S eborrheic dermatitis is a common inflammatory chronic-recurrent disorder characterized by erythema and fine scaling, with or without symptoms such as pruritus. The scalp is affected in up to 90% of cases and the face in up to 75% of patients; other sites of predilection include the periauricular region, central chest, axillae and groin regions.1-4

A variety of effective therapeutic agents are available, including topical corticosteroids, topical antifungal agents, sulfur-sulfacetamide combinations, sulfacetamide, zinc pyrithione and selenium sulfide; multiple vehicle formulations (for example shampoo, foam, cream, gel, lotion, solution, etc.), allow for usage applicable to specific body locations. Although the etiology of seborrheic dermatitis has not been fully elucidated, the commensal yeast, Malassezia furfur (Pityrosporum spp), appears to play a pivotal role in the pathogenesis.1,4

The topical calcineurin inhibitors, pimecrolimus (Elidel) and tacrolimus (Protopic), are FDA-approved in the United States for treatment of atopic dermatitis and have also been shown to be effective in the treatment of other inflammatory dermatoses, including seborrheic dermatitis.5-11 Effective reduction in signs and symptoms coupled with favorable safety with chronic administration supports their consideration as viable treatment options for managing seborrheic dermatitis.

This article reviews office-based observational experience with pimecrolimus and tacrolimus in the treatment of seborrheic dermatitis. A perspective on overall treatment recommendations is also reviewed based on available literature and clinical experience.

Pathogenesis of Seborrheic Dermatitis
The pathogenesis of seborrheic dermatitis is poorly understood.1,4 The histological pattern of seborrheic dermatitis suggests a progressive inflammatory process.1,12 Biopsy early in the course of the disease reveals a spongiform pattern; older lesions exhibit parakeratotic and orthokeratotic follicular plugging and an irregular rete ridge pattern.12 Edema and subsequent intermittent infiltration with granulocytes erupting from dermal papillae have been described during periods of disease exacerbation.4

The role of the commensal yeast, Malassezia, in the pathogenesis of seborrheic dermatitis is based on multiple studies.1,13 A variety of species of Malassezia have been identified based on advances in evaluating ultrastructural, morphologic, biologic and molecular properties among this unique collection of yeast forms. Although several species have been suggested in association with development of seborrheic dermatitis, M. globosa and M. restricta have been most closely associated with this disorder.13

Malassezia spp do not appear to be the only direct causative factor, but appear to act as a significant “co-factor” in augmenting the inflammatory process associated with seborrheic dermatitis.1,13 As seborrheic dermatitis improves with treatment, a reduction in Malassezia organism count has been noted in some studies, with recolonization correlating with recurrent disease.1,13 It has also been suggested that seborrheic dermatitis develops secondary to an exaggerated or abnormal host-dependent immune response to Malassezia and not necessarily due to overgrowth of the organism.1,4,13

Multiple immunologic mechanisms have been proposed in relation to Malassezia.1,4,13 These include recognition of complement activation by Malassezia, effect on local cytokine patterns, immune complex deposition in stratum corneum below clusters of Malassezia, and lipase production by Malassezia, which stimulates formation of arachidonic acid.1,13-17 Despite eradication or reduction of Malassezia after treatment of seborrheic dermatitis with antifungal agents such as ciclopirox (Loprox, Penlac) or ketoconazole (Nizoral), some patients achieve only partial or limited response. This suggests that other pathogenic mechanisms are also operative.

Therapeutic Armamentarium for Seborrheic Dermatitis
Multiple agents representing a variety of chemical and therapeutic classes are available for the treatment of seborrheic dermatitis.1,4,18-20 A variety of vehicle choices (shampoo, cream, gel, foam, lotion) allow for practical and cosmetically acceptable use for different body locations. Agents found to be effective for seborrheic dermatitis directly reduce inflammation associated with the disease and/or decrease the number of M. furfur organisms. As a more clear understanding of the pathogenesis of seborrheic dermatitis is elucidated by additional research, the mechanisms of action of treatments for seborrheic dermatitis will be better defined.

The following discussion addresses the treatment of seborrheic dermatitis using specific topical agents and formulations that require prescribing by a licensed practitioner. (See Table 1 above for a detailed list of therapeutic choices.)

