ARTICLE
Auteur(s) : Giuseppe Stinco1,
Fabio Piccirillo1, Marina Forcione1,
Francesca Valent2, Pasquale Patrone1
1Department of Clinical and Experimental
Pathology and Medicine, Institute of Dermatology,
University of Udine, Ospedale “San Michele” di Gemona, piazza
Rodolone 1, 33013 Gemona del Friuli (Udine), Italy
2Institute of Hygiene and Epidemiology,
University of Udine, Italy
accepté le 22 Juin 2009
Vitiligo is an acquired, idiopathic disorder characterized by
depigmented macules that result from damage to and destruction of
melanocytes [1, 2]. It affects from 0.5 to 2% of the general
population causing cosmetic and psychosocial problems [3, 4]. The
treatment of vitiligo is often stressful and unsatisfying and
remains a challenge for the dermatologist, although a wide range of
therapeutic options have been proposed and are currently available.
The mainstays of vitiligo therapy include the application of potent
topical corticosteroids and the administration of phototherapy,
either psoralen-UVA (PUVA) or, more recently, narrow band UVB
(NB-UVB) [5-8]. Topical calcineurin inhibitors are another option
recently introduced for the treatment of vitiligo that offers the
advantage of a prolonged use period while avoiding the adverse
events related to the long-term use of topical steroids [9-14]. The
aim of our study was to compare the efficacy and safety of NB-UVB,
pimecrolimus 1% cream and tacrolimus 0.1% ointment in the treatment
of chronic vitiligo.
Subjects and methods
The study included 44 patients with chronic and stable vitiligo who
were referred to our dermatology outpatient clinic between
September 2007 and April 2008. Patients over 18 years old with
vitiligo for almost 1 year (chronic) and without any new
depigmented patches in the past 12 months (stable) were included in
the study. Nursing or pregnant women and patients under 18 or
affected by infections, neurological or psychiatric disorders,
autoimmune disease, immune defects, heart deficiency, kidney
failure, previous or current history of neoplasms were excluded.
The patients were clearly informed about their disease, possible
options of treatment, possible side effects and the study plan.
Each patient was given a signed informed consent to the treatment
and to the photos. No conflict of interest concerning sponsorship
of any kind was noted in this study.
According to the classification of sun-reactive skin types, 8
patients showed skin phototype II, 26 showed skin phototype III and
10 patients showed skin phototype IV. The disease duration ranged
from 1 to 5 years. Twelve patients (27%) started these
treatments as their first treatment option for vitiligo while for
the others topical steroids, PUVA, and topical calcipotriol had
been previously received with unsatisfactory results. The wash out
phase for current treatment was 4 weeks.
Study plan
We performed a randomized, open study to compare the efficacy and
safety of NB-UVB phototherapy, pimecrolimus 1% cream, tacrolimus
0.1% ointment in the treatment of vitiligo. The patients were
randomized on basis of a computer-generated randomization schedule
into three groups (A, B and C) corresponding to three different
therapeutic programs: A) NB-UVB phototherapy, B) treatment with
pimecrolimus 1% cream and C) treatment with tacrolimus 0.1%
ointment. All patients were examined by the same dermatologist at
baseline (T0) and every three weeks for 24 (T24) weeks. Digital
lesional photographs, both with normal ambient light and with
Wood’s lamp were obtained in a standard pose before treatment and
at every subsequent evaluation. Estimation of response was
performed visually by 2 clinicians not involved in the study.
Response to treatment was determined for each anatomical site
(face, upper and lower limbs, hands/wrists, foots/ankles) by
assessing the entire lesion. A 0% score at the beginning of
the study indicated a baseline of no repigmentation and a second
percentage value at the end of the study represented the level of
repigmentation. The area of repigmentation was analyzed by serial
mapping of body lesions. Based on the area of repigmentation,
treatment outcome was calculated for each anatomical site according
to a scale ranging from 0 to 4 and classified as “0, absent” (0),
“1, poor” (1-25%), “2, moderate” (26-50%), “3, good” (51-75%), and
“4, excellent” (> 75%). During the whole period of the
study, possible side effects were recorded.
