Journal of Dermatological Treatment

ISSN: 0954-6634 (Print) 1471-1753 (Online) Journal homepage: http://www.tandfonline.com/loi/ijdt20

Treatment of Seborrheic Dermatitis: A

Comprehensive Review

Luis J. Borda, Marina Perper & Jonette E. Keri

To cite this article: Luis J. Borda, Marina Perper & Jonette E. Keri (2018): Treatment of
Seborrheic Dermatitis: A Comprehensive Review, Journal of Dermatological Treatment, DOI:
10.1080/09546634.2018.1473554

To link to this article: https://doi.org/10.1080/09546634.2018.1473554

Accepted author version posted online: 08

May 2018.

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 Treatment of Seborrheic Dermatitis: A Comprehensive Review

Luis J. Borda, M.D.; Marina Perper, B.S.; Jonette E. Keri, M.D.; Ph.D.*

Department of Dermatology & Cutaneous Surgery

University of Miami Miller School of Medicine
Miami, Florida, U.S.A.

*Address for correspondence:

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Jonette E. Keri, M.D.; Ph.D.

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Department of Dermatology & Cutaneous Surgery
University of Miami Miller School of Medicine

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1600 NW 10th Avenue, RMSB 2023A
Miami, FL, 33136

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U.S.A.
Phone: (305) 243-6734
Email: Jkeri@med.miami.edu

Word Count: 6914

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Reference Count: 126
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Figure Count: 0
Table Count: 0
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Funding Sources:
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This article received NO specific grant from any funding agency in the public, commercial, or
not-for-profit sectors.
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Conflict of Interest:
The authors of this review article have NO conflict of interest to declare.
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Prior Presentation:
The authors declare that this review has NOT been published previously.

Authorship:
Every author listed meets the qualifications for authorship and has had the opportunity to read
and comment upon the submitted manuscript.
 Treatment of Seborrheic Dermatitis: A Comprehensive Review

Abstract

Seborrheic Dermatitis (SD) is a chronic, recurring inflammatory skin disorder that manifests as

erythematous macules or plaques with varying levels of scaling associated with pruritus. The

condition typically occurs as an inflammatory response to Malassezia species and tends to occur

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on seborrheic areas, such as the scalp, face, chest, back, axilla, and groin areas. SD treatment

focuses on clearing signs of the disease; ameliorating associated symptoms, such as pruritus; and

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maintaining remission with long-term therapy. Since the primary underlying pathogenic

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mechanisms comprise Malassezia proliferation and inflammation, the most commonly used
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treatment is topical antifungal and anti-inflammatory agents. Other broadly used therapies

include lithium gluconate/succinate, coal tar, salicylic acid, selenium sulfide, sodium
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sulfacetamide, glycerin, benzoyl peroxide, aloe vera, mud treatment, phototherapy, among

others. Alternative therapies have also been reported, such as tea tree oil, Guassia amara, and
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Solanum chrysotrichum. Systemic therapy is reserved only for widespread lesions or in cases that
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are refractory to topical treatment. Thus, in this comprehensive review, we summarize the
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current knowledge on SD treatment and attempt to provide appropriate directions for future cases

that dermatologists may face.

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Key Words: Seborrheic dermatitis, treatment, Malassezia sp.

I. Introduction

Treatment of Seborrheic Dermatitis (SD) focuses not only on clearing signs and symptoms of

the condition but also to promote normalization of skin function and structure; maintaining

remission with long-term therapy [1, 2]. Since Malassezia proliferation and local skin

irritation, and inflammation are the primary pathogenic mechanism, the treatment involves

topical antifungal and anti-inflammatory agents. Other broadly used treatment options

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include coal tar, selenium sulfide, metronidazole, lithium gluconate/succinate, and

phototherapy. Alternative options have also been reported, such as aloe vera, mud,

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coconut/tea tree oil, quassia amara, among others. Efficacy, side effects, ease of use, and age

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of the patient need to be considered before deciding the kind of treatment to be used [3].
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Systemic therapy may also be used, mainly in cases of widespread SD and/or refractory to

topical treatment [1, 4, 5].

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II. Types of Treatment

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A. Topical Treatment (Table 1)

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a. Antifungals:
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Since SD is a chronic inflammatory disease that occurs in response to the presence of

fungus on the skin, antifungals play a key role in the treatment of SD. Topical
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antifungals are used in the treatment of SD due to their ability to decrease Malassezia

burden and subsequent inflammatory response [3]. Therefore, topical antifungals are

generally one of the first line treatment for SD. Topical azoles, such as ketoconazole,

clotrimazole, and miconazole have been shown to be effective. Their mechanism of

action consists of inhibition of fungal cell wall synthesis. Topical ketoconazole 2% in

different presentations as shampoo, cream or gel has shown to be effective in the

treatment of SD [6, 7]. Furthermore, topical ketoconazole 2% treatment showed a

remission rate similar to that of steroids; however, the occurrence of adverse effects

was 44% lower in the ketoconazole arm than in the steroid group [8]. A study showed

that miconazole 2% shampoo is at least as effective and safe as ketoconazole

shampoo for the treatment of scalp SD [6], and another study reported effectiveness

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for treatment and prophylaxis of SD [9]. Clotrimazole 1% cream is another option for

treatment of SD that is routinely prescribed to treat SD [10]. Goldust et al. reported

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that sertaconazole 2% cream is an effective and well-tolerated treatment for moderate

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to severe facial SD with no relapse of the disease after one month of stopping the

treatment [11].
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Ciclopirox olamine 1% (cream, shampoo, and gel) is a broad-spectrum antifungal

agent, whose mechanism of action involves inhibition of metal-dependent enzymes

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inside of the fungal cell with anti-inflammatory activity [1, 12], has been shown to be
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effective for SD of the face and scalp [3]. One study demonstrated that significantly
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more ciclopirox-treated patients reached over 75% improvement between third and

fourth week of treatment of scalp SD [13].

