Pharmacology and therapeutics

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2008 The
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Publishing
International
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of Dermatology
Society of Dermatology

Efficacy and safety of tarcrolimus cream 0.1% in the treatment of

Efficacy
Xu
Pharmacology
et al.and safety
and therapeutics
of tarcrolimus cream

vitiligo
Ai-E. Xu, BS, Di-Min Zhang, MM, Xiao-Dong Wei, BS, Bo Huang, MM, and Liang-Jun Lu, MM

From the Department of Dermatology, the Abstract

Third Hospital of Hangzhou, Hangzhou, Background Vitiligo is an acquired, pigmentary skin disorder which is disfiguring and difficult
China to treat. Phototherapy and application of topical corticosteroids are most commonly prescribed.
However, these therapies are often not effective and use of corticosteroids on the face may lead
Correspondence
Ai.-E. Xu to cutaneous atrophy, telangiectasia, and ocular complications.
Department of Dermatology Objective We sought to assess the efficacy of topical tacrolimus ointment in the treatment
Third Hospital of Hangzhou of vitiligo.
Hangzhou Methods A prospective pilot study was performed of 30 patients with vitiligo. Patients were
China
treated with tacrolimus ointment for at least 4 months. Clinical responses were documented
E-mail: xuaiehz@msn.com
during clinic visits, and by pretacrolimus and post-tacrolimus photography.
Results Twenty-five (83.3%) patients showed some repigmentation at the end of 4 months.
Patients with vitiligo for more than 5 years also responded well to tacrolimus ointment.
Repigmentation in active vitiligo was superior to that in stable vitiligo. 80% of patients with
segmental vitiligo of the head and neck showed some response to tacrolimus, but there was
no statistical significance between segmental and vulgaris vitiligo. The mean percentage of
repigmentation on the head and neck was greater than that on the trunk and extremities.
Four patients initially experienced burning on application.
Conclusions Topical tacrolimus ointment is an effective and well-tolerated alternative therapy
for vitiligo especially involving the head and neck.

Introduction
Vitiligo is an acquired pigmentary skin disorder with an esti-
mated incidence of about 1% of world population affecting
both sexes equally.1,2 It is a disfiguring disease causing great
psychosocial stress and is characterized clinically by the develop-
ment of depigmented macules and patches that correspond
histologically to decreased or absent cutaneous melanocytes.
The main mechanism of melanocyte destruction in vitiligo
is theorized to be an autoimmune lymphocytic attack on
melanocytes.1
Current treatment options aiming at repigmentation include
the application of potent topical corticosteroids and the admin-
istration of phototherapy, either psoralen-UVA (PUVA) or,
more recently, narrowband UVB.3–5 Although as many as
64% patients respond at least partially to the application of
medium-strength to potent topical corticosteroids,6 the risk of
cutaneous atrophy and telangiectasia, especially on the face
and in intertriginous areas, and of ocular adverse events when
applied to periorbital sites, precludes the prolonged use of
topical corticosteroids. Besides the problem of compliance for
regular hospital visits, narrow-band UVB treatment requires
86 expensive equipment and trained personnel, and PUVA is
associated with a risk for cancer induction. So, the search for
newer therapeutic modalities continues.
Recently, successful treatment of vitiligo with the topical
calcineurin inhibitors tacrolimus ointment 0.1% and 0.03%
(Protopic®) or pimecrolimus cream 1% (Elidel®) has been
reported.7–9 Calcineurin-inhibitors act on T cells and mast cells,
inhibiting T-cell activation and production of cytokines and
preventing the release of pro-inflammatory mediators in mast
cells by degranulation.10 Tacrolimus ointment does not cause
the atrophy, telangiectasia, or adverse potential ocular effects
of topical corticosteroids and limited application to the face and
intertriginous areas.11 The present study was conducted in order
to assess the effect of tacrolimus ointment in treating vitiligo.
Materials and Methods
Study design
This was a prospective pilot study of response to treatment with
tacrolimus ointment of vitiligo in 30 patients conducted in 2005
and 2006.
Information collected in the routine clinical history included
patient sex, location and distribution of the disease, percentage of
depigmentation, age at onset, family history, and disease activity.

