2005 ANNUAL SCIENTIFIC MEETING 181 MALASSEZIA AND SEBORRHEIC DERMATITIS: ETIOLOGY AND TREATMENT Thomas L. Dawson, Jr., Ph.D. Beauty Care Technology Division, The Procter & Gamble Company, Cincinnati, Ohio, USA Etiologic Mechanism or Dandruff and Seborrheic Dermatitis (D/SD) Dandruff and seborrheic dermatitis are chronic clinical scalp conditions affecting greater than 50% of the population, the primary symptom or which is visibly excessive scalp scaling. Seborrheic dermatitis is a more severe disorder which includes increased desquamation or areas other than the scalp and visible inflammation1• D/SD are more than just superficial disorders of the stratum comeum, including alteration of the epidermis with hyperproliferation, excess intercel\ular and intracellular lipids, interdigitation of the corneal envelope, and parakeratosis1·1. Combination of several recent lines of investigation points out a novel mechanism for the etiology of DISD. Scalp Malassezia degrade sebum, freeing multiple fatty acids from triglycerides. They consume the specific satw"ated fatty acids necessary for their proliferation, leaving behind the unsaturated fatty acids. The free fatty acids then penetrate the scalp skin, and in susceptible individuals breach the skins barrier function and induce a hyperproliferative response4• The role or Sebum Hwnan sebaceous glands (SG) are found over the entire skin surface (except the palms of the hands and soles of the feet), but seburn secretion is highest on the scalp, face, chest, and back5• Seburn is produced under hormonal control, with SG active at birth under the control of maternal androgens. They quickly reduce in size and sebum Mnlnssezia Mediated Degradation of Human Sebum -!lfl&llill..._...__. i.. ................ ,.J.-.,...,J..�11,o-.1��-� , J J 4 111 • • •1111nu1111u•1ta11a production until puberty. As puberty begins the SG activate, this time under the control of circulating androgens. The sebum secretion rate increases throughout the teens, remains steady through the twenties and thirties, then lessens with age1·6. D/SD show a strong temporal correlation with SG activity, following the pattern of early cradle cap, low incidence until puberty, increasing incidence through the teens, 2nd and 3rd decades, then declining1·0. Human sebum is a complex mixture of triglycerides. fatty acids, wax esters, sterol esters, cholesterol, cholesterol esters, and squalene. As the sebum is secreted, it consists primarily of triglycerides and esters, which are broken down by commensal microbes into diglycerides, monoglycerides, and free fatty acids. Human sebum contains both saturated and unsaturated fatty acids, with a preponderance of unsaturates. The fatty acid chain lengths of human sebum vary considerably, but are predominantly 16 and 18 carbons. The role of specific fatty acids of human sebum becomes apparent when we examine the metabolism of Malassezia. Role or Malassezia Over one hundred years ago, Malassez implicated the yeast Malassezia in the etiology of dandruff". While Malassezia are not numerically correlated to dandruff and seborrheic dermatitis (D/SD), recent evidence strongly supports their causal role4• This evidence includes the effectiveness of multiple chemical entities whose sole common mechanism or action is antifungal activity, as well as the very distinct numerical correlation of reduction in severity with reduction of Malassezia numbers9, and there is now general a,reement1 as to their causal role00. Interestingly, Malassezia have a very specific taste for individual fatty acids 1. :_ The Malassezia lipases are non-specific and degrade any available triglycerides (Fig. 2). The saturated fatty acids are consumed, and the abundant unsaturates, predominantly oleic (Cl8:1�9) and palmitoleic (Cl6:1�9) are left on the skin (Fig. 2, Fig.3). Recently, novel molecular methods have overcome the difficulties presented by culture or Malassezia, and the specific Malassezia species present on human scalp have been elucidated4.I , and the most common species on human scalp are M. restricta and M. g/obosa. The Role of Individual Susceptibility It has now been shown that a representative Malassezia fatty acid metabolite ( oleic acid) is able to induce scalp flaking in susceptible individuals, but not in non-susceptible individuals (Fig.2)u. The Malassezia most commonly found on human scalp, M. globosa and M. restricta, non-specifically degrade human seburn and release unsaturated fatty acids like oleic and palmitoleic onto the scalp (Fig. 1). This strongly supports that dandruff sufferers display an underlying defect in permeability barrier function that renders them more susceptible to fatty acid-induced barrier disruption. In this regard, dandruff-susceptibility may be determined, at least in part, by a defect in Role or lndlvldual Sensitivity i.o I 0.5: Flakln1 o.o 1 olelc ,. - + - +

