Seborrheic Dermatitis Update: A Review of the Etiology and Treatment of Seborrheic Dermatitis

Seborrheic dermatitis (SD) is an inflammatory skin condition that often involves flaky, erythematous patches on sebum-rich areas of the body such as the face and scalp.1 At least 50 million Americans have a form of seborrheic dermatitis on the scalp, more commonly known as dandruff. SD presents in all age groups with diverse skin findings. As with other inflammatory skin diseases, SD is a burdensome disease with an annual over-the-counter (OTC) treatment cost of $300 million in the US. Many OTC options can be expensive despite having limited efficacy. SD also affects the face and other visible areas leading to a negative psychosocial impact for patients. As a result, growing research on seborrheic dermatitis is necessary to address the significant burden of disease. In this review we summarize the clinical presentations of SD, the proposed mechanisms of pathogenesis, as well as provide an updated review of treatments.

Clinical Presentation

In infants, SD frequently appears as “cradle cap,” which is characterized by greasy scales on the scalp and is usually self-limited.2 The face, body folds, and diaper-area may also be affected, but SD is rarely generalized in infants. Clinical findings in teenagers and adults can be characterized by chronic, relapsing inflammation involving the scalp and face, and less commonly on the chest, back and shoulders. Greasy, yellow scales overlie well-demarcated, erythematous patches. It is important to recognize that erythema can be less detectable in more richly pigmented skin.3 Arcuate, annular, and hypopigmented lesions may appear more frequently on SD patients with darker skin tones.

SD also often presents as a malar rash and is the most common cause of malar rashes for adults.2 As a result, systemic lupus erythematosus may be on the differential diagnosis for SD. Other conditions on the differential include eczema, psoriasis, lupus, and tinea versicolor.

Men are generally more affected than women.1 SD is also more prevalent among the immunocompromised, particularly among HIV/AIDS patients. The most severe presentations of SD occur in the context of comorbid HIV or Parkinson’s disease.2 In the next section, we will further explore this association with Parkinson’s disease and immunosuppression in relation to the potential mechanisms of pathogenesis.

Etiology

The exact etiology of seborrheic dermatitis is still not well understood. The pathogenesis of SD appears to involve a complex interaction of both genetic and environmental factors. One of the most long-standing hypotheses implicates the overgrowth of Malassezia yeast.4 Higher Malassezia colonization has been correlated with more intense symptoms in patients with SD. Malassezia has also demonstrated lipase activity that hydrolyzes human sebum triglyceride, generating metabolites that contribute to abnormalities in keratinocyte differentiation and stratum corneum. This ultimately leads to epidermal barrier dysfunction and inflammatory response. Additionally, Malassezia may explain the role of skin microbiome in the pathogenesis of SD. The unsaturated fatty acids released from Malassezia can increase pH, providing a favorable environment for S. Aureus.5 Dysbiosis has the potential to induce proliferation of staphylococcus in patients with SD, which is associated with more inflammation and skin barrier damage.

Unfortunately, there isn’t substantial evidence to prove a causal relationship between Malassezia and SD. In fact, some findings challenge the causative role of Malassezia in SD. For instance, colonization of Malassezia also occurs in a majority of healthy adults without seborrheic dermatitis.4 Additionally, a decrease in Malassezia count was not always observed in improved lesional skin after treatment with ketoconazole. It is possible that a genetic predisposition to epidermal barrier dysfunction can influence a Malassezia-associated pathogenesis of SD. Genetic studies on families with SD have brought attention to a ZNF750 mutation, which codes for a transcription factor that regulates many epidermal barrier genes, including FLG and Mpzl3. This mutation may have a role in early onset seborrheic dermatitis with red flaky skin. Defective epidermal barrier and sebaceous lipid composition have also been connected to Malassezia overgrowth. Consequently, Malassezia may have an association, or may be necessary but not sufficient to cause seborrheic dermatitis from underlying genetic susceptibility.

Furthermore, seborrheic dermatitis disproportionately impacts immunodeficient individuals. In HIV-positive patients, the incidence of SD has been reported to be 30% to 82%.4 The disruption in skin microbiota and altered immune response may explain the higher prevalence of SD. HIV-positive individuals also present with a more severe form of SD. Some even consider it a separate entity, as lesions tend to be thicker, greasier, and more generalized.2 Treatment failure is more common as well, in this context. HIV-positive SD patients also have negative or minimal growth of Malassezia compared to SD patients without HIV, further questioning the role of Malassezia.