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Terbinafine has primarily fungicidal action as a result of squalene epoxidase

inhibition leading to the accumulation of squalene while becoming deficient in

ergosterol, a key component of fungal cell membranes [14]. Terbinafine 1% cream

 has been reported as safe and effective as ketoconazole 2% cream in treating SD with

no serious side effects and no difference in the recurrence rate either [7].

b. Corticosteroids:

Low to mild potency topical corticosteroids are effective in clearing of signs and

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symptoms associated with SD. Topical corticosteroids can be used alone or in

combination with antifungal agents; however prolonged use is not suggested due to

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their side effects, such as telangiectasias, hyperthrichosis, atrophy, and perioral

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dermatitis. In one study, Betamethasone valerate 0.1% was reported to be highly
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effective reducing erythema, scaling, and pruritus faster the pimecrolimus in the face

and the scalp; but relapses were observed more frequently and more severe than
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pimecrolimus [15]. On the other hand, ketoconazole 2% has been shown to be

superior to betamethasone diproprionate 0.05% in reducing symptoms and reducing

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the Malassezia burden [16]. Hydrocortisone showed lesion clearing and adverse
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effects rate similar to those of sertaconazole with more improvement evidenced

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within the hydrocortisone arm at the second week of treatment [17]. Also, Goldust et

al. recommend sertaconazole as a nonsteroidal alternative to topical steroid therapy

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when compared to hydrocortisone 1% cream [18].

c. Non-steroidal anti-inflammatory agents:

Non-steroidal anti-inflammatory agents are topical therapies that treat scalp and non-

scalp seborrheic dermatitis primarily through the inhibition of the growth of the
Malassezia species anti-inflammatory, antimycotic, keratolytic, and antioxidant

effects [19-22]. Studies involving non-steroidal anti-inflammatory agents indicate

these treatments to be efficacious and well-tolerated. Adverse effects are generally

mild and are limited to a temporary pricking sensation, stinging, itching, burning,

erythema, and viral gastroenteritis [19-21]. Overall, non-steroidal anti-inflammatory

agents appear to be effective, viable, and safe therapeutic modalities for SD.

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1. Climbazole/piroctone olamine cream

The combination of piroctone olamine and climbazole offers an effective

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treatment option with little to no adverse effects. Additionally, it has the

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advantages of decreasing wet hair combing force and increasing hair conditioning
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[23]. Piroctone olamine is found in numerous cosmetic products at a maximal

concentration of 1% (rinse-off products) or 0.5% (other products), including anti-

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dandruff shampoo [19]. It is an ethanolamine salt of the hydroxamic acid

derivative piroctone and serves as a hydroxypyridone anti-mycotic agent.

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Piroctone olamine has antifungal effects and its mechanism of action involves
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penetrating the cell membrane and creating complexes with iron ions, ultimately
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barring energy metabolism in the mitochondria [19, 24]. Conversely, climbazole

is an imidazole antifungal agent, frequently used to treat human fungal infections,

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including dandruff and seborrheic dermatitis. Its mechanism of action involves

blocking P-450 mediated reactions through the binding of azoles to the protein

moiety of fungal P-450s [19, 25, 26].

 In a split-face study, Youn et al. investigated the daily application of

climbazole/piroctone olamine (C/P) cream versus emollient cream on mild to

moderate sebhorreic dermatitis over the course of four weeks. The C/P cream

significantly reduced sebum and erythema levels, and quantitatively compared

favorably with the emollient cream treated side of the face. Additionally, only the

C/P cream achieved minimal inhibitory concentrations of the M. restricta, M.

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globose, M. sympodialis, and M. slooffiae species [19]. Schmidt-Rose et al.

conducted a comparison clinical trial, evaluating the effectiveness of 0.5%

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piroctone olamine, 0.45% climbazole, and 2% polydocanol shampoo versus that

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of 1% zinc pyrithione shampoo in subjects with moderate to severe dandruff.
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Subjects used the shampoos in a 2-8 mL dosage three times a week for a period of

four weeks. Results indicated that both shampoos significantly reduced the
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amount of visible dandruff on scalps as compared with baseline or control and

were equally as effective in treating dandruff. Additionally, 2% polidocanol

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shampoo decreased pruritus by 90% [23].

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2. Bisabolol

Bisabolol is a monocyclic sesquiterpene alcohol that is usually applied to affected

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areas in the form of a topical. In vitro studies have demonstrated that bisabolol

downregulates human polymorphonuclear neutrophil (PMN) release of reactive

oxygen species (ROS), inducing antioxidant and anti-inflammatory effects [27,

28]. Further, it has anti-oxidant properties against neutrophil bursts that result in

increased amounts of reactive oxygen species. Bisabolol protects the gastric

 epithelium from damage from prostaglandins and nitric oxide, which may be

carried over to the skin due to the similarities in behavior of the two in turnover

and barrier function [29]. In reference to sebhorreic dermatitis, bisabolol has an

anti-inflammatory effect that is more specific than that of steroids and anti-fungal

therapies, but is probably not as potent as monotherapy [27]. Studies evaluating

skin conditioning agents containing bisabolol have indicated that these creams

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result in early and significant improvement with limited complications [28, 30].

Dall’Oglio et al. conducted an intra-subject controlled trial evaluating the

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effectiveness of a topical non-steroidal anti-inflammatory product containing

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1.2% bisabolol, 1% piroctone olamine, 1% alglycera, and 0.01% telmesteine on
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patients with mild-to-moderate facial seborrheic dermatitis. The product was

applied twice daily for 30 days and produced significant improvement in

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erythema, desquamation, and pruritus compared to baseline. The Physician Global

Assessment indicated improvement in 89% of patients, 56% of which showed a

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complete response [28].

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3. Glycyrrhetinic acid

Glycyrrhetinic acid, an ingredient in black licorice, is primarily indicated for

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hypertension management due to its mineralcorticoid properties, but also has

broad-spectrum anti-microbial and anti-inflammatory activity, making it

beneficial in the treatment of SD. It is a potent inhibitor of 11-B- hydroxysteroid

hydroxygenase, the enzyme that facilitates the conversion of hydrocortisone in

normal steroid metabolism, potentiating anti-inflammatory effects [31].