A group (NB-UVB group)
13 patients, 7 male and 6 female, between 27 and 72 years old (mean
age 48.8) were treated with NB-UVB as monotherapy using Spectra 724
UVB lamps with a digital timer, of the FS 72 T 12/HO Daavlin type.
Phototherapy was given three times a week on non-consecutive days,
for 6 months, 50 sessions in total. Initial photo testing was not
done. The minimal erythematous dose (MED) was pre-determined
(280 mJ/cm2) according to the concept that the
depigmented skin lesions of vitiligo are considered as photo-type I
[5]. The standard initial dose of 280 mJ/cm2 was started
on all patients and dose increment was done at the rate of 15% of
the previous dose. If symptomatic erythema (burning, pain) or
blistering developed the irradiation dose was decreased by 15%. The
optimal constant dose was achieved when minimal erythema appeared
in the lesions. Standard photoprotection protocol for NB-UVB was
observed. During treatment, the genital area was shielded and the
eyes were protected by UV-blocking goggles. Barring these protected
areas, whole-body irradiation was performed. If vitiligo was
present in the eyelid area, patients did not wear goggles but were
advised to keep their eyes shut during the sessions. Patients were
advised to apply a very high protection sunscreen with frequent
reapplication and to use sun avoidance techniques (avoidance of
midday sun and wearing a hat).
B group (pimecrolimus group)
15 patients, 5 male and 10 female were enrolled. Two female
patients withdrew from the study for personal reasons. The other 13
patients between 27 and 56 years old (mean age 42.9), completed the
study. The patients were to apply the medication. The patients were
instructed to apply pimecrolimus 1% cream in a thin layer to the
affected areas twice daily for 24 weeks on dry skin, with a fine
massage until the product was fully absorbed. In generalized types
of vitiligo, for cost and practicality reasons, the patients were
asked to treat only the anatomical site that they considered the
most disturbing from an aesthetic and psychological point of view.
They were also asked to stop the treatment in the case of signs of
infection and to avoid contact with eyes. All patients were asked
to avoid direct UV exposition during the whole period of study and
they were advised to apply a very high protection sunscreen with
frequent reapplication and to incorporate of sun avoidance
techniques (avoidance of midday sun and wearing a hat).
C group (tacrolimus group)
16 patients, 2 male and 14 female were enrolled. Four female
patients withdrew from the study: 3 for personal reasons and 1 for
the appearance of herpes simplex infection of the lips after one
week of tacrolimus application in the perioral area. The other 12
patients, who were between 30 and 61 years old (mean age 43.2),
completed the study. The patients were instructed to apply
tacrolimus 0.1% ointment in a thin layer to the affected areas
twice daily for 24 weeks on dry skin, with a fine massage until the
product was fully absorbed. In generalized type of vitiligo, for
cost and practicality reasons, the patients were asked to treat
only the anatomical site that they considered the most disturbing
from an aesthetic and psychological point of view. They were also
asked to stop the treatment in the case of signs of infection and
to avoid contact with the eyes. All patients were asked to avoid
direct UV exposition during the whole period of study and they were
advised to apply a very high protection sunscreen with frequent
reapplication and to incorporate sun avoidance techniques
(avoidance of midday sun and wearing a hat).
Statistical analysis
Within each treatment group, the proportion of patients with
different degrees of repigmentation was calculated. In addition,
mean and median repigmentation scores were calculated for each
anatomical site and for photo-exposed (face and neck) and
non-exposed areas. Within each treatment group, Wilcoxon’s rank
sums test was used to assess the difference in median
repigmentation scores between photo-exposed and covered areas.
Fisher’s exact tests were used to compare the categories
representing the degree of repigmentation among the three
treatments. P-values < 0.05 were considered statistically
significant. For statistical analyses, the statistical package SAS
v9 (SAS Institute Inc., Cary, NC, USA) was used.
