Single-blind, randomized controlled trial evaluatingthe treatment of facial seborrheic dermatitis with

hydrocortisone 1% ointment compared withtacrolimus 0.1% ointment in adults

Kim A. Papp, MD, PhD, FRCPC, Alexine Papp, BA, Betty Dahmer, RN, and Christina S. Clark, MSc

Waterloo, Ontario, Canada

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Background: Tacrolimus is a topical calcineurin inhibitor with immunomodulatory, anti-inflammatory,and fungicidal properties that may be beneficial in the treatment of facial seborrheic dermatitis.

Objectives: We sought to compare the efficacy and safety of tacrolimus with standard corticosteroidtreatment in adults with facial seborrheic dermatitis in a phase II, single-blind, randomized controlled trial.

Methods: Adult patients were enrolled in a 12-week study. Subjects were randomized to tacrolimus 0.1%ointment (n = 16) or hydrocortisone 1% ointment (n = 14) applied twice daily to symptomatic regions of theface. The primary efficacy measure was the severity of facial seborrhea at the end of treatment (day 84) asmeasured by the Seborrhea Area and Severity IndexeFace. Secondary efficacy measures includedphysician and patient assessment of seborrhea, the frequency of medication application, and adverseevents.

Results: The severity of facial seborrhea was similarly improved in both treatment groups (P = .86).Tacrolimus 0.1% ointment was used on significantly fewer days than 1% hydrocortisone ointment (meanmissed doses per patient at first visit: 15.6 vs 7.6, P\ .05; at last visit: 13.5 vs 7.7, P = .08). The majority ofdoses were missed because of lack of symptoms. The adverse event profile for both agents was similar;however, there was a numerically higher incidence of adverse events in the hydrocortisone group.

Limitations: This was a small, open-label study.

Conclusion: Tacrolimus 0.1% ointment required significantly fewer applications compared with hydro-cortisone 1% ointment to achieve a comparable clinical response in adults with facial seborrheic dermatitis.Tacrolimus was generally well tolerated. ( J Am Acad Dermatol 2012;67:e11-5.)

Key words: calcineurin inhibition; facial seborrheic dermatitis; frequency of application; hydrocortisone;topical tacrolimus ointment.

Seborrheic dermatitis is a chronic skin disorderthat typically affects sebum-rich areas of theskin such as the scalp, face, and trunk, and

intertriginous areas.1,2 Topical antifungals2,3 or

Probity Medical Research Inc.

lark, an independent medical writer, was involved in drafting

is manuscript, with financial support provided by Astellas

arma Canada Inc. This study was an investigator-initiated

search project funded by Astellas Pharma Canada Inc.

osure: Dr K. A. Papp has been a consultant and investigator

r and has received grants and honoraria from Astellas Pharma

anada Inc. Ms Papp, Ms Dahmer, and Ms Clark have no

nflicts of interest to declare.

pted for publication February 14, 2011.

corticosteroids2 are generally the first line of treat-ment for seborrheic dermatitis, and are sometimesused in combination.2 The clinical usefulness oftopical corticosteroids may be limited by their

This study was presented as a poster at the Canadian Dermatology

Association Annual Conference in St. John’s, Newfoundland on

July 2, 2010.

Reprint requests: Kim A. Papp, MD, PhD, FRCPC, Probity Medical

Research Inc, 135 Union St E, Waterloo, Ontario, Canada, N2J

1C4. E-mail: kapapp@probitymedical.com.

Published online November 21, 2011.

0190-9622/$36.00

� 2011 by the American Academy of Dermatology, Inc.

doi:10.1016/j.jaad.2011.02.032

e11

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JULY 2012e12 Papp et al

propensity to cause skin thinning and atrophy,4-7 andepidermal barrier dysfunction.8 Topical calcineurininhibitors have been used for patients with sebor-rheic dermatitis because of their fungicidal, immu-nomodulatory, and anti-inflammatory properties.1,9

At least two small, open-label, uncontrolled studiessupport the efficacy and safety of topical tacrolimus

