Single-blind, randomized controlled trial evaluating

the treatment of facial seborrheic dermatitis with

hydrocortisone 1% ointment compared with
tacrolimus 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
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 corticosteroid
treatment 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 the
face. The primary efficacy measure was the severity of facial seborrhea at the end of treatment (day 84) as
measured by the Seborrhea Area and Severity IndexeFace. Secondary efficacy measures included
physician and patient assessment of seborrhea, the frequency of medication application, and adverse
events.
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 (mean
missed 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 of
doses 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 hydrocortisone 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.

eborrheic dermatitis is a chronic skin disorder

that typically affects sebum-rich areas of the
skin such as the scalp, face, and trunk, and
intertriginous areas.1,2 Topical antifungals2,3 or

corticosteroids2 are generally the first line of treatment for seborrheic dermatitis, and are sometimes
used in combination.2 The clinical usefulness of
topical corticosteroids may be limited by their

From Probity Medical Research Inc.

Ms Clark, an independent medical writer, was involved in drafting
this manuscript, with financial support provided by Astellas
Pharma Canada Inc. This study was an investigator-initiated
research project funded by Astellas Pharma Canada Inc.
Disclosure: Dr K. A. Papp has been a consultant and investigator
for and has received grants and honoraria from Astellas Pharma
Canada Inc. Ms Papp, Ms Dahmer, and Ms Clark have no
conflicts of interest to declare.
Accepted for publication February 14, 2011.

This study was presented as a poster at the Canadian Dermatology

Association Annual Conference in St. Johns, 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

e12 Papp et al

J AM ACAD DERMATOL

JULY 2012

propensity to cause skin thinning and atrophy,4-7 and

Study protocol
epidermal barrier dysfunction.8 Topical calcineurin
Enrolled subjects were randomly assigned to
inhibitors have been used for patients with sebortreatment with hydrocortisone 1% ointment or to
rheic dermatitis because of their fungicidal, immutacrolimus 0.1% ointment applied twice daily as a
nomodulatory, and anti-inflammatory properties.1,9
thin coating, rubbed in gently over symptomatic
At least two small, open-label, uncontrolled studies
regions of the face. Study medication was not
support the efficacy and safety of topical tacrolimus
applied if there was no evidence of active seborrhea.
for the treatment of seborThe study duration was 12
rheic dermatitis,10,11 and one
weeks. After subjects were
CAPSULE SUMMARY
small study suggests it is at
randomized into the study,
least as effective as betamethassessment visits took place
Studies suggest that topical calcineurin
asone lotion or zinc pyriat days 28, 56, and 84. The
inhibitors are effective for the treatment
thione shampoo for the
primary investigator was
of seborrheic dermatitis; however, there
treatment of scalp dermatiblinded to treatment; mediare no comparative trials of tacrolimus
tis.12 To our knowledge, there
cation was dispensed in
against the standard treatment, topical
are no studies directly comcommercial tubes by an uncorticosteroids.
paring tacrolimus ointment
blinded pharmacist, who
Over 12 weeks, topical tacrolimus 0.1%
with topical corticosteroids
used a confidential, secured
ointment was equally effective as
for the treatment of sebordispensing log to assign inhydrocortisone 1% ointment but
rheic dermatitis of the face.
dividual subjects to a particThe primary objective of
required significantly fewer treatment
ular treatment arm. Subjects
this study was to compare
applications to achieve the same level of
were instructed not to disthe efficacy and safety of
disease control.
cuss the labeling, texture, or
tacrolimus 0.1% ointment
constituency of study drug.
Topical tacrolimus was well tolerated,
with hydrocortisone 1% ointmaking it cosmetically a favorable
ment in adult subjects for the
Assessments
treatment option for facial seborrheic
treatment of seborrheic derThe primary efficacy end
dermatitis.
matitis of the face.
point was the objective evaluation of the severity of facial
METHODS
seborrhea at the end of 12 weeks of treatment using
Patient selection
an exploratory clinical measure for seborrhea that
This was a phase II, single-center, single-blind,
was developed specifically for this study, the
randomized, controlled study. Subjects were eligible
Seborrhea Area and Severity IndexeFace (SASIeF).
for inclusion if they were aged 18 years or older, with
The SASIeF is a modified version of the Psoriasis
seborrheic dermatitis on the face, an erythema score
Area and Severity Index that was developed for
of 1 or greater, and an area index of 5% or greater.
psoriasis. SASIeF scores are calculated as follows:
Subjects were excluded if they had clinically signifthe relative area of facial involvement is denoted as a
icant medical conditions that were not well confraction of 1 with the normal hairline defining the
trolled, any condition interfering with the ability to
boundaries of the face. Erythema and scale are
evaluate facial seborrheic dermatitis, any known or
scored on a 5-point scale using the definitions used
suspected hypersensitivity to any constituent of
to conduct Psoriasis Area and Severity Index scoring
study medication, untreated or uncontrolled infec(ie, 0 = none, 1 = slight, 2 = moderate, 3 = striking,
tion involving the face, or untreated cutaneous
and 4 = exceptionally striking). The two scores are
malignancies on the face at the baseline visit.
then summed and multiplied by the relative area of
Subjects were not allowed to use systemic corticofacial involvement ratio. The maximal seborrhea
steroids at doses of prednisone greater than or equal
score is 8 whereas no involvement would have a
to 10 mg daily or equivalent, topical agents other
score of 0. The SASIeF score was measured at all
than bland emollients on the face within 2 weeks
scheduled visits by the primary investigator.
before study initiation, or throughout the study
Other efficacy assessments included the average
period up to the final visit (day 84). Use of systemic
severity of all lesions, which was evaluated at every
agents with significant microbial activity against
visit during treatment by the primary investigator
yeast organisms was not allowed during the study
using the Physician Static Global AssessmenteFace
period. Any woman who was pregnant, breastusing a 6-point scale averaged over all lesions where
feeding, or planning on becoming pregnant during
0 = clear, 1 = almost clear, 2 = mild, 3 = moderate, 4 =
the course of the study period was excluded.
severe, and 5 = very severe. Patients assessed the
d