International Journal of Dermatology 2009, 48, 86–90 © 2009 The International Society of Dermatology
Xu et al.
Informed consent was obtained from all patients. Patients with a
known sensitivity to study drug or class of study drug and patients
who had used any other investigational agent in the last 30 days
were excluded as well as pregnant or breastfeeding women and
women with childbearing potential not using an adequate
contraception method.
Forty target lesions were selected to apply 0.1% tacrolimus
ointment (Protopic Ointment, Fujisawa Healthcare Inc) twice
a day. In all, 25 patients used tacrolimus ointment to treat only
involvement of the head and neck; two patients used the
tacrolimus ointment to treat vitiliginous sites only on the trunk
and/or extremities, including the hands; and three patients
applied the tacrolimus ointment for both head/neck and
body/extremities involvement.
No concomitant treatment was allowed and a washout period of
6 weeks was mandatory before topical tacrolimus was prescribed.
Patients were evaluated by the same observers at 4-weekly
intervals until 16 weeks and repigmentations were recorded.
During spring and summer months, patients were advised to apply
sunscreen of SPF 30 or higher with frequent reapplication and
incorporation of sun avoidance techniques (avoidance of midday
sun and wearing a hat). Safety was assessed by monitoring and
recording all adverse events throughout the study and by physical
examination, including visual evaluation of skin atrophy in target
lesions at each visit. Patients were asked to return all unused
medication at each visit and at the end of the study; the quantity
of returned medication was documented to assess patient
compliance.
Photography was done in a standard pose at baseline and at
4-week intervals thereafter to document the pattern and extent of
repigmentation. The area of repigmentation was analyzed by
serial mapping of body lesions. Depending on the extent of
repigmentation, the response to treatment was categorized
as marked to excellent (76–100%), moderate (51–75%), mild
(26–50%), minimal (1–25%), or no response. Patients were
followed up to 8 weeks after discontinuation of therapy to assess
the stability of pigmentation.
Statistical analysis
Statistical analyses were performed using the analysis of
variance function and paired Student t-test with software.
Results
The mean age of the 30 patients was 22.3 ± 7.8 years (range
7–40 years). There were 9 males and 21 females, and 25 of
them were less than 30 years old. The majority of patients
(80%) had vitiligo vulgaris, and 20% showed segmental
involvement. The mean duration of vitiligo before the initia-
tion of therapy was 4 years (range: 0.25–14 years). There were
7 patients with active vitiligo and 23 patients with stable
vitiligo. None of the patients had any associated autoimmune
disease and no one had previously repigmented spontaneously.
© 2009 The International Society of Dermatology
Efficacy and safety of tarcrolimus cream Pharmacology and therapeutics 87
Overall, 25 patients used tacrolimus ointment to treat only
involvement of the head and neck; two patients used the tac-
rolimus ointment to treat vitiliginous sites only on the trunk
and/or extremities, including the hands; and three patients
applied the tacrolimus ointment for both head/neck and
body/extremities involvement.
Twenty-five (83.3%) patients showed some repigmentation
at the end of 4 months and the other five patents had no
response. Initial repigmentation was noted in the sixth week
in the majority. One patient achieved excellent (100%) repig-
mentation at the end of 14 weeks with twice daily tacrolimus
ointment 0.1%, and at the end of 16 weeks, another two patients
also showed excellent repigmentation. Of these 25 patients,
repigmentation was marked to complete in 6 (20%), moderate
in 6 (20%), mild in 7 (23.3%) and minimal in 6 (20%) patients.
In all, 40 target lesions were treated. Among them, 10 lesions
were on the cheek, 7 lesions were on the forehead, 2 lesions were
on the eyebrow, 5 lesions were on the eyelid, 3 lesions were on the
prenarse, 3 lesions were perioral, 5 lesions were on the neck,
4 lesions were on the trunk, and 1 lesion was on the back of the
hand. Of the 35 lesions in the head and neck regions treated, 33
(94.3%) overall responded to tacrolimus ointment application.
Of the 5 lesions with involvement of the trunk or extremities,
only 20% responded at least partially to tacrolimus.
Excellent repigmentation was noted in 37.1% of patients
with head and/or neck involvement, but none with involve-
ment of the trunk and/or extremities. The mean percentage
of repigmentation within the treated vitiliginous areas was
65% for the head/neck responders; the mean percentage of
repigmentation on the trunk or extremities was 4% of the treated
vitiliginous areas, despite at least a 4-month trial in all patients
with trunk or extremity involvement. The mean percentage of
repigmentation on the head/neck was statistically greater
than that on the trunk and extremities (P < 0.01) Table 1.
The best repigmentation was observed in the lesions over
the face and areas with greater hair follicle density. Eyelid
involvement tended to respond the most rapidly and com-
pletely. Response to treatment was poor in lesions located
over the trunk and hands. In our series, 20% of the patients
showed segmental involvement, most commonly of the head
and/or neck. Of all, 66.7% of patients with segmental vitiligo
responded at least partially to tacrolimus ointment, especially
those with facial involvement (80%). But there was no statis-
tical significance between segmental and vulgaris vitiligo of
the head and neck.
Seven patients with active vitiligo had more or less responded
to tacrolimus ointment application, and excellent repigmenta-
tion was noted in 28.8% of these patients. Of the 23 patients
with stable vitiligo, 18 (78.3%) responded to tacrolimus
ointment application, and excellent repigmentation was noted
in 13.0% of these patients. The effect of topical application of
tacrolimus ointment in active vitiligo was superior to that in
stable vitiligo (P < 0.05) Table 2.
International Journal of Dermatology 2009, 48, 86–90
88 Pharmacology and therapeutics Efficacy and safety of tarcrolimus cream Xu et al.