182 JOURNAL OF COSMETIC SCIENCE basal permeability barrier function as is well established in the case of atopic dermatitis. This also explains the lack of a simple quantitative relationship between Malassezia species and D/SD presence or severity. Integrating all available data, it appears that dandruff and seborrheic dermatitis most likely results from three specific etiologic factors: 1 - Individual susceptibility 2 - Sebaceous secretion and 3 - Malassezia fungi. Individual susceptibility is most likely related to basal permeability barrier function, immune system function, and possibly even the overall microbial community. Treatment As D/SD are the result of sebum secretion, fungal activity, and innate susceptibility, the easiest, safest, and most effective treatments remain anti-fungal shampoos. The most common anti-fungal materials in use today are pyrithione zinc (ZPT), selenium sulfide (SexSy), ketoconazole, and to a lesser extent climbazole and octopirox. As rinse off products leave only small amounts of active material, in the microgram per square centimeter range, much caution must be taken with pharmacology. The deposition profile must be adequate for the materials potency, the residual material must be deposited in the appropriate location in a bioavailable manner, and the product must be cosmetically appealing enough for the patient to continue use. Several ZPT particles with differing deposition and bioavailability profiles will be discussed. Conclusions The common etiology ofD/SD is therefore a convergence of three factors: 1) SG secretions, which provide the substrate for Malassezia growth 2) Malassezia metabolism of the sebaceous secretions, releasing irritating unsaturated fatty acids and 3) individual susceptibility to the penetration of the fatty acids and the resultant inflammation. The optimal and most efficacious method for treatment is anti-fungal actives delivered from rinse-off products. The low deposition inherent in rinse-off products places significant constraints on the potency of the active material and the delivery pharmacology of the product chassis. References 1. Dawber, R: Diseases of the Hair and Scalp. London, Blackwell Science, 1997 p 499-504 2. McOsker, DE, Hannon, DP: Ultrstructural studies of dandruff-involved scalp tissue. The Toilet Goods Association 47: 5-8, 1967 3. Warner, RR Schwartz, JR Boissy, Y Dawson, TL: Dandruff has an altered stratum comeum ultrastructure that is improved with zinc pyrithione shampoo. J Am Acad Dermatol 45: 897-903, 2001 4. Gupta, AK Batra, R Bluhm, R Boekhout, T Dawson, TL: Skin diseases associated with Malassezia species. J Am Acad Dermatol Sl:785-98, 2004 5. Strauss, JS Pochi, PE: Histology, histochemistry, and electron microscopy of sebaceous glands in man. In: Gans, 0, Steigleder, GK (ed). Handbuch der Haut-und Geschlechtskrankheiten Normale und Pathologische Anatomie der Haut I. Berlin: Springer-Verlag, 1968 p 184-223 6. Strauss, JS Downing, DT Ebling, FJ: Sebaceous glands. In: Goldsmith, LA (ed). Biochemistry and Physiology of Skin. New York: Oxford University Press, 1983 p 569-595 7. Gupta, AK Bluhm. R Cooper, EA Summerbell, RC Batra, R: Seborrheic dermatitis. Dermatol Clin 21: 401-412, 2003 8. Malassez, L: Note Sur le Champignon du Pityriasis Simple. Arch. De Physiologie l: 451, 1874 9. Shuster, S: The aetiology of dandruff and the mode of action of therapeutic agents. Br J Dermatol l l l: 235- 42, 1984 10. Pierard-Franchimont, C, Hermanns, JF, Degreef, H, Pierard, GE: From axioms to new insights into dandruff. Dermatology 200: 93-8, 2000 11. Gueho, E, Boekhout, T, Ashbee, HR, Guillot, J, Van Bellcum A, Faergemann, J: The role of Malassezia species in the ecology of human skin and as pathogens. Med Mycol 36 Suppl 1 220-9, 1998 12. Guillot, J, Gueho, E: The diversity ofMalassezia yeasts confirmed by rRNA sequence and nuclear DNA comparisons. Antonie van Leeuwenhoek 67: 297-314, 1995 13. Gemmer, CM, DeAngelis, YM Theelen, B, Boekhout, T, Dawson, TL: Fast, Noninvasive Method for Molecular Detection and Differentiation of Malassezia Yeast Species on Human Skin and Application of the Method to Dandruff Microbiology. J Clin Microbiol 40: 3350-3357, 2002 14. DeAngelis, YM., Gemmer, CM, Kaczvinsky, JR, Kenneally, D, Schwartz, JR, and TL Dawson, Jr. (2005) 1bree etiologic facets of dandruff and seborrheic dermatitis: Malassezia fungi, Sebaceous lipids, and Individual sensitivity. J Invest Dermatol. (in press).