Papp et al e13

J AM ACAD DERMATOL
VOLUME 67, NUMBER 1

severity of seborrhea using an 11-point patient

global seborrhea assessment scale where 0 = no
seborrhea, and 10 = the worst seborrhea you can
imagine. At every visit the investigator recorded
the frequency of application of study medication,
the interval between periods of application, and the
amount of medication used.
Safety and tolerability were assessed at all scheduled visits by questioning subjects about adverse
events and serious adverse events. Subjects recorded
any adverse events including irritation, pruritus, and
other possible study medicationerelated adverse
events in a study diary.
Statistical methods
As a prespecified assessment, efficacy was determined by comparing the mean improvement in
SASIeF scores between treatment groups at the
end of the 12-week treatment period using a twosided Fisher test. All statistical results were considered significant if P values were .05 or less. Subjects
withdrawing early from the study had had a final visit
on day 84. All enrolled subjects were considered in
the safety analysis. Only subjects completing 4
weeks or more of treatment were included in the
efficacy analyses on an intent-to-treat basis.

RESULTS
Patient population
A total of 33 subjects were screened for this study
and of these, 30 were randomized to study treatment.
Fourteen subjects were randomized to hydrocortisone 1% ointment and 16 to tacrolimus 0.1% ointment. All subjects (n = 16) from the tacrolimus group
and 13 subjects from the hydrocortisone group
completed the 12-week study (one subject in the
hydrocortisone group was lost to follow-up).
The two treatment groups were well balanced for
baseline demographics (Table I).
Treatment efficacy
Both hydrocortisone 1% ointment and tacrolimus
0.1% ointment groups showed a statistically significant improvement in mean SASIeF score from
baseline to study end (Fig 1). This difference was
observed as early as week 4 and was sustained until
study end, with no further improvements beyond
week 4. There was no difference between the two
treatment groups at study end (P = .86).
A similar pattern of improvement in the Physician
Static Global AssessmenteFace score was observed
as for the SASIeF (data not shown). Patient global
assessment of seborrhea severity showed a significant improvement from baseline to study end in the
tacrolimus 0.1% group (P \ .001) but not for the

Table I. Baseline demographics of randomized

subjects
Hydrocortisone
(n = 14)

Age, y, mean (range)

Gender
Men, n (%)
Women, n (%)
Race
Caucasian, n (%)
SASIeF score,* mean
(range)
PSGAeF score,y mean
(range)
Patient global seborrhea
assessment score,z mean
(range)
Comorbid diagnoses, n (%)
Hypertension
Hypercholesterolemia
Type 2 diabetes
Concomitant medications, n
Antihypertensives
Hypercholesterolemics
Antidiabetics

Tacrolimus
(n = 16)

52.9 (20-80)

52.8 (25-70)

10 (71.4)
4 (28.6)

14 (87.5)
2 (12.5)

14 (100)
16 (100)
0.64 (0.1-1.75) 0.78 (0.15-4.5)
2.79 (2-4)

2.88 (2-4)

4.36 (1-8)

5.0 (1-8)

2 (14.3)
0
3 (21.4)
(%)
4 (28.6)
1 (7.1)
1 (14.3)