Table 1 Percentage repigmentation of different site

Cheek Forehead Eyebrow Eyelid Prenarse Perioral Neck Trunk Hand

Repigmentation rate (%) (n = 10) (n = 7) (n = 2) (n = 5) (n = 3) (n = 3) (n = 5) (n = 4) (n = 1)

0 1 0 1 0 0 0 0 3 1
1–25 1 0 0 0 1 0 1 1 0
26–50 2 2 0 2 1 2 3 0 0
51–75 2 2 0 1 0 0 0 0 0
76–100 4 3 1 2 1 1 1 0 0

Table 2 Percentage repigmentation of different stage
Progressive Stable phase
Repigmentation rate (%) phase (n = 7) (n = 23)
0 0 5
1–25 1 5
26–50 2 5
51–75 1 5
76–100 3 3
In all, 10 patients had experienced their vitiligo for 5 years
or longer (range: 5–14 years). Their mean age was 27.4 years
and mean body surface area affected by the vitiligo was 21%.
In all, two patients had lesions limited to the head/neck
involvement, other eight on both the body and the head/neck.
About 80% patients responded at least partially to therapy.
Overall, these patients showed a mean extent of repigmenta-
tion of 27% of nonfacial vitiliginous areas, and 49% repig-
mentation of lesional skin on the head and/or neck. The mean
repigmentation rates did not vary statistically from that of
patients with disease for less than 5 years.
Information about the pattern of repigmentation was
available in 25 responders. Almost all of the target lesions
present over the face and neck showed repigmentation in a
diffuse pattern characterized initially by hypopigmentation,
both clinically and by Wood’s light examination, and subse-
quently progression to full repigmentation. Repigmentation
was homogenous and of same color as that of patient skin
type. The pattern of repigmentation was follicular in 42%
target lesions on the trunk and extremities.
In all, 19 patients continued to apply tacrolimus ointment
as prophylatic therapy to previously affected sites to retain
pigmentation, generally with application daily to every other
day. At least 3 patients using topical tacrolimus ointment
were noted to have progression of the vitiligo at new sites in
other areas on the body, suggesting that tacrolimus has no
systemic effect on the course of disease outside of the treated
areas.
Side-effects of therapy were minimal and limited to applica-
tion site symptoms. 4 patients (13.3%) reported burning with
initial applications, but this subsided spontaneously and did
not necessitate stopping of therapy Figs 1 and 2.
Discussion
In this study, we have provided evidence that application of
tacrolimus ointment promotes repigmentation of vitiligo.
The better response of lesions of vitiliginous areas of the face
and neck compared with that of lesions on the trunk and
extremities is consistent with both the increased follicular
density on the face and neck and the superior response to
tacrolimus of dermatitis and psoriasis on the head and neck
than on the trunk and extremities.
Repigmentation for patients with long-term vitiligo is noto-
riously difficult to achieve. However, patients with vitiligo
for more than 5 years also responded well to tacrolimus

Figure 1 Depigmentation of forehead

before trial of tacrolimus 0.1% ointment
(a) and after 4 months of twice daily
application (b)