CAPSULE SUMMARY

d Studies suggest that topical calcineurininhibitors are effective for the treatmentof seborrheic dermatitis; however, thereare no comparative trials of tacrolimusagainst the standard treatment, topicalcorticosteroids.

d Over 12 weeks, topical tacrolimus 0.1%ointment was equally effective ashydrocortisone 1% ointment butrequired significantly fewer treatmentapplications to achieve the same level ofdisease control.

d Topical tacrolimus was well tolerated,making it cosmetically a favorabletreatment option for facial seborrheicdermatitis.

for the treatment of sebor-rheic dermatitis,10,11 and onesmall study suggests it is atleast as effective as betameth-asone lotion or zinc pyri-thione shampoo for thetreatment of scalp dermati-tis.12 To our knowledge, thereare no studies directly com-paring tacrolimus ointmentwith topical corticosteroidsfor the treatment of sebor-rheic dermatitis of the face.

The primary objective ofthis study was to comparethe efficacy and safety oftacrolimus 0.1% ointmentwith hydrocortisone 1% oint-ment in adult subjects for thetreatment of seborrheic der-matitis of the face.

METHODSPatient selection

This was a phase II, single-center, single-blind,randomized, controlled study. Subjects were eligiblefor inclusion if they were aged 18 years or older, withseborrheic dermatitis on the face, an erythema scoreof 1 or greater, and an area index of 5% or greater.Subjects were excluded if they had clinically signif-icant medical conditions that were not well con-trolled, any condition interfering with the ability toevaluate facial seborrheic dermatitis, any known orsuspected hypersensitivity to any constituent ofstudy medication, untreated or uncontrolled infec-tion involving the face, or untreated cutaneousmalignancies on the face at the baseline visit.Subjects were not allowed to use systemic cortico-steroids at doses of prednisone greater than or equalto 10 mg daily or equivalent, topical agents otherthan bland emollients on the face within 2 weeksbefore study initiation, or throughout the studyperiod up to the final visit (day 84). Use of systemicagents with significant microbial activity againstyeast organisms was not allowed during the studyperiod. Any woman who was pregnant, breast-feeding, or planning on becoming pregnant duringthe course of the study period was excluded.

Study protocolEnrolled subjects were randomly assigned to

treatment with hydrocortisone 1% ointment or totacrolimus 0.1% ointment applied twice daily as athin coating, rubbed in gently over symptomaticregions of the face. Study medication was notapplied if there was no evidence of active seborrhea.

The study duration was 12weeks. After subjects wererandomized into the study,assessment visits took placeat days 28, 56, and 84. Theprimary investigator wasblinded to treatment; medi-cation was dispensed incommercial tubes by an un-blinded pharmacist, whoused a confidential, secureddispensing log to assign in-dividual subjects to a partic-ular treatment arm. Subjectswere instructed not to dis-cuss the labeling, texture, orconstituency of study drug.

AssessmentsThe primary efficacy end

point was the objective eval-uation of the severity of facial

seborrhea at the end of 12 weeks of treatment usingan exploratory clinical measure for seborrhea thatwas developed specifically for this study, theSeborrhea Area and Severity IndexeFace (SASIeF).The SASIeF is a modified version of the PsoriasisArea and Severity Index that was developed forpsoriasis. SASIeF scores are calculated as follows:the relative area of facial involvement is denoted as afraction of 1 with the normal hairline defining theboundaries of the face. Erythema and scale arescored on a 5-point scale using the definitions usedto conduct Psoriasis Area and Severity Index scoring(ie, 0 = none, 1 = slight, 2 = moderate, 3 = striking,and 4 = exceptionally striking). The two scores arethen summed and multiplied by the relative area offacial involvement ratio. The maximal seborrheascore is 8 whereas no involvement would have ascore of 0. The SASIeF score was measured at allscheduled visits by the primary investigator.