6 (37.5)
5 (31.3)
2 (12.5)
5 (31.3)
5 (31.3)
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).
y
PSGAeF uses 6-point scale averaged over all lesions where
0 = clear, 1 = almost clear, 2 = mild, 3 = moderate, 4 = severe, and
5 = very severe.
z
Patient global assessment uses 11-point scale where 0 = no
seborrhea, and 10 = worst seborrhea you can imagine.

hydrocortisone 1% group (P = .5). At study end, the

mean patient assessment score was significantly
lower in the tacrolimus 0.1% group compared with
the hydrocortisone 1% group (1.75 vs 3.79, P \.05),
indicating that subjects treated with tacrolimus
thought their facial seborrhea was less severe than
those treated with hydrocortisone (data not shown).
There was a significant decline in the frequency of
study medication application in both the tacrolimus
and hydrocortisone treatment groups from baseline
to study end (P \ .005 for both treatment groups).
The greatest reduction in medication use was observed between the baseline assessment and the first
visit at week 4 (Fig 2). There was a statistically
significant difference between the two treatment
groups at week 4 (P \.05), with only a trend toward
a significant difference between the groups at 8
weeks (P = .1) and at study end (P = .08). Overall,
subjects in the tacrolimus group applied medication
on significantly fewer days over the course of the

e14 Papp et al

J AM ACAD DERMATOL

JULY 2012

Fig 1. Within-group change from baseline to study end: P \.05 for both treatment groups. No
significant difference between treatment groups at any time point. SASIeF, Seborrhea Area and
Severity 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 hydrocortisone
1% group at visit 2 (P \ .05) but not at visit 3 (P = .1) or at visit 4 (P = .08).

12-week study than those in the hydrocortisone

group (711 vs 334 total missed doses, P \.05).
Safety and tolerability
Both hydrocortisone 1% ointment and tacrolimus
0.1% ointment were generally well tolerated. Only 3
adverse events were considered by the investigator
to be possibly related to study drug (all in the
tacrolimus group: two cases of flushing and one
case of irritation at the application site). There were
no serious adverse events reported.

DISCUSSION
This phase II, single-center, randomized controlled trial compared the efficacy and safety of
tacrolimus 0.1% ointment with hydrocortisone 1%
ointment in subjects with facial seborrheic dermatitis.
Our results indicate that topical tacrolimus is equally
effective at clearing seborrheic dermatitis as a standard topical corticosteroid, but offers the benefit of
fewer medication applications to achieve the same
level of disease control, without the long-term adverse effects associated with topical corticosteroids.

J AM ACAD DERMATOL
VOLUME 67, NUMBER 1

Although clinical assessment and physician global

assessment scores showed similar improvements
with either topical tacrolimus or hydrocortisone
ointment, the patients subjective global assessment
suggested that facial seborrhea was less severe at
study end in those treated with tacrolimus.
Our findings support the results of previous small
pilot studies evaluating the efficacy of tacrolimus
ointment for the treatment of seborrheic dermatitis.
Meshkinpour et al10 evaluated tacrolimus 0.1% ointment in 18 consecutive patients with seborrheic
dermatitis in a single-center, open-label study.
Tacrolimus treatment resulted in complete clearance
in 61% of patients, and the remaining patients
showed a 70% to 99% clearance at the end of
treatment. Another small, open-label, uncontrolled
trial in 16 subjects with seborrheic dermatitis evaluated 6 weeks of daily treatment with tacrolimus 0.1%
ointment.11 Mean lesional erythema and scaling
scores were statistically significantly improved at
study end compared with baseline (both P \ .05).
In a small, uncontrolled trial of tacrolimus 0.1%
ointment, 5 of 6 subjects with facial seborrheic
dermatitis (83%) responded very well to treatment
within 2 weeks.13 Topical tacrolimus was directly
compared against topical betamethasone lotion or
zinc pyrithione shampoo for the treatment of scalp
seborrheic dermatitis in an open-label trial of 83
subjects.12 Tacrolimus was found to be as effective as
betamethasone or zinc pyrithione; however, tacrolimus offered more prolonged remission compared
with topical betamethasone.
Limitations of this study include its open-label
design and small number of subjects recruited. Time
to relapse was not evaluated; therefore, this study
provides no information on the duration of effect.
Despite these limitations, this phase II study provides
a rationale for evaluating the use of topical tacrolimus ointment in larger, longer-term randomized,
double-blinded trials.

CONCLUSIONS
Our results demonstrate that facial seborrheic
dermatitis was equally controlled by treatment with

Papp et al e15

topical tacrolimus 0.1% ointment and hydrocortisone 1% ointment, with tacrolimus offering the
benefit of significantly less frequent medication
application. This is an important distinction, because seborrheic dermatitis is a chronic condition
requiring long-term treatment to maintain disease
control. The results reported here suggest that
topical tacrolimus may be an effective and cosmetically favorable treatment for facial seborrheic
dermatitis.
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