Pharmacology and therapeutics

Blackwell
Oxford,
International
IJD

0011-9059
46 2007 The
UK
Publishing,
International
Journal of
Ltd.
Dermatology
Society of Dermatology

Two therapeutic challenges: periocular and genital vitiligo in

Periocular
Leite
Pharmacology
and Leite
and and
genital
therapeutics
vitiligo in children

children successfully treated with pimecrolimus cream

Rubens Marcelo Souza Leite, MD, and Adriana Arago Craveiro Leite, MD

From the Universidade Catlica de Braslia Abstract

and Instituto Saint Louis de Braslia Vitiligo is characterized by the selective destruction of melanocytes resulting in patches of skin
depigmentation. Vitiligo is a therapeutic challenge. Eyebrows, eyelids and genital vitiligo are a
Correspondence
therapeutic dilemma, especially in children. The possible side effects of topical corticosteroids
Rubens Marcelo Souza Leite
SMHN Q2, Bloco A, # 10 and the difficulties for choosing any other adequate treatment option are a major concern.
Edificio de Clinicas We present two children, one with vitiligo of the eyelids and the other with genital vitiligo,
Sala 108, Zip 70710-100 both treated with pimecrolimus 1% cream with almost full repigmentation of the lesions, showing
Brazilia-DF pimecrolimus could be an adequate option for the treatment of vitiligo for these special vitiligo
Brazil
areas in children.
E-mail: rmsl@terra.com.br

Vitiligo is the most common of the primary disorders of used in Brazil) showed no improvement. The patch was
pigmentation. It affects 1% of the worlds population and its getting larger and the boys parents complained that their son
onset in at least half of the cases occurs before the age of 20.1 was feeling unhappy with the lesion, and facing relationship
It is characterized by a selective destruction of melanocytes problems at school. No other macule was observed during
resulting in patches of skin depigmentation.1,2 There is a familial examination. Laboratory tests were on the normal range.
incidence of 30%, with inheritance pattern not explained There were no familial vitiligo cases. Focal vitiligo was
by simple Mendelian genetics, otherwise characterized by diagnosed and treatment with pimecrolimus 1% cream twice
incomplete penetrance, multiple susceptibility loci, and a day was started.
genetics heterogenecity.1,3 Vitiligo is clinically divided into After 4 months of treatment, the positive result was
localized and generalized forms.4 It is a therapeutic challenge, unquestionable, with almost complete pigmentation of the
and spontaneous regression of this disease is unusual.5 treated patch (Fig. 2). One year after treatment, there was no
Eyebrows, eyelids, and genital vitiligo are a therapeutic relapse of vitiligo.
dilemma, especially in children. The possible side-effects with
topical corticosteroids therapy and the difficulties for choosing
any other adequate treatment option are a major concern.5,6
The new calcineurin inhibitors tacrolimus and pimecrolimus,
with their known topical safety profile, have been reported as
a therapeutic option for vitiligo.7,8 We present here two children,
one with vitiligo of the eyelids and eyebrows and the other
with genital vitiligo, both treated with pimecrolimus 1%
cream, with almost full repigmentation of the treated lesions,
showing that pimecrolimus could be an effective option for
the treatment of vitiligo in children, particularly for these
special skin areas.

Clinical Case 1

An 8-year-old boy was referred to our service with complaint

of a large white patch on his left eyelid and eyebrow area
(Fig. 1). Topical therapy with hydrocortisone cream and
986 mama cadela lotion (Brosimum gaudichaudii a psoralenic Figure 1 Eyebrow and eyelid vitiligo before treatment