Other efficacy assessments included the averageseverity of all lesions, which was evaluated at everyvisit during treatment by the primary investigatorusing the Physician Static Global AssessmenteFaceusing a 6-point scale averaged over all lesions where0 = clear, 1 = almost clear, 2 = mild, 3 = moderate, 4 =severe, and 5 = very severe. Patients assessed the

Table I. Baseline demographics of randomizedsubjects

Hydrocortisone

(n = 14)

Tacrolimus

(n = 16)

Age, y, mean (range) 52.9 (20-80) 52.8 (25-70)GenderMen, n (%) 10 (71.4) 14 (87.5)Women, n (%) 4 (28.6) 2 (12.5)

RaceCaucasian, n (%) 14 (100) 16 (100)

SASIeF score,* mean(range)

0.64 (0.1-1.75) 0.78 (0.15-4.5)

PSGAeF score,y mean(range)

2.79 (2-4) 2.88 (2-4)

Patient global seborrheaassessment score,z mean(range)

4.36 (1-8) 5.0 (1-8)

Comorbid diagnoses, n (%)Hypertension 2 (14.3) 6 (37.5)Hypercholesterolemia 0 5 (31.3)Type 2 diabetes 3 (21.4) 2 (12.5)

Concomitant medications, n (%)Antihypertensives 4 (28.6) 5 (31.3)Hypercholesterolemics 1 (7.1) 5 (31.3)Antidiabetics 1 (14.3) 1 (6.3)

PSGAeF, Physician Static Global AssessmenteFace; SASIeF,Seborrhea Area and Severity IndexeFace.

*SASIeF assesses erythema and scale relative to total area of facial

involvement, with maximal severity score of 8 (0 denotes no

involvement).yPSGAeF uses 6-point scale averaged over all lesions where

0 = clear, 1 = almost clear, 2 = mild, 3 = moderate, 4 = severe, and

5 = very severe.zPatient global assessment uses 11-point scale where 0 = no

seborrhea, and 10 = worst seborrhea you can imagine.

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severity of seborrhea using an 11-point patientglobal seborrhea assessment scale where 0 = noseborrhea, and 10 = the worst seborrhea you canimagine. At every visit the investigator recordedthe frequency of application of study medication,the interval between periods of application, and theamount of medication used.

Safety and tolerability were assessed at all sched-uled visits by questioning subjects about adverseevents and serious adverse events. Subjects recordedany adverse events including irritation, pruritus, andother possible study medicationerelated adverseevents in a study diary.

Statistical methodsAs a prespecified assessment, efficacy was deter-

mined by comparing the mean improvement inSASIeF scores between treatment groups at theend of the 12-week treatment period using a two-sided Fisher test. All statistical results were consid-ered significant if P values were .05 or less. Subjectswithdrawing early from the study had had a final visiton day 84. All enrolled subjects were considered inthe safety analysis. Only subjects completing 4weeks or more of treatment were included in theefficacy analyses on an intent-to-treat basis.

RESULTSPatient population

A total of 33 subjects were screened for this studyand of these, 30 were randomized to study treatment.Fourteen subjects were randomized to hydrocorti-sone 1% ointment and 16 to tacrolimus 0.1% oint-ment. All subjects (n = 16) from the tacrolimus groupand 13 subjects from the hydrocortisone groupcompleted the 12-week study (one subject in thehydrocortisone group was lost to follow-up).

The two treatment groups were well balanced forbaseline demographics (Table I).

Treatment efficacyBoth hydrocortisone 1% ointment and tacrolimus

0.1% ointment groups showed a statistically signifi-cant improvement in mean SASIeF score frombaseline to study end (Fig 1). This difference wasobserved as early as week 4 and was sustained untilstudy end, with no further improvements beyondweek 4. There was no difference between the twotreatment groups at study end (P = .86).

A similar pattern of improvement in the PhysicianStatic Global AssessmenteFace score was observedas for the SASIeF (data not shown). Patient globalassessment of seborrhea severity showed a signifi-cant improvement from baseline to study end in thetacrolimus 0.1% group (P \ .001) but not for the

hydrocortisone 1% group (P = .5). At study end, themean patient assessment score was significantlylower in the tacrolimus 0.1% group compared withthe hydrocortisone 1% group (1.75 vs 3.79, P\.05),indicating that subjects treated with tacrolimusthought their facial seborrhea was less severe thanthose treated with hydrocortisone (data not shown).