 Turlier and colleagues performed a randomized, controlled clinical trial testing

the effects of an antidandruff maintenance shampoo containing beta-

glycyrrhetinic acid, cyclopiroxolamine, and zinc pyrithione versus neutral

shampoo on chronic, recurrent SD over a period of 10 weeks. The study contained

two treatment periods, an intensive treatment phase in which the shampoo was

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applied three times a week for two weeks and a maintenance period, in which the

shampoo was applied one time a week for eight weeks. The intensive treatment

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phase significantly decreased clinical signs of SD, the Malassezia species,

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cohesion proteins, and inflammation and pruritus markers. These improvements
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persisted throughout the maintenance phase [21].
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4. Lactoferrin

Although the mechanism by which lactoferrin modulates inflammatory and

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immune response is not well-elucidated, it may be accounted for through the

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modulation of the migration, maturation, and function of immune cells, as well as

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iron binding and interactions with other compounds [32]. Dall'oglio et al.

measured the effects of a cosmetic topical gel containing ciclopiroxolamine,

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lactoferrin, glycero-phosphoinositol (GPI), and aloe vera applied twice daily

against baseline in a prospective clinical trial lasting 45 days. Patients receiving

the topical gel achieved significant reductions in all treatment parameters

(desquamation, itch, erythema, pruritus) as compared with baseline, and a large

 proportion of patients (47.9%) rated their results as “excellent” (>80%

improvement) [22].

5. Promiseb® Topical Cream

Promiseb® Topical Cream is a nonsteroidal cream that combines many of the

active ingredients previously mentioned (ex. lycyrrhetinic acid and piroctone

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olamine) to enhance anti-inflammatory and anti-fungal activity. In a comparative

study, Elewski et al. found that Promiseb Cream and desonide cream had nearly

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equivalent effects on the signs and symptoms of SD. Moreover, they concluded

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that Promiseb Cream has improves the time to relapse, most probably because of
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its impact on M. furur [33]. As such, a daily regimen involving maintenance with

Promiseb Cream rather than steroids, with episodic use of steroids when
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necessary to control flares, may prove to be a safe and reliable therapeutic

modality, with less probability of relapse [29].

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d. Immunomodulators:
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Immunomodulators primarily treat SD through the inhibition of calcineurin, a

calcium-dependent phosphase necessary for T-cell activation and proinflammatory

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cytokine production. In addition to producing anti-inflammatory effects,

immunomodulaters may have antifungal activity against Malessezia furfur ⁄ P. ovale

[34]. The two main immunomodulators indicated for the treatment of SD include

tacrolimus [34-37] and pimecrolimus [38-50], and are especially beneficial for facial

SD due to their limited adverse events. They are generally implicated when treatment
with topical corticosteroids and antifungal do not effectively control SD [40]. In

2005, the FDA placed a cautionary black box warning based on the development of

immunosuppression-related lymphoproliferative disorders after oral therapy of

Pimecrolimus in monkeys for approximately 40 weeks [51]. Nevertheless, this

regimen would be equivalent to topical treatment in humans surpassing 30 times the

highest recommended dose [52]. Therefore, to date there has been no association

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between use of topical calcineurin therapy and development of malignancy neither in

children or adults [51].

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1. Tacrolimus: Tacrolimus ointment is a topical, noncorticosteroid
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immunosuppressant, similar to cyclosporine, and approved for the treatment of

atopic dermatitis [34, 37]. Its anti-inflammatory properties also make it a suitable
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treatment for SD. Tacrolimus is advantageous over topical corticosteroids in

terms of safety. Unlike corticosteroids, tacrolimus is not linked with skin atrophy,
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striae, or skin thinning, and can be safely administered on the face, neck, and
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intertriginous regions [34, 36, 37]. Additionally, tacrolimus 0.03% cream may be
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equally as effective as certain corticosteroids such as sertaconazole 2% cream, as

demonstrated in a clinical trial conducted by Goldlust et al. [35]. The main

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adverse effects reported with the use of tacrolimus 0.1% ointment in the treatment

of SD are burning and tingling sensations at the application site, although pruritus,

burning, mild sunburn, irritation, mild viral gastroenteritis, facial flushing, and

warmth after ingestion of alcohol have been documented as well [34-37]. These
 symptoms generally occur within the first few days of application and subside in

severity over time [36].

Clinical trials have determined that tacrolimus 0.1% ointment results in a marked

improvement in features such as scaling, erythema, and pruritus compared with

baseline and vehicle ointment and that it may also be used as maintenance

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treatment. Treatment regimen includes once-daily [34] or twice daily [36, 37, 53]

application over the course of 28 days to 6 weeks [34-37]. Meshkinpour et al.

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conducted a single-center, open-label study evaluating the efficacy of 0.1%

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tacrolimus applied twice daily for a total of 28 days or until complete clearance
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occurred, if sooner. Eleven patients (61%) demonstrated 100% SD clearance,

whereas the remaining 7 patients showed 70% to 99% clearance. Although

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treatment was efficacious and well-tolerated in many patients, SD began to recur

two weeks following the end of treatment [37]. Subsequently, other studies
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investigated the use of tacrolimus as maintenance therapy to optimize long-term

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response. A randomized, double-blind, vehicle-controlled, multi-centre trial by

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Kim et al., for example, demonstrated the effectiveness of intermittent topical

tacrolimus to prevent relapse in patients with stabilized facial seborrhoeic

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dermatitis. Once- and twice-weekly tacrolimus ointment treatment in subjects

with stabilized facial SD maintaned decreased erythema, scaling and pruritus and

improvement in global assessments and successfully kept SD in remission [36].

2. Pimecrolimus: Since creams tend to produce greater cosmetic acceptability, more

studies have been conducted on pimecrolimus than tacrolimus [30]. Pimecrolimus

1% cream is a topical macrolactam immunomodulator, widely used in the

treatment of atopic dermatis [38]. Unlike tacrolimus, it was specifically created as

a therapeutic modality for inflammatory dermatoses, but like its counterpart, it has

numerous advantages over corticosteroids [40]. Due to its higher lipophilicity and

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higher molecular weight, pimecrolimus may have a more favorable skin

permeation profile because of its lower degree of percutaneous absorption when

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compared with corticosteroids [54]. Since both tacrolimus and pimecrolimus

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typically do not cause skin atrophy or hypopigmentation, they may be excellent
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treatment modalities for treating SD in African Americans [44]. Pimecrolimus is

generally applied twice daily over the course of four weeks [38-50], although
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studies have also monitored its effectiveness over the course of 2[48], 6[49],

8[50], and 16[44] weeks. Overall, pimecrolimus is generally well tolerated,

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especially on the face, but does induce adverse effects comparable with those of
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tacrolimus including burning, tingling, pruritus, feeling of warmth, itching, and

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erythema [38-50].
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Pimecrolimus 1% cream significantly improves erythema, scaling, and pruritus

after four weeks of treatment. Improvement is first generally noticed following

one week of treatment and is maximized after two weeks of treatment [38, 40,

41]. Ozden et al. noted significant reductions in all SD parameters following

twice-daily application of pimecrolimus 1% cream over the course of two weeks,

 but reported recurrence after the treatment period ended [40]. Conversely, Rallis

et al. found that pimecrolimus may be used as a maintenance therapy in

exacerbations for a 9-week duration [43]. In comparative clinical trials,

pimecrolimus 1% fared equally as well as hydrocortisone acetate cream 1%

applied twice daily over two weeks and ketoconazole 2% cream applied twice

daily over six weeks, but induced more side effects than either of these

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medications [48, 49]. However, it outperformed and resulted in fewer side effects

than metronidazole 0.75% gel and methylprednisolone aceponate 0.1% cream

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applied twice daily over the course of eight weeks [50].