International Journal of Dermatology 2009, 48, 86–90 © 2009 The International Society of Dermatology
Xu et al.
Figure 2 (a) Depigmentation of nasolabial
groove before initiation of tacrolimus
0.1% ointment. (b) Excellent
repigmentation 4 months after initiating
application of tacrolimus ointment 0.1%
twice daily
ointment. Although the efficacy rate was slightly lower, there
was no statistical difference in mean response for patients with
vitiligo of greater than or less than 5 years’ duration. Segmen-
tal vitiligo has also been difficult to repigment. In our study,
66.7% of patients with segmental vitiligo responded to
tacrolimus ointment, especially those with facial involvement
(80%), suggesting that tacrolimus ointment is particularly
valuable for this recalcitrant patient group.
Sliverberg et al. 12 have described the different response to
tacrolimus by season of initiation: response rate was 100%
of patients who began in summer, 67% who began in spring,
80% of who began in fall, and 61% who began in winter.
Though response can occur independent of seasons, the
response in the summer was statistically greater than that in
the winter (P < 0.05). Their results suggest that the combina-
tion of tacrolimus ointment and UV light may be superior
to that of tacrolimus ointment alone, but that UV light is not
necessary for the beneficial effect of tacrolimus ointment.
However, in our study, all of the patients’ treatment was
initiated during the winter. We can imagine that if our patients
started therapy in summer, the results would be much better.
Follicular repigmentation is the predominant form of
repigmentation of vitiligo,13 but in our trial, almost all of the
patients instead demonstrated increased pigmentation spread
diffusely throughout the individual lesion, first as hypo-
pigmentation and eventually as full repigmentation. This
diffuse pattern has recently been shown to be particularly
common in response to topical corticosteroids, in contrast to
the follicular pattern, and in facial and segmental lesions.13
The many patients showing diffuse repigmentation supports
the concept that a reservoir of persistent, dopa-negative
melanocytes in the depigmented epidermis of vitiligo is
responsible for the diffuse form of repigmentation.14,15
Tacrolimus, unlike topical corticosteroids, does not inter-
fere with collagen synthesis and has no effect on keratinocyte
proliferation in vitro.16 These findings correspond with the
clinical experience of lack of atrophogenic effects in vivo,
thereby allowing a longer period of use as generally required
in the management of vitiligo. Also, the lack of risk of inducing
ocular cataracts or glaucoma with tacrolimus ointment use12
positions this new topical immunosuppressant as a particu-
larly welcome agent for treating vitiligo of the eyelid.
© 2009 The International Society of Dermatology
Efficacy and safety of tarcrolimus cream Pharmacology and therapeutics 89
In vitiligo, there is no abnormality of skin barrier functions
or inflammation to increase drug absorption. However, use
of tacrolimus ointment for patients with vitiligo raises a poten-
tial dilemma. UV light exposure has been a key element
in encouraging repigmentation of vitiliginous skin, whether
through use of PUVA or sun exposure. Chronic systemic
immunosuppression in patients with transplant is associated
with an increased risk of nonmelanoma skin cancer, particu-
larly in adult patients with previously sun-damaged skin.17
Although topical application of tacrolimus is not associated
with systemic immunosuppression, the long-term risk of applica-
tion of tacrolimus ointment to skin is unknown. Studies using
tacrolimus 0.1% ointment for up to 3 years in adults older
than age 40 years with atopic dermatitis have not suggested
an increased risk of nonmelanoma skin cancer.18 Prolonged
or unprotected UV light exposure would not be advisable
concurrent with tacrolimus ointment application. We suggest
that patients using the medication during months with sig-
nificant sun exposure risk should be counseled about sun
protection and effective use of sunscreens while using the
medication until additional years of experience showing
safety are accrued.
Silverberg et al. have described at least partial repigmenta-
tion in 48 of 57 children with vitiligo treated with tacrolimus
ointment.12 Excellent repigmentation was noted in 47% of
patients with head and/or neck involvement, but only in 25%
with involvement of the trunk and/or extremities. Facial vitil-
igo of the segmental type showed the best response rate. Our
study of 30 patients confirms their results.
As in other inflammatory and immunologically mediated skin
disorders, the effective role of topical tacrolimus in the treat-
ment of vitiligo may relate to its suppression of autoantibody
recognition of cell-surface melanocyte antigens and inhibi-
tion of subsequent cytotoxic T-lymphocyte reactions.19
Given its immunomodulatory properties and lack of cuta-
neous side-effects seen with topical corticosteroids, tacrolimus
is a potential therapeutic alternative for vitiligo of the head
and neck even in pediatric patients with an improved benefit:
risk ratio. Our early results of treatment vitiligo with topical
tacrolimus are promising. However, this is a pilot study and
more robust data need to be obtained in large double-blind
controlled studies with long-term follow up to prove the safety,
International Journal of Dermatology 2009, 48, 86–90
90 Pharmacology and therapeutics Efficacy and safety of tarcrolimus cream
efficacy and stability of repigmentation with topical tacrolimus
in the treatment of vitiligo. It will also be interesting to deter-
mine whether longer periods of therapy or its combination
with other therapeutic modalities could result in better response
in repigmentation.
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© 2009 The International Society of Dermatology