There was a significant decline in the frequency ofstudy medication application in both the tacrolimusand hydrocortisone treatment groups from baselineto study end (P \ .005 for both treatment groups).The greatest reduction in medication use was ob-served between the baseline assessment and the firstvisit at week 4 (Fig 2). There was a statisticallysignificant difference between the two treatmentgroups at week 4 (P\.05), with only a trend towarda significant difference between the groups at 8weeks (P = .1) and at study end (P = .08). Overall,subjects in the tacrolimus group applied medicationon significantly fewer days over the course of the

Fig 1. Within-group change from baseline to study end: P\.05 for both treatment groups. Nosignificant difference between treatment groups at any time point. SASIeF, Seborrhea Area andSeverity IndexeFace.

Fig 2. Within-group change from baseline to study end: P\ .005 for both treatment groups.There were significantly more missed doses in tacrolimus 0.1% group than in hydrocortisone1% group at visit 2 (P\ .05) but not at visit 3 (P = .1) or at visit 4 (P = .08).

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12-week study than those in the hydrocortisonegroup (711 vs 334 total missed doses, P\ .05).

Safety and tolerabilityBoth hydrocortisone 1% ointment and tacrolimus

0.1% ointment were generally well tolerated. Only 3adverse events were considered by the investigatorto be possibly related to study drug (all in thetacrolimus group: two cases of flushing and onecase of irritation at the application site). There wereno serious adverse events reported.

DISCUSSIONThis phase II, single-center, randomized con-

trolled trial compared the efficacy and safety oftacrolimus 0.1% ointment with hydrocortisone 1%ointment in subjects with facial seborrheic dermatitis.Our results indicate that topical tacrolimus is equallyeffective at clearing seborrheic dermatitis as a stan-dard topical corticosteroid, but offers the benefit offewer medication applications to achieve the samelevel of disease control, without the long-term ad-verse effects associated with topical corticosteroids.

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Although clinical assessment and physician globalassessment scores showed similar improvementswith either topical tacrolimus or hydrocortisoneointment, the patients’ subjective global assessmentsuggested that facial seborrhea was less severe atstudy end in those treated with tacrolimus.

Our findings support the results of previous smallpilot studies evaluating the efficacy of tacrolimusointment for the treatment of seborrheic dermatitis.Meshkinpour et al10 evaluated tacrolimus 0.1% oint-ment in 18 consecutive patients with seborrheicdermatitis in a single-center, open-label study.Tacrolimus treatment resulted in complete clearancein 61% of patients, and the remaining patientsshowed a 70% to 99% clearance at the end oftreatment. Another small, open-label, uncontrolledtrial in 16 subjects with seborrheic dermatitis evalu-ated 6 weeks of daily treatment with tacrolimus 0.1%ointment.11 Mean lesional erythema and scalingscores were statistically significantly improved atstudy end compared with baseline (both P \ .05).In a small, uncontrolled trial of tacrolimus 0.1%ointment, 5 of 6 subjects with facial seborrheicdermatitis (83%) responded very well to treatmentwithin 2 weeks.13 Topical tacrolimus was directlycompared against topical betamethasone lotion orzinc pyrithione shampoo for the treatment of scalpseborrheic dermatitis in an open-label trial of 83subjects.12 Tacrolimus was found to be as effective asbetamethasone or zinc pyrithione; however, tacroli-mus offered more prolonged remission comparedwith topical betamethasone.

Limitations of this study include its open-labeldesign and small number of subjects recruited. Timeto relapse was not evaluated; therefore, this studyprovides no information on the duration of effect.Despite these limitations, this phase II study providesa rationale for evaluating the use of topical tacroli-mus ointment in larger, longer-term randomized,double-blinded trials.

CONCLUSIONSOur results demonstrate that facial seborrheic

dermatitis was equally controlled by treatment with

topical tacrolimus 0.1% ointment and hydrocorti-sone 1% ointment, with tacrolimus offering thebenefit of significantly less frequent medicationapplication. This is an important distinction, be-cause seborrheic dermatitis is a chronic conditionrequiring long-term treatment to maintain diseasecontrol. The results reported here suggest thattopical tacrolimus may be an effective and cosmet-ically favorable treatment for facial seborrheicdermatitis.

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