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e. Miscellaneous:
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1. Metronidazole: Metronidazole is an antiprotozoal and imidazole-derived

antibacterial agent. When used systematically, it has strong antibacterial activity

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against anaerobic bacteria. This drug decreases oxidative damage via inhibition of

neutrophil-generated inflammatory mediator [55]. It also has immunomodulatory

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effects on leukocyte chemotaxis and suppression of cell-mediated immunity [56].

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Therefore, these findings make topical metronidazole an effective therapy option

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for SD. Furthermore, one study showed effectiveness of 1% metronidazole gel in

SD in comparison to placebo, reporting 67% of improvement in treated patients

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[57]. Other studies have revealed the efficacy of metronidazole in gel (either

0.75% or 1%) for facial SD [58, 59]. The regimen consist of metronidazole 0.75%

gel twice daily for 4 weeks with rare contact sensitization with prolonged use [1].
2. Keratolytic Agents

i. Coal tar: Coal tar may be efficacious against SD due to its keratoplastic

effects. In an open-label study, Garcia et al. studied the effects of special crude

coal tar extract, Fractar, in a detergent vehicle on treating recalcitrant scalp SD

and psoriasis. Results indicated that the application of Fractar 8.75% in liquid

detergent vehicle daily for two hours prior to shampooing and then two times

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per week after improvement over the course of three weeks improved SD

subjectively and objectively by 86.4% and psoriasis by 81.7%. Mild pruritus

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was noted as an adverse effect [60].

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ii. Salicylic acid/Lipohydroxy acid (LHA): Seite et al. conducted a randomized

study comparing the efficacy and tolerability of lipohydroxy acid shampoo

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(containing 0.1% lipohydroxy acid (LHA) and 1.3% salicylic acid) with

ciclopiroxolamine shampoo (containing 1.5% ciclopiroxolamine (CPO), 3%

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salicylic acid, and 0.5% menthol) in patients with scalp dermatitis. LHA’s
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mechanism of action includes exfoliation, stimulation of epidermal renewal,

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and antimicrobial activities against Malassezia ovalis. One hundred subjects

with mild to moderate scalp SD used the shampoos every 2 days over the
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course of four weeks. Although both shampoos reduced symptoms of scale,

erythema, itching, cutaneous discomfort and dryness, by day 28, LHA

shampoo demonstrated a significantly global efficacy and tolerance as

compared with CPO shampoo [61].

 iii. K301: K301 (Kaprolac) is a relatively new topical solution consisting of a

homogeneous mixture of urea, propylene glycol and lactic acid with small

amounts of glycerol and water, all of which are biodegradable. These

ingredients treat SD through keratolytic, exfoliating, anti-fungal, and hydrating

activities. In two multi-centre, randomized, double-blind studies, Emestam et

al. evaluated the use of K301a (propylene glycol, urea, lactic acid, glycerol,

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water) and K301b (propylene glycol, urea, lactic acid, glycerol water,

isopropyl alcohol) applied daily for four weeks and then three times a week for

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four weeks as a maintenance treatment. Both treatments showed significant

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improvements in SD symptoms over placebo after four weeks. K301 began to
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demonstrate clinical improvements in SD after two weeks of treatment.

Adverse effects were mild but included smarting pain, redness, burning, rash,
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itching, eczema, ulceration [62].
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3. Selenium Sulfide: Topical selenium sulfide has antifungal activity mainly via the
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promotion of shedding of the infected stratum corneum. Danby et al. evaluated

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the safety and effectiveness of selenium sulfide 2.5% shampoo and ketoconazole

2% shampoo for dandruff treatment finding that both were effective in the
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treatment of moderate to severe dandruff for reduction of irritation and itching.

However, ketoconazole appeared to be better tolerated [63]. Selenium sulfide is

primarily used for the treatment of dandruff and the regimen of topical treatment

consist of Selenium sulfide 2.5% shampoo once daily for 3 days followed by the
 same procedure one week later. The maintenance therapy is once every 3 months

[64].

4. Sodium Sulfacetamide: The combination of 10% sodium sulfacetamide and 5%

sulfur has demonstrated to be effective as the treatment of several inflammatory

facial dermatoses including seborrheic dermatitis. Sodium sulfacetamide has

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antibacterial and anti-inflammatory properties while sulfur is a nonspecific

antifungal and antibacterial. The foam formulation of 10% sodium sulfacetamide

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and 5% sulfur permits a slight application film, leaving behind no remnant on hair

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bearing or non-hair bearing skin [65]. This preparation may be found as foam or
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lotion and can be applied once or twice daily on scalp, face, and body [66].
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5. Lithium Gluconate/Succinate: Lithium succinate ointment has been studied in

various formulations (lithium succinate 8%, zinc sulphate 0.05%, preservative in

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wool alcohol ointment 0.1%)[67], ((lithium succinate 8%, zinc sulphate 0.05%,
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dl-a tocopherol in a lanolin base)[68], and (8% lithium succinate, 0.05% zinc
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sulfate, 0.1 % preservative in wool alcohols ointment) [69]. The ointment treats

SD through inhibiting the growth of fungi and yeast that cause SD as well as
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through inhibiting arachidonic acid, which is the first step generating the

production of leukotriene and prostaglandin. It is typically applied twice daily

over the course of 4 to 8 weeks [67-69]. The most common adverse events of

lithium succinate ointment include skin irritation, stinging, and erythema [67-69].