International Journal of Dermatology 2007, 46, 986989 2007 The International Society of Dermatology
Leite and Leite
Figure 2 Eyebrow and eyelid vitiligo after treatment
Clinical Case 2
An 11-year-old boy presented with a history of white patches
on his penis skin and mucosa. There were also white macules
on his pubis area. The patient noticed that the patches were
enlarging during the previous months, but refused to tell
his parents. The boys mother recently saw the white lesions
during his bath. The patient gave a detailed account of his
condition, refusing contact with his peers and left his football
team, ashamed of having to take showers with his peers after
games. Upon physical examination, he had multiple small
well-defined and isolated white macules on his penis skin
(Fig. 3). There was no parental history of vitiligo. A diagnosis
of genital vitiligo was made. Laboratory tests, including
hemogram, thyroid function, glycemia, liver, and renal
functions, were within normal limits. The parents refused a
proposed therapy with topical corticosteroids, and pime-
Figure 3 Genital vitiligo before treatment
2007 The International Society of Dermatology
Periocular and genital vitiligo in children Pharmacology and therapeutics 987
Figure 4 Genital vitiligo after treatment
crolimus 1% cream was initiated twice a day for 1 month.
There was no initial response, but the treatment was
continued for more than 3 months, after which the patient
showed almost complete remission of all vitiligo lesions on his
penis and pubic areas (Fig. 4).
Discussion
Vitiligo is a therapeutic challenge and spontaneous regression
of the disease is unusual.5 The variable expression of vitiligo
is characterized by different clinical presentations of the
disease.
Generalized vitiligo is usually symmetric and involves
the elbows, knees, wrists, hands, feet, and periorificial areas.
It is divided into several types, according to its clinical presen-
tation: acrofacial, vulgaris, or mixed. Localized vitiligo is
divided into focal, segmental or mucosal vitiligo. There is also
an extensive form of vitiligo, the universal vitiligo, which
involves the entire body.9
There are theories concerning the pathogenesis of
vitiligo. Immune mechanisms are felt to have an important
role on vitiligo development.3 Vitiligo is far more common in
patients suffering from certain autoimmune diseases such as
thyroiditis, anemia perniciosa, and diabetes.4 Patients with
vitiligo also produce specific melanocytes antibodies.10
The direct relation of these antibodies titles and the extent
of vitiligo favors a direct pathogenic role of these antibodies
on the disease.10,11 Some studies have addressed the role of
peripheral blood and lesional cytokine expression in
patients with vitiligo.1113
A recent study supports that cytokine imbalance plays
at least some role in the depigmentation process of vitiligo.
Analyzing 19 patients for 24 weeks, at baseline, compared
to healthy controls, vitiligo patients demonstrated a statistic-
ally significant increase in the expression of interferon-
International Journal of Dermatology 2007, 46, 986 989
988 Pharmacology and therapeutics Periocular and genital vitiligo in children
in involved and adjacent uninvolved skin; significantly
increased tumor necrosis factor (TNF) expression in involved
and uninvolved skin; and significantly increased interleukin-
10 expression in involved and uninvolved skin. After treatment,
TNF expression decreased in the depigmented and adjacent
uninvolved skin.14
Tacrolimus ointment and pimecrolimus cream, novel
topical immunomodulatory drugs, are used for the treatment
of atopic dermatitis in both adults and children.15 In recent
studies, tacrolimus has been reported to induce repigmentation
in vitiligo patients.7,16 Grimes, in an open-label study, docu-
mented the efficacy of tacrolimus ointment in six patients
with generalized vitiligo. Five of the six patients achieved
moderate to excellent repigmentation (50 100%), and one
patient had 25 to 50% repigmentation.17 Lepe, in a double-
blind study assessing the safety and efficacy of topical 0.1%
tacrolimus vs. 0.05% clobetasol propionate in children with
vitiligo, observed that 18 (90%) of the 20 patients studied
experienced some repigmentation. The mean percentage of
repigmentation was 49.3% for clobetasol and 41.3% for
tacrolimus. Side-effects for the tacrolimus-treated group was
just mild burning sensation in two treated lesions, while three
patients using clobetasol presented atrophy, and two lesions
incurred telangiectasias.16 There are few studies concerning
the use of pimecrolimus for vitiligo. Coskun recently studied
prospectively 10 patients with bilateral symmetrical lesions
of vitiligo comparing the efficacy of the 0.05% clobetasol
propionate and 1% pimecrolimus. It was determined that
both treatment modalities resulted in a comparable rate of
repigmentation.8 The calcineurin inhibitors are believed to
exert its therapeutic effects on vitiligo by inhibiting T-cell
activation, thereby obstructing the production and release of
pro-inflammatory cytokines that could be responsible for
vitiligo genesis.
Periocular and genital vitiligo in children are specific
situations when trying to develop an adequate treatment
plan. Although it is in general a benign disorder, vitiligo may
lead to considerable psychologic distress and social isolation