Results
A group (NB-UVB group)
Results of the clinical evaluation are summarized in table 1. Within 24 weeks of therapy the 13 patients
of this group underwent a mean of 37.15 sessions of phototherapy.
All treated patients with vitiligo lesions localized on the face,
neck, upper limbs and trunk obtained a variable repigmentation from
poor to good; for the other anatomical sites (hands/wrists, lower
limbs and feet/ankles) cases of lack of repigmentation were
recorded. All five treated patients with vitiligo lesions of the
feet/ankles showed no signs of repigmentation. The best results of
repigmentation were obtained for the neck (median repigmentation
score 2, moderate), followed by the face (median repigmentation
score 1.5, between poor and moderate), upper and lower limbs,
hands/wrists (meadian repigmentation score 1, poor) (table 2). The difference between the
repigmentation score for photo-exposed (mean = 1.73, median = 2)
and covered treated areas (mean = 0.87, median = 1) was
statistically significant (p = 0.0058). During the study a slight
erythema and pruritus within 5 hours after the phototherapy session
was recorded in two patients; these side effects were well managed,
keeping the irradiation dose steady during the next session.
Table 1 The table shows the repigmentation score for
each anatomical site for the nb-UVB treated patients. Only for
hands/wrists, lower limbs and feet/ankles cases of lack of
repigmentation were recorded
|
Anatomical sites
|
Face
|
Neck
|
Upper limbs
|
Hands/ Wrists
|
Trunk
|
Lower limbs
|
Feet/ Ankles
|
|
Number of patients with lesions
|
8
|
3
|
6
|
11
|
4
|
6
|
5
|
|
Degree of Repigmentation
|
|
|
|
|
|
|
|
|
0 Absent
|
0
|
0
|
0
|
5 (45%)
|
0
|
1 (17%)
|
5 (100%)
|
|
1 Slight
|
4 (50%)
|
1 (33%)
|
4 (67%)
|
5 (45%)
|
3 (75%)
|
5 (83%)
|
0
|
|
2 Moderate
|
2 (25%)
|
2 (67%)
|
0
|
1 (9%)
|
0
|
0
|
0
|
|
3 Good
|
2 (25%)
|
0
|
2 (33%)
|
0
|
1 (25%)
|
0
|
0
|
|
4 Excellent
|
0
|
0
|
0
|
0
|
0
|
0
|
0
|
Table 2 Based on the area of repigmentation, treatment
outcome was calculated according to a scale ranging from 0 to 4 (0
= absent, 1 = poor, 2 = moderate, 3 = good, 4 = excellent). The
table shows the mean repigmentation score for each anatomical sites
and for each treatment. The differences among treatments, for each
anatomic sites, were not significant (P-values › 0.05)
|
Anatomical site
|
NB-UVB group
|
Pimecrolimus group
|
Tacrolimus group
|
|
Face
|
1.5
|
4
|
2.5
|
|
Neck
|
2
|
1.5
|
2
|
|
Upper limbs
|
1
|
1
|
1.5
|
|
Hands/Wrists
|
1
|
1
|
0.5
|
|
Trunk
|
1
|
0.3
|
1
|
|
Lower limbs
|
1
|
0
|
1
|
|
Feet/Ankles
|
0
|
1.5
|
0
|
B group (pimecrolimus group)
Results of the clinical evaluation are summarized in table 3. All treated patients with vitiligo lesions
localized on the face and feet/ankles obtained a variable
repigmentation from poor to excellent; for the other anatomical
sites (neck, upper limbs, trunk and hands/wrists) cases of lack of
repigmentation were recorded. The only patient with vitiligo
lesions of the lower limbs showed no signs of repigmentation. The
best results of repigmentation were obtained for the face (median
repigmentation score 4, excellent), followed by the neck and
feet/ankles (median score 1.5, between poor and moderate), upper
limbs and hands/wrists (median score 1, poor) and trunk (median
score 0.3, between absence and poor) (table
2). The difference between the repigmentation score for
photo-exposed (mean = 2.47, median = 3) and covered treated areas
(mean = 0.89, median = 1) was statistically significant (p =
0.0042). During the study side effects were recorded: two patients
referred to soreness and erythema, one to only erythema and four to
a heat sensation on the face that increased when it was exposed to
direct heat. These irritation phenomena appeared few days after the
beginning of the treatment. One female patient referred to an
intense erythema and soreness that did not recede during the next
applications; therefore she was instructed to apply pimecrolimus
once a day with disappearance of symptoms. One female patient
stopped the treatment for an intense lachrymation that did not
recede when she applied the cream once a day. One female patient
with vitiligo lesions on the dorsum of the hands referred to the
appearance of erythema and dryness that receded within the first
two weeks of treatment. Two female patients referred to the
appearance of red-flushing on the face after a small amount of
alcohol intake (a glass of beer or wine).