In a nineteen-patient clinical trial, Boyle et al. found that applying lithium

 succinate ointment to facial SD twice daily over the course of four weeks

improved the SD of most patients (14). Two patients did not respond to neither

treatment nor placebo, and one patient responded to placebo. Lithium succinate

ointment significantly improved SD compared with placebo, and the response to

treatment typically appeared after the first two weeks of treatment. Nevertheless,

SD recurred at various intervals following cessation of active treatment [68].

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Randomized controlled clinical trials have shown that the topical application of

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lithium gluconate ointment 8% is also an effective and well-tolerated treatment

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for SD. Lithium gluconate ointment treats SD by inhibiting Malasezzia furfur
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through the inhibition of the production of free fatty acids necessary for the

growth of the species. Like lithium succinate, it also produces anti-inflammatory

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activity. Treatment regimen includes a twice daily application of lithium

gluconate over the course of eight weeks [70, 71]. Dreno et al. conducted a
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comparative, randomized, multi-centre clinical trial studying the effects of lithium

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gluconate 8% versus ketoconazole 2% in the treatment of SD. Two-hundred

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eighty-eight patients applied lithium twice daily over eight weeks and

ketoconazole twice a week for four weeks and then once a week for four weeks.
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Both produced similar adverse events (erythema, burning, dryness, upper

respiratory tract infection), but lithium was deemed to be superior in terms of

erythema, desquamation, pruritus, itching, and burning [71].

6. Phototherapy: It has been shown that patients improve with exposure to natural

sunlight during summer months, and two studies have reported the benefit of

treatment with selective ultraviolet (UV) phototherapy or oral photo-

chemotherapy [72, 73]. However, SD may be precipitated by psoralen and

ultraviolet A therapy [74]. Narrow-band UVB phototherapy is a kind of

phototherapy that uses specially filtered fluorescent lamps emitting selective UVB

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spectra in the range of 311 to 313nm (narrow-band UVB). UVB radiation (280 to

320nm) is absorbed in the epidermis and superficial dermis by molecules called

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chromophores, including DNA, urocanic acid (product of histidine breakdown in

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stratum corneum), melanin, and keratin [75]. Photochemical reactions transform
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the chromophores into photoproducts leading to cell cycle arrest and apoptosis.

Reduced cell proliferation, immunosuppression, and T cell apoptosis may play an

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important role in the UVB-mediated suppression of disease activity in

inflammatory skin conditions such as SD [76]. Comparative studies in a wide

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range of skin diseases (e.g. psoriasis, atopic dermatitis, mycosis fungoides, and
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vitiligo) have revealed that narrow-band UVB is more effective than broadband
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UVB [77-79]. Pirkhammer et al. found that narrow-band UVB to be an effective

and safe treatment option for patients with severe SD [80]. There is not
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established regimen in phototherapy; however, one study found that the

administration of narrow-band UVB three times weekly until complete clearing or

to a maximum of 8 weeks was very effective for severe SD with occasional

moderate erythema post-exposure [80].

7. Glycerin: In a research letter, Benaim-Pinto described the disappearance of SD

after using pure glycerin (1,2,3-propanetriol) to cleanse the external auditory

canal. Similar results were obtained in other areas such as the paranasal folds, and

the author reported no tolerance and no rebound effect. However, he did mention

that glycerin is not curative, for in order to be effective, it needs to be applied at

least every four days after the initial healing. Pure glycerin may help heal SD

t
ip
through its emollient, dehydrating, and slightly irritating effects [81].

cr
8. Benzoyl Peroxide: Benzoyl peroxide is deemed one of the first-line treatments for

us
acne due to its antibacterial and comedolytic properties. Benzoyl peroxide washes
an
also are helpful in seborrhea control of the trunk and face [66]. Bonnetblanc et al.

reported efficacy of 2.5% benzoyl peroxide wash for SD on the face. The main
M
results included reduction of the scaling and erythema. Irritant dermatitis was very

mild in some patients [82]. Treatment regimens include application of benzoyl

e d

peroxide wash (i.e. 2.5%, 5%, and 10%) on face or body for 5 to 10 minutes,
pt

followed by rinsing. However, patients should be aware that high concentrations

ce

could lead to increased skin irritation manifested as scaling, erythema, xerosis,

stinging, or burning sensation. Since drying might be produced, patients may

Ac

benefit from application of a moisturizer after treatment. Patients also should be

warned that benzoyl peroxide could cause bleaching of clothing and hair [83].

9. Crude Honey: Honey may help manage SD through its antifungal, antibacterial,

and antioxidant activity as well as its high nutrient value. It has been
 demonstrated to inhibit Candida albicans resistant to nystatin, miconazole and

clortimazole, and contains numerous inhibines including hydrogen peroxide,

flavonoids, and phenolic acid. In a prospective clinical trial, Al-Waili et al.

examined the potential therapeutic and prophylactic effects of crude concentrated

honey (90%) on 30 patients with chronic SD and dandruff associated with hair

loss in areas of the scalp, front of chest, eyebrows, and lashes. After dilution with

t
ip
warm water up to 90%, honey was applied on the skin for 3 hours. Treatment was

performed every other day over the course of four weeks. All patients had great

cr
improvement, with a complete disappearance in itching, burning, macules,

us
papules, scaling, and plaques. No adverse events were reported. After four weeks,
an
half of the patients were treated with honey once weekly over six months and the

other half served as control; none of the treated, but 12/15 of control patients
M
experienced relapse 2-4 months after ceasing honey applications [84].
e d

10. Aloe Vera: Aloe vera is a plant that belongs to Liliaceae family and it grows in
pt

hot and arid areas. Some pharmacological effects of aloe vera include anti-
ce

inflammatory, antibacterial and antifungal, and hypoglycemic activity [85]. Since

it has antibacterial and antifungal properties, this plant has widely used for
Ac

prevention of dandruff and other fungal infections [86]. Aloe vera has also been

used to hasten wound healing and as anesthetic [85]. In a double blind, placebo-

controlled clinical trial, the efficacy of an emulsion derived from aloe vera was

assessed showing a significant reduction of pruritus and scaling in 58% of patients

with SD. A recent study of a new cosmetic topical gel in which one of the
 component was aloe vera reported a significant improvement in 48% of patients

with no case of worsening [22]. These study results indicate that an extract of aloe

vera may be an effective treatment for SD.

11. Mud Treatment: Comacchi et al. conducted a clinical trial, involving 12

volunteers, investigating the effects of mud treatment on facial SD. The virgin

t
ip
mud of Montecatini Terme Spa (Italy) was applied over the entire face for 20

minutes in a single application. Results indicated that the mud decreased

cr
transepidermal water loss (TEWL), skin surface pH, and sebum content, and

us
significantly increased stratum corneum hydration, thereby suggesting that mud
an
treatment be a valuable alternative seborrheic dermatitis treatment [87].
M
12. Borage and Tea Tree Oil: Borage and tea tree oils are deemed as topical essential

oils with historic use for SD. Borage oil contains approximately 25% of gamma-
e d

linolenic acid (GLA) found in seed of the plant Borago officinalis [88]. GLA is
pt

one of the several essential amino acids involved in skin barrier restoration and
ce

has been shown to be reduced in infants with SD. One study reported topical

application of borage oil on patients with infantile SD showing complete

Ac

improvement in 100% of patients within 10-12 days of treatment [88]. A later

study showed no change in Malassezia sp. burden after 3 weeks of treatment with

borage oil in patients with infantile SD [89].

 Tear tree oil (TTO) is an essential oil obtained from the leaves of Melaleuca

alternifolia in Australia [90]. It has been shown to be effective against several

skin infections, as anti-inflammatory, antioxidant, and anti-skin cancer agent.

Terpinen-4-ol is the major TTO component and is able to reduce the production

of tumore necrosis factor, interleukin-1 (IL-1), IL-8, IL-10, and prostaglandin E2

[90]. Satchel et al. reported that 5% TTO shampoo to be effective for the

t
ip
treatment of mild to moderate dandruff with a 41% of improvement in

comparison to placebo [91]. This effect has been attributed to the antifungal

cr
activity shown by Nenoff et al. revealing susceptibility of the yeast Malassezia

us
furfur towards TTO [92].
an
13. Quassia amara: Quassia amara is a shrub or small tree from South America that
M
contains high levels of active phytochemicals, such as the triterpenoid

quassinoids. It has been demonstrated to have antimicrobial, anti-inflammatory,

e d

and antifungal activities, especially on Malassezia yeast, thereby making it a

pt

potential treatment for SD. Diehl et. conducted a comparative clinical trial to
ce

evaluate the efficacy and safety of 4% Quassia amara extract versus that those of

topical 2% ketoconazole and topical 1% ciclopiroxolamine in the treatment of

Ac

facial SD in 60 patients. Each treatment was applied twice daily over the course

of four weeks. Although the three therapeutic options were very effective, 4%

Quassia extract significantly outperformed topical 2% ketoconazole and topical

1% ciclopiroxolamine [93].
 14. Solanum chrysotrichum: It has been shown that extract acquired from the leaves

of the plant Solanum chrysotrichum has activity against yeast and dermatophytes.

The main component of this plant, i.e. steroidal saponins, has been isolated from

the active extract and demonstrated to have antimycotic properties [94, 95].

Herrera et al. reported no significant difference between a shampoo containing a

standardized extract of Solanum chrysotrichum and 2% ketoconazole shampoo in

t
ip
therapeutic effectiveness and tolerability on the local treatment of dandruff [94].

However, the evidence is scarce; therefore, there is no determined dosage to apply

cr
to patients with dandruff.

us
an
15. Copper Hair Brush: An experimental study conducted by Gupte et al. indicated

that Cu++ enhances the anti-Malassezia oval activity of hamycin, making it a

M
potential treatment of dandruff or seborrheic dermatitis [96]. Although there is

anecdotal evidence for the safety and efficacy of using a copper hairbrush for
e d

treating SD, as of yet, no studies evaluating this therapeutic modality have been
pt

reported in the literature.

ce

B. Systemic Treatment
Ac

Systemic treatment is generally reserved for seborrheic dermatitis that is severe or

recalcitrant [97]. Oral terbinafine [98-100] and oral fluconazole [97, 101, 102] are the

main systemic therapies used for treating SD, although prednisone (0.5mg/kg/day) taken

over the course of 15 days and low-dose oral isotretinoin (0.1 mg/kg/day every other day)

over the course of 6 months have proven effective in treating moderate to severe
seborrheic dermatitis [103, 104]. In addition to prednisone, other systemic corticosteroids

have been implicated in treating recalcitrant moderate to severe SD. Itraconazole has

been used because of its reduced hepatotoxicity and anti-inflammatory, lipophilic and

keratinophilic properties. Due to their established risks, prolonged and/or frequent use of

systemic corticosteroids should be avoided [103].

t
ip
a. Itraconazole

Systemic antifungals such as Itraconazole, ketoconazole, terbinafine, and fluconazole

cr
have been tried as treatment options of patients with both moderate to severe and/or

us
refractory-to-treat SD [105]. Itraconazole is highly keratinophilic and lipophilic
an
triazole which makes it suitable for the systemic treatment of SD and secretion in

sebum is the main mechanism via which the drug gets to the stratum corneum [106].
M
Itraconazole is the most common oral treatment for severe SD associated with a good

therapeutic and safety profile. Ghodsi et al. showed significantly higher improvement
e d

of SD symptoms and lower recurrence rate when compared with placebo with up to
pt

93.8% of clinical improvement seen at the end of the second week of treatment under
ce

a dosage of 200mg/day without serious adverse effects [105]. Another study revealed

significant improvement of erythema, itching, and scaling associated with mild

Ac

improvement in burning sensation and decreased number of Malassezia spores after

treatment [107]. These findings suggest that Itraconazole is not only effective and

safe therapy for SD exacerbations but also effective for maintenance therapy.
b. Terbinafine

Terbinafine is an anti-mycotic agent that possesses antioxidant and anti-inflammatory

properties, as well as anti-mycotic activities against dermatophytes, molds, dimorphic

fungi, and other pathogenic yeasts as it inhibits Malassezia furfur subgroups. It may

be used topically or orally. When used orally, it is administered daily at a dosage of

250 mg, generally over the course of 4 to 6 weeks[98-100]. Cassano et al. found that

t
ip
intermittent treatment with oral terbinafine (250 mg/day for 12 days monthly over

three consecutive months) was effective and more convenient than a continuous

cr
regimen in costs, tolerability, and compliance [99]. Since the drug is very liophilic

us
and widely distributed in the body, very high concentrations of oral terbinafine have
an
been found in the skin and appendages two to three weeks after cessation of treatment

[98]. A study by Jensen found that after administering oral terbinafine for four weeks,
M
measurable plasma levels of the treatment remained for up to three months. As such,

a one-month terbinafine treatment may delay SD remission during this period of time
e d

[108]. Additionally, in a multi-centre, double-blind placebo controlled study, Vena et

pt

al. found that the drug is an effective and well-tolerated treatment for patients with
ce

SD localizations primarily situated in non-exposed skin areas such as the scalp,

hairline, chest and/or the interscapular area [98]. Adverse effects of the drug have
Ac

been reported to include mild tachycardia, insomnia, gastrointestinal complaints,

migraine, cutaneous rash, hypogeusia and hyposmia [98-100].

c. Fluconazole

Fluconazole is a broad-spectrum bistriazole derivative that inhibits dermatophytes,

yeasts, and dimorphic fungi and has generated satisfactory therapeutic results in the

treatment of seborrheic blepharitis and Malassezia folliculitis [97, 102]. It has

demonstrated effective excretion in the sebum and high sebum concentration at a dose

of 150 mg/weekly and 300 mg/weekly over four weeks [101]. In a randomized,

t
ip
controlled trial, Comert et al. attempted to determine if a 300 mg/week dosage over

two weeks would be effective in treating SD, but found that during this treatment

cr
period, fluconazole provided a marginal and statistically insignificant benefit for the

us
therapy of SD as compared with placebo, thus indicating that the treatment should be
an
administered for at least four weeks [102]. Adverse effects of the drug have been

documented to include elevated liver function tests and nausea [97, 101, 102].
M

d. Ketoconazole
e d

Ketoconazole was one of the first drugs used as systemic treatment for SD. However,
pt

there is usually a rapid SD recurrence when ketoconazole is stopped, it may produce

ce

hepatotoxicity, and it can alter the metabolism of testosterone. Due to this reasons,

ketoconazole is not suitable for prolonged treatment of SD [109]. A randomized

Ac

double-blind placebo-controlled study was carried out with ketoconazole 200mg/day

in nineteen patients with SD showing significant body and scalp lesions and itch

regression; however, due to the potential adverse effects ketoconazole is not

recommended as systemic treatment for SD [110].

e. Pramiconazole

Pramiconazole is also a triazole antifungal whose main mechanism of action consists

of inhibition of ergosterol synthesis. It has a broad activity against Candida sp.,

dermatophytes, and Malassezia sp. [111]. Pramiconazole has the highest activity via

minial inhibitory concentration testing against Malassezia spp., showing 10 times

more potent than ketoconazole [112]. Its strong activity is due to its high affinity

t
ip
towards fungal cytochrome P450, involved in the synthesis of ergosterol. Single

doses of Pramiconazole up to 1,200mg were safe with limited adverse events reported

cr
such as diarrhea and gastrointestinal upset. Piérard et al. showed main improvement

us
in erythema, itching, and desquamation at 1 and 4 weeks after treatment of single
an
dose 200mg of Pramiconazole [113]. Thus, there is more research work to carry out

to reach to an adequate dosage or the systemic treatment of SD.

M

f. Isotretinoin
e d

Oral isotretinoin is considered the drug of choice in the treatment of severe acne.
pt

Usual treatment reduce the secretion of sebum via reduction of the sebaceous glands
ce

size, proliferation decrease, and stimulating basal sebocyte apoptosis [114]. Anti-

inflammatory properties have recently been reported, such as reduction of interleukin

Ac

production by sebocytes and keratinocytes, Toll-like receptor 2 activity, and

polymorphonuclear cell migration [114, 115]. However, the effectiveness of

isotretinoin in the treatment of SD has been scarcely researched in randomized

clinical trials. One study showed reduction of sebaceous gland size by 51% and

sebum production by 64% associated with a reduction in Malassezia spp. within

 weeks of treatment start [116]. Another study, in which the majority of patients had

seborrhea with concomitant moderate to severe SD, the rate of sebum production

significantly decreased in the group treated with low dose of isotretinoin (i.e.10mg

every other day) [104]. Recently, Rademaker described a significant improvement

with completely resolved severe and refractory SD in 89% and a starting dose

20mg/day with the most common adverse effect being cheilitis (43%) followed by

t
ip
nose bleed, skin fragility, and eczema [117]. Therefore, low-dose oral treatment

isotretinouin may be considered as a treatment option for moderate to severe

cr
seborrhea and SD on the scalp and face; but further studies are necessary to clarify

us
the adequate dose and the underlying molecular mechanism of the drug in SD.
an
g. Homeopathic mineral medicine
M
Smith et al. tested the effects of a low-dose, oral homeopathic medication consisting

of potassium bromide, sodium bromide, nickel sulfate, and sodium chloride in a

e d

double-blind, placebo-controlled study as an over-the-counter remedy for chronic

pt

dandruff. Forty-one patients received either active medication or a placebo vehicle

ce

over the course of 10 weeks. After 10 weeks, all patients crossed over to the active

medication for an additional 10 weeks. Following the initial 10 weeks of treatment,

Ac

the disease state of patients who received the active medication was significantly

improved as compared with patients receiving placebo. Further, 10 weeks after

patients in the placebo group crossed over to the active medication, they too

experienced a significant improvement in their SD, indicating that oral, low-dose,

 homeopathic therapy is an effective treatment for SD. Adverse effects were minimal,

but included stomach upset, stomach pain, and nausea [118].

C. Seborrheic Dermatitis and Nutrition

a. Vitamins

Numerous nutrient mediators such as essential fatty acids, vitamins A, E and D,

t
ip
vitamins B1, B2, B6, niacin and biotin, vitamin C selenium, zinc, and iron may play a

role in treating psoriasis and seborrheic dermatitis [119, 120].

cr
us
1. Biotin: Biotin, or vitamin H, may either be found in foods such as egg yolk, liver,
an
and yeast, or may be produced by normal intestinal flora. It is a coenzyme that

aids in the metabolism of fats, carbohydrates, and inorganic substances, and is

M
known to be essential in long-chain fatty acid synthesis [121, 122]. Since

seborrheic dermatitis may be indirectly related to impaired fatty acid synthesis,

e d

the condition may be improved by administering biotin in the form of food or

pt

through injection [121]. Studies involving the use of biotin for treating SD have
ce

had conflicting results. In a double-blind cross-over trial of oral biotin treating

infants with SD, Keipert et al. found that oral biotin (4 mg, daily, cross-over after
Ac

3 weeks) did not significantly improve SD as compared with placebo (2 mg,

daily, cross-over after 3 weeks) [123]. Messaritakis et al., however, determined

that infants treated with vitamin B complex plus biotin given slowly intravenously

over 24 hours, only biotin intravenously over 2-3 hours, intravenous biotin over 1-

2 minutes, and intravenous biotin and antibiotics produced excellent improvement

 in SD. Lesions improved within four to eight days and completely disappeared

after 15 to 30 days. No adverse effects were reported in either study [122, 123].

2. Nicotinamide: Nicotinamide may treat SD by regulating cellular inflammation. It

has been demonstrated to downregulate, dose dependently, the cytokine response,

thus confirming its potential as a modulator of cytokine effects in inflammatory

t
ip
conditions. In an open, randomized study, Fabbrocini et al. evaluated the effects

of daily administration of topical nicotinamide 4% cream over the course of 12

cr
weeks in 48 patients with mild to moderate facial SD. Topical nicotinamide was

us
determined to have therapeutic potential; topical nicotinamide was determined to
an
be 75% effective, whereas placebo was shown to be significantly less effective

(35%) [124].
M

3. Tacalcitol: A case series, Nakayama described the use of an active vitamin D3

e d

compound, 1a-24 (R)-dihydroxycholecalciferol D3 (tacalcitol) cream, in treating

pt

potential seborrheic dermatitis in a 71-year-old woman. After applying the cream

ce

twice daily over four weeks, her facial eruptions completely cleared. Even after

the use of tacalcitol cream was stopped, recurrence was not reported at two-month
Ac

follow-up. An additional three patients were treated with tacalcitol cream

thereafter, all of whose seborrheic dermatitis-like eruptions experienced rapid

improvement. Thus, tacalcitol cream may be a useful treatment for sebopsoriasis

and facial and scalp SD [125].

 4. Zinc: Zinc may regulate sebum production from its antiandrogen activity through

the inhibition of the 5 alpha-reductase, thus serving as a potential therapeutic

modality for SD. Additionally, zinc may help treat SD through modulation of

epithelial differentiation, and anti-inflammatory and antibacterial activity. Pierard

and Pierard-Franchimont measured the rate of sebum delivery to the skin surface

during treatment with a topical 4% erythromycin and 1-2% zinc acetate

t
ip
formulation applied twice daily over 18 weeks. Results showed that the

formulation significantly decreased sebum delivery to the skin, first at week 9,

cr
and that the decrease in sebum excretion reached a plateau between weeks 9 and

us
15. Thus the erythromycin-zinc preparation’s inhibitory effects were not fully
an
expressed during the early phase of treatment, and were limited in intensity even

if the medication was continued later on in the treatment [126].

M

III. Summary
e d

A wide range of therapeutic modalities are currently used to treat SD including topical
pt

antifungal and anti-inflammatory agents, coal tar, selenium sulfide, metronidazole, lithium
ce

gluconate/succinate, phototherapy, aloe vera, mud, coconut/tea tree oil, quassia amara, and

systemic therapy. The safety and efficacy profiles of the various treatments should be
Ac

considered and individualized depending on each patient a dermatologist faces.

IV. Conflict of Interest

The authors of this review article have NO conflict of interest to declare.

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e d
pt
ce
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VI. Tables

Table 1. Topical treatment of seborrheic dermatitis

Dose/
Medication Mechanism of Action Side Effects
Formulation
ICD† in <1% of patients.
2% Shampoo, cream,
Ketoconazole Itching, burning sensation and
gel or foam Inhibition of fungal cell wall
dryness in 3% of patients.
synthesis.
ICD, itching, burning
Antifungals

Miconazole Cream
sensation.
Inhibition of metal-dependent ICD in <1% of patients.
1.5% shampoo, cream,
Ciclopirox Olamine enzymes. Itching, burning sensation in
gel or lotion
2% of patients.
Increased cellular copper
Zinc Pyrithione 1% shampoo interferes with iron-sulfur ICD in <10% of patients

t
proteins.

ip
Hydrocortisone 1% cream Risk of skin atrophy,
Cortico-
steroids

Betamethasone telangiectasias, folliculitis,

0.05% lotion
dipropionate Anti-inflammatory, anti-irritant. hypertrichosis, and
hypopigmentation with

cr
Desonide 0.05% lotion, gel
prolonged use.
Pimecrolimus 1% cream
Immuno-
modulat

Risk of skin malignancy and

Inhibition of cytokine
ors

us
lymphoma with prolonged use
Tacrolimus 0.1% ointment production by T-lymphocyte.
(Blackbox warning).
TOPICAL

Local folliculitis, ICD on

fingers, psoriasis aggravation,
Antifungal, anti-inflammatory,
an skin atrophy, telangiectasias,
Coal tar 4% shampoo keratolytic, reduces sebum
hyper-pigmentation. Risk of
production.
squamous cell carcinoma with
prolonged use.
M
ICD in ~3% of patients.
Miscellaneous

Selenium sulfide 2.5% shampoo Cytostatic and keratolytic. Orange-brown scalp

discoloration.
d

Anti-inflammatory via
Lithium gluconate/ increased IL-10 and
e

8% ointment or gel ICD in <10% of patients.

succinate decreased TLR2 and TLR4 in
keratinocytes.
pt

Anti-inflammatory via inhibition Rare contact sensitization with

Metronidazole 0.75% gel
of free radical species. prolonged use.
Sebostatic, comedolytic and
Benzoyl Peroxide 2.5% wash ICD in <10% of patients
inhibitory to P. acnes in-vivo
ce

UVB: Cumulative dose Immuno-modulation and Burning, itching sensation

Phototherapy
of 9.8J/cm2 inhibition of cell proliferation. during/after therapy.

Note: Shampoos, foams and lotions are better suited for treating seborrheic dermatitis and dandruff on the scalp; gels, creams and
Ac

ointments are used to treat seborrheic dermatitis on body locations other than the scalp.
† ICD: Irritant contact dermatitis.