An informal survey of 100 dermatologists (completed by the author) indicated that the vast majority prescribe topical corticosteroids and topical antifungal agents for treatment of seborrheic dermatitis.21 The survey results included the following:
• Three-fourths of the recommended prescribing of antifungal agents was reported to be in the formulation of a shampoo for scalp involvement.
• The use of antifungal agents for facial skin was reported to be helpful for long-term control, especially in patients with tendency for chronic involvement and frequent exacerbations.
• Foam corticosteroid and sulfacetamide formulations were reported to be highly effective and popular among physicians and patients, especially for hair bearing areas (scalp, beard and moustache region).
• Another common observation was the increased use of topical calcineurin inhibitors, pimecrolimus and tacrolimus, for seborrheic dermatitis of glabrous skin.

Use of Topical Calcineurin Inhibitors In Seborrheic Dermatitis
Pimecrolimus (Elidel) cream (1%) and tacrolimus (Protopic) ointment (0.03%, 0.1%) are currently FDA-approved in the United States for atopic dermatitis in adults and children aged 2 years and older.6 Efficacy and safety with both agents are well established for this indication.

The mechanism of action of the calcineurin inhibitors relates to reversible inhibition of nuclear transcription and release of specific pro-inflammatory cytokines from activated T-lymphocytes.6 Over evaluation periods of 6 months and 12 months, maintenance therapy with topical pimecrolimus has been shown to be topical steroid-sparing in the chronic management of atopic dermatitis.8-10

Although underlying pathogenic mechanisms, several clinical features and histologic characteristics may differ, similarities between seborrheic dermatitis and atopic dermatitis include presence of cutaneous inflammation, the common association of pruritus as a related symptom, chronicity of disease, tendency for exacerbation and responsiveness to topical corticosteroid therapy.

Topical corticosteroids are commonly used to rapidly control disease exacerbations, especially flares associated with symptoms or flaking and erythema.1,4,18,19 Limitations related to the duration of topical corticosteroid use continue to support the search for additional agents for seborrheic dermatitis that meet the following requirements:
1. Effective control of signs and symptoms.
2. Efficacy within a reasonable time period.
3. May be used repeatedly and chronically without concern for significant adverse effects.

The use of topical calcineurin inhibitors has been suggested for treatment of seborrheic dermatitis.7,11,22,23 In addition to their anti-inflammatory effects, these agents have demonstrated in vitro antifungal activity against M. furfur and Pityrosporum spp.11 The
following offers a closer look at the performance of these agents.

Topical pimecrolimus. The efficacy of topical pimecrolimus 1% cream has been documented in open-label evaluations and case reports. Fifteen adult patients with recurrent seborrheic dermatitis involving the face and/or auricular and periauricular regions were treated with topical pimecrolimus applied twice daily as monotherapy.22 In 80% of patients, the visible eruption and pruritus resolved within 7 to 10 days or less. The remainder cleared using either a short course of medium potency topical corticosteroid therapy or topical sulfacetamide 10%/ sulfur 5% topical suspension. No adverse reactions were reported. Other case reports have also documented the efficacy of topical pimecrolimus 1% cream for facial and hair line seborrheic dermatitis, including cases with poor response to topical ketoconazole 2% shampoo and cream and hydrocortisone 1% cream.23,24 Complete clearance of seborrheic dermatitis in less than 10 days has been documented. No significant adverse effects or local tolerability reactions have been noted.

A randomized, open-label study reported results comparing pimecrolimus 1% cream versus betamethasone 17-valerate 0.1% cream applied twice daily for treatment of seborrheic dermatitis in adult patients (n=20).25 Treatment was to be discontinued upon disappearance of symptoms. A gradual reduction of erythema, scaling and pruritus was noted in both groups with all patients discontinuing therapy within nine days. With the exception of pruritus, betamethasone 17-valerate tended to reduce signs and symptoms faster than pimecrolimus; differences in reduction were not statistically significant. Evaluation on day 21 revealed relapse of seborrheic dermatitis in six of 11 (55%) patients treated with pimecrolimus and seven of nine (78%) patients treated with betamethasone 17-valerate with disease presentation milder than at baseline. All relapses were treated with pimecrolimus 1% cream twice daily with clearance observed within 3 days. In this trial, pimecrolimus exhibited a statistically significant faster reduction in pruritus than betamethasone 17-valerate.