Table 3 The table shows the repigmentation score for
each anatomical site for the pimecrolimus treated patients. For
neck, upper and lower limbs, hands/wrists and trunk cases of lack
of repigmentation were recorded
|
Face
|
Neck
|
Upper limbs
|
Hands/Wrists
|
Trunk
|
Lower limbs
|
Feet/Ankles
|
|
Number of patients
|
13
|
4
|
4
|
8
|
3
|
1
|
2
|
|
Repigmentation score
|
|
|
|
|
|
|
|
|
0
|
0
|
1 (25%)
|
1 (25%)
|
3 (37%)
|
2 (67%)
|
1 (100%)
|
0
|
|
1
|
5 (38%)
|
1 (25%)
|
2 (50%)
|
4 (50%)
|
0
|
0
|
1 (50%)
|
|
2
|
0
|
1 (25%)
|
0
|
1 (12%)
|
1 (33%)
|
0
|
1 (50%)
|
|
3
|
1 (8%)
|
1 (25%)
|
1 (25%)
|
0
|
0
|
0
|
0
|
|
4
|
7 (54%)
|
0
|
0
|
0
|
0
|
0
|
0
|
C group (tacrolimus group)
Results of the clinical evaluation are summarized in table 4. All treated patients with vitiligo lesions
localized on the face, neck and upper limbs obtained a variable
repigmentation from poor to excellent; for the other anatomical
sites (hands/wrists, trunk and upper and feet/ankles) cases of lack
of repigmentation were recorded. The only patient with lesions on
the feet/ankles showed no signs of repigmentation. The best results
of repigmentation were obtained for the face (median repigmentation
score 2.5, between moderate and good), followed by the neck (median
score 2, moderate), upper limbs (median score 1.5, between poor and
moderate) and trunk and lower limbs (median score 1, poor),
hands/wrists (median score 0.5, between absent and poor) (table 2). The difference between the
repigmentation score for photo-exposed (mean = 2.33, median = 2)
and covered treated areas (mean = 2.33, median = 1) was
statistically significant (p = 0.0292). All 12 patients in this
group referred to side effects. Nine patients, 7 female and 2 male,
referred to a heat sensation on the face during the first days of
application; in one case the application of the ointment was
reduced to once a day for two weeks with disappearance of the
symptoms. One female patient referred to the appearance of
soreness, one female patient referred to pruritus on the eyelids
associated with formication of the lips, and 1 female patient
presented erythema of the bulbar conjunctiva. Five patients
referred to the appearance of red-flushing on their face after a
small amount of alcohol intake (a glass of beer or wine). All side
effects resolved in 2-3 weeks.