Parkinson’s disease is another condition strongly associated with SD. Around 52% to 59% of Parkinson’s patients present with SD compared to 3% of the general population.6 The mechanism for this is unclear, but autonomic dysfunction may promote sebum production, greater yeast colonization, and subsequent inflammation. Dopamine deficiency from Parkinson’s disease results in increased levels of α-MSH, which boosts sebum production. Facial immobility in Parkinson’s patients could also contribute to increased sebum accumulation. Remarkably, treatment of Parkinson’s with L-Dopa, a dopamine precursor, has demonstrated a reduction in sebum production and improved SD symptoms. Parkinson’s disease may not be the only neuroendocrine disorder with a potential link; SD is also more prevalent with emotional stress and depressive disorders.7

Treatments

Existing treatments for seborrheic dermatitis are generally designed to modulate Malassezia colonization, sebum production, and immune activity, or some combination of those (summarized in Table 1). Antifungals are common first-line agents to control Malassezia proliferation.8 Scalp dandruff is often treated with topical fungicidal azoles (eg, ketoconazole and miconazole) that block the synthesis of ergosterol—an important component of fungal membrane—and come in both shampoo and leave-on preparations. Ciclopirox is another topical drug that inhibits important fungal enzymes and also acts as an anti-inflammatory agent, inhibiting prostaglandin and leukotriene activity. Other shampoo ingredients directed against dandruff include selenium sulfide and zinc pyrithione. Zinc pyrithione dominates OTC anti-dandruff shampoo formations because of affordability as well as their odorless and colorless properties.7

Topical corticosteroids act as powerful anti-inflammatory agents. Low-to-mild potency topical steroids, including 1% hydrocortisone, 0.05% desonide, and 0.1% betamethasone valerate, can be effective treatments for clearing SD lesions.9 Unfortunately, steroids are generally indicated for short-term use due to unwanted side effects, particularly on sensitive areas such as the face. Steroid-free alternatives including UVB therapy and calcineurin inhibitors—tacrolimus and pimecrolimus—may be used instead to treat SD by targeting specific pathways of the immune system and subsiding inflammation, although they are not FDA-approved for this indication.

Biologics have also been considered as potential systemic treatments. IL-4 increase has been reported in some SD cases, but an IL-4 blockade may actually exacerbate SD.2 Worsening head and neck dermatitis occur in some patients on dupilumab, a powerful biologic that blocks IL-4 and IL-13. Researchers suspect a baseline overactivity of Th17 in SD patients, which may intensify from the IL-4 blockade that results in unopposed elevation of IL-17 levels.¹⁰ However, more research must be conducted to understand the impact of IL-17 and if IL-17 blockers may offer a therapeutic solution for SD.

Recently, roflumilast 0.3% foam has been submitted to the US Food and Drug Administration (FDA) for approval for a seborrheic dermatitis indication.¹¹ The FDA assigned a Prescription Drug User Fee Act (PDUFA) goal date of December 16, 2023, for roflumilast 0.3% foam. Roflumilast is a PDE-4 inhibitor that has drawn much attention for its promising outcomes during phase 3 trials. At the eighth week of once daily use, more than 70% of participants achieved the Investigator Global Assessment (IGA) status of clear or almost clear skin.¹² This new agent also showed improvements in erythema, scaling, and worst-itch scale with a reassuring safety profile. The foam formulation would theoretically allow easy use on the scalp and bearded face.

Conclusion

Currently available treatments help mediate symptoms and signs of seborrheic dermatitis but have limited efficacy and/or unwanted side effects. Meanwhile, SD continues to affect many individuals and causes large psychosocial and financial burdens. Diverse skin findings also make it difficult to diagnose and can delay treatment. Roflumilast is poised to be a new, effective SD therapy, more research investigating the underlying pathogenesis of disease may provide much-needed insight into targeted therapies in the future.

Disclosure

Dr. Lio reports research grants/funding from AbbVie, AOBiome, Eczema Foundation, National Eczema Association; is on the speaker’s bureau for AbbVie, Eli Lilly, Galderma, Hyphens Pharma, Incyte, La Roche-Posay/L’Oreal, MyOR Diagnostics, ParentMD, Pfizer, Pierre-Fabre Dermatologie, Regeneron/Sanofi Genzyme; reports consulting/advisory boards for AbbVie, Almirall, Amyris, Arbonne, Arcutis, ASLAN, Boston Skin Science, Bristol-Myers Squibb, Burt’s Bees, Castle Biosciences, Codex Labs, Concerto Biosci, Dermavant, DermVeda, Eli Lilly, Galderma, IntraDerm, Janssen, Johnson & Johnson, Kaleido Biosci, Kimberly Clark, LEO Pharma, Lipidor, L’Oreal, Menlo Therapeutics, Merck, Micreos, MyOR Diagnostics, Regeneron/Sanofi Genzyme, Skinfix, Sonica, Theraplex, UCB, Unilever, Verrica, Yobee Care; stock options: Micreos, Modernizing Medicine, Yobee Care. In addition, Dr. Lio has a patent pending for a Theraplex product with royalties paid and is a Board member and Scientific Advisory Committee Member of the National Eczema Association.

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11. Arcutis submits topical roflumilast foam 0.3% new drug application to the FDA for the treatment of seborrheic dermatitis in adults and adolescents. Arcutis Biotherapeutics. https://www.arcutis.com/arcutis-submits-topical-roflumilast-foam-0-3-new-drug-application-to-the-fda-for-the-treatment-of-seborrheic-dermatitis-in-adults-and-adolescents/. Published February 21, 2023. Accessed March 28, 2023.

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