Additional comparative trials in a larger population of patients are warranted in order to evaluate therapeutic differences among the various topical agents used to treat seborrheic dermatitis.
Topical tacrolimus. Tacrolimus 0.1% ointment has been shown to be effective for seborrheic dermatitis in two open-label studies inclusive of 31 patients treated for periods of 2 to 6 weeks.26,27 Effective clearance or significant improvement was demonstrated in many patients within the first 2 weeks of therapy, with a trend toward continued improvement noted in the patient group treated for 6 weeks. No significant adverse reactions were observed and overall local tolerability was favorable. Five patients noted mild, transient application site stinging or burning.

Additional Experience in Treating Seborrheic Dermatitis
Observational Experience. An open, office-based, observational evaluation was completed to evaluate the efficacy and tolerability of pimecrolimus 1% cream applied twice daily for seborrheic dermatitis involving the face, hairline and/or auricular-periauricular regions.28 Fourteen adult patients (12 males, 2 females), age range 28 through 66 years were included in the analysis. None of the patients had used other therapies for at least 2 weeks prior to presentation. Previous treatments reported by patients included in the evaluation included hydrocortisone 1% cream (nine patients), ketoconazole 2% cream (four patients) and ketoconazole 2% shampoo (six patients).

All of the patients included in the analysis by the investigator were rated to have disease of at least moderate severity. The shortest duration of seborrheic dermatitis reported since the initial recognition of the disorder was 2 years, with most patients noting presence of the disease for >5 years with periodic exacerbations and remissions. All patients presented with erythema and fine scaling involving the eyebrows, glabella area of the forehead and paranasal region. Hairline, auricular and periauricular involvement was noted in nine patients. Symptoms of pruritus or “irritation” (characterized as stinging or burning) were present in 10 of the patients. Features of rosacea overlap with seborrheic dermatitis were not present in any of the patients included in the evaluation. Excluded systemic mediations were corticosteroids, antifungal agents, antibiotics and immunosuppressive drugs. No other topical agents were utilized to the face, ears or scalp regions during the evaluation.

Treatment Protocol. All patients were instructed to use a gentle, non-lipid liquid cleanser for facial washing and a non-medicated shampoo for the scalp. Instructions were given to apply
pimecrolimus 1% cream twice daily to affected regions of involvement until follow-up. Return appointments for follow-up examination was arranged for within 3 to 4 weeks depending on scheduling availability of the patient. The patients were instructed to keep a diary of their response to treatment, inclusive of evaluations of erythema, flaking and scaling and associated symptoms (stinging, itching, burning, other).

Results. Clearance of seborrheic dermatitis was noted in 13 of 14 patients. Based on patient diary assessments,complete clearance of seborrheic dermatitis was observed in 10 patients and marked, visible improvement noted in three patients. Of patients noting complete or significant clearance, 11 of 13 reported this response within the first 7 to 14 days of therapy; six reported clearance within the first few days.

In patients reporting associated symptomatology of seborrheic dermatitis, the resolution of symptoms such as itching, stinging and burning correlated with clearance of visible disease in all cases.

At the point of follow-up with the investigator, 100% consistency was noted between the assessments of the investigator and the patient. All 13 patients who reported complete clearance or improvement of seborrheic dermatitis with pimecrolimus 1% cream agreed to continue future therapy with this same agent.

Effective treatment of periauricular seborrheic dermatitis with pimecrolimus 1% cream applied twice daily is demonstrated in photographs 1A and 1B. Efficacious results with the same therapy in another patient with forehead glabella involvement is depicted in photographs 2A and 2B.
One patient discontinued application of pimecrolimus 1% cream to the eyebrow and glabella areas after sensing stinging at the application site. The patient did not repeat additional applications and did not note an associated eruption (increased redness or rash) or worsening of the primary disease. At follow-up, there was no evidence of contact dermatitis or abnormality other than features of seborrheic dermatitis at the same facial sites as noted initially. This patient chose not to be rechallenged and was subsequently treated with a low potency topical corticosteroid for facial seborrheic dermatitis.

Looking Ahead
The pathogenesis of seborrheic dermatitis is poorly understood; however, multiple studies indicate that certain Malassezia organisms play a role in the pathogenesis of seborrheic dermatitis. Presently, a variety of treatments are available for seborrheic dermatitis, and the most effective agents are those that directly reduce inflammation associated with the disease or those
that decrease the number of M. furfur organisms.

Recently, topical calcineurin inhibitors (pimecrolimus and tacrolimus) have been suggested for treatment of seborrheic dermatitis. At this point, additional studies, including larger controlled trials, are needed to further define efficacy parameters and treatment regimens for initial therapy and maintenance treatment.