Table 4 The table shows the repigmentation score for
each anatomical site for the tacrolimus treated patients. For
hands/wrists, trunk, lower limbs and feet/ankles cases of lack of
repigmentation were recorded
|
Face
|
Neck
|
Upper limbs
|
Hands/Wrists
|
Trunk
|
Lower limbs
|
Feet/Ankles
|
|
Number of patients
|
12
|
3
|
2
|
2
|
6
|
4
|
1
|
|
Repigmentation score
|
|
|
|
|
|
|
|
|
0
|
0
|
0
|
0
|
1 (50%)
|
2 (33%)
|
1 (25%)
|
1 (100%)
|
|
1
|
4 (33%)
|
1 (33%)
|
1 (50%)
|
1 (50%)
|
2 (33%)
|
2 (50%)
|
0
|
|
2
|
2 (17%)
|
1 (33%)
|
1 (50%)
|
0
|
0
|
0
|
0
|
|
3
|
3 (25%)
|
1 (33%)
|
0
|
0
|
0
|
1 (25%)
|
0
|
|
4
|
3 (25%)
|
0
|
0
|
0
|
2 (33%)
|
0
|
0
|
Comparison among treatments
For each anatomic location, the distribution of the various degrees
of repigmentation (tables 1, 3, and 4)
were not significantly different among the three treatments:
p-values of Fisher’s exact tests were 0.1082 for the face, 1.000
for the neck, 0.5455 for the upper limbs, 1.0000 for the hands and
wrists, 0.1106 for the trunk, 0.3939 for the lower limbs, and
0.1071 for the feet and ankles.
Discussion
Although treatment of vitiligo is difficult and challenging, NB-UVB
phototherapy and topical calcineurin inhibitors are included among
the most interesting and innovative approaches to this disease
[5-14].
NB-UVB phototherapy has emerged in recent years as an accepted
and well-tolerated therapy for generalized vitiligo. Since the
first report by Westerhof and Nieuweboer-Krobotova, several studies
have been published on the treatment of vitiligo with NB-UVB in
different populations with variable results [15, 16]. Sitek JC
et al. reported that 1/3 to 2/3 of NB-UVB treated patients can
obtain a significant repigmentation [17]. Our study confirmed that
NB-UVB phototherapy is an effective therapeutic option in vitiligo.
Repigmentation seemed to have different responses with regard to
the anatomical location of the lesions. The face, neck, trunk and
upper limbs resulted more responsive than hands/wrists, lower limbs
and feet/ankles. The best results have been obtained for the neck,
with a median score of repigmentation of 2 (moderate). In the
literature many studies have reported better results for the face
in comparison with the body [15, 16, 18, 19]. Adverse effects were
minimal and no patient had to discontinue treatment because of
them.
Topical immunomodulators, tacrolimus and pimecrolimus, represent
a novel therapeutic approach in the treatment of vitiligo and they
offer many advantages over corticosteroids for the management of
chronic skin disorders in which prolonged treatment periods are
needed.
Pimecrolimus has been available since 2002 in the United States
for the treatment of slight-moderate atopic dermatitis. Its
efficacy in the treatment of vitiligo is still debated. Dawid
et al. compared the efficacy of pimecrolimus cream versus a
simple vehicle for symmetrical vitiligo lesions of skin areas
except on the face, showing no differences of repigmentation rates
between the two types of treatment [20]. On the other hand, Coskun
et al. compared the efficacy of clobetasol propionate 0.05%
with pimecrolimus applied twice a day for vitiligo lesions and no
statistically significant differences in repigmentation rates were
noted [21]. The role of pimecrolimus in inhibiting T cell
activation is well known but no experimental evidence about its
direct role in the activation/proliferation of melanocytes
isavailable up to date [20]. The current study confirmed that
pimecrolimus cream is an effective therapeutic option in vitiligo.
Also topical pimecrolimus seems to develop different extents of
repigmentation according to the anatomical location of the
vitiligo. Lesions on the face were much more responsive to the
treatment than ones in other anatomical locations (table 2). Moreover there was a statistically
significant difference in repigmentation rates between
photo-exposed and non photo-exposed areas. Pimecrolimus was
demonstrated to be safe: frequent cases of erythema, soreness and
dryness, well managed by changing the frequency of administration,
have been recorded and only in one case did the treatment have to
be stopped for the appearance of lachrymation that did not recede
with once a day application.
Topical tacrolimus has been approved by the US Food and Drug
Administration for the treatment of moderate-severe atopic
dermatitis. Studies of reported efficacy of tacrolimus alone in the
treatment of vitiligo have been reported [22]. Experimental
evidence shows that the rationale of the use of tacrolimus in the
treatment of vitiligo is due to its capability to down-regulate the
expression of Il-2, -3, -4, -5, IFN-γ, TNF-α and GM-CSF genes and
to increase the SCF (Stem Cell Factor) and melanocyte proliferation
[9, 23]. Lepe et al. compared the safety and efficacy of
clobetasol propionate 0.05% and tacrolimus 0.1% in the treatment of
symmetrical vitiligo lesions in 20 children showing no
statistically significant differences of repigmentation between the
two treatments; moreover, while for the topical steroid, atrophy
and telangiectasia were recorded, tacrolimus induced only a
soreness sensation. The authors obtained the best repigmentation on
the face and in the skin areas rich in hair follicles, while the
dorsum of the hands showed no signs of repigmentation [11]. In our
study, similarly to pimecrolimus, for tacrolimus the best results
were obtained for the vitiligo lesions of the face and a
significant difference was shown between photo-exposed and covered
treated areas. Tacrolimus proved to be safe: erythema, pruritus,
formication and soreness have been recorded but no serious adverse
events occurred that required stopping the treatment.
In our study, all three treatments were shown to induce at least
partial repigmentation. Even if no statistically significant
differences in repigmentation for each anatomical site were
recorded, the best results were obtained for the treatment of
vitiligo lesions of the face with pimecrolimus cream (median
repigmentation score 4) and tacrolimus ointment (median
repigmentation score 2.5). The reason behind this anatomical
variation in response to treatment is unclear, but may have to do
with the regional variation in the density of hair follicles, which
have been shown to be reservoirs for melanocytes. Furtheremore the
non-significant difference in the repigmentation rates on the face
between the two calcineurin inhibitors could be linked to the
noteworthy lipophilia of pimecrolimus that probably can penetrate
and act better than tacrolimus. Both for pimecrolimus and for
tacrolimus, taken alone, statistically significant differences in
repigmentation between photo-exposed and covered skin areas were
recorded although the patients were asked to avoid direct UV
exposition and to apply a very high protection sun screen on
vitiligo lesions after almost two hours after the application of
the topical immunomodulators. In the literature it has been
reported that a combined therapy tacrolimus plus UVB irradiation
could be better than tacrolimus alone but UV irradiation is not
necessary for its beneficial effect, as confirmed by our
observation. Side effects were moderate and well managed by
modifying the therapies and resulted in no sequelae [24, 25].
NB-UVB irradiation may represent the optimal treatment choice in
patients with generalized vitiligo but there are other issues to
consider: i) risk of carcinogenesis ii) inconvenience, since it is
available only in a hospital setting and iii) the effect of
irradiation on the adjacent healthy skin. Topical immunomodulators,
since the results are similar to steroids and without the risk of
atrophy and telangiectasia, might be the optimal choice for the
long-term treatment of localized vitiligo with the great benefit of
being taken at home [11]. In addition, since some patients do not
tolerate the shininess effect of the ointment and with its better
repigmentation score, pimecrolimus cream might be preferred to
tacrolimus ointment for the treatment of vitiligo lesions of the
face.
Although the topical application of calineurin-inhibitors is not
associated to systemic immunosuppression, the long term risk of
their topical application is not known [26]; for this reason and
for practical reasons, the use of topical calcineurin-inhibitors
should be limited only to localized vitiligo, better for the face,
and not for prolonged periods.
Acknowledgements
Fincancial support: none. Conflict of interest: none.
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