 2000;71(suppl 1):S3-S20. foam formulation of ketoconazole 2% for the treatment 25. Ferrer Group Research Centre. Sertaconazole Product of seborrheic dermatitis on multiple body regions. J Drugs Monograph. Madrid, Spain: Content’Ed Net Dermatol. 2007;6:1001-1008. Communications SL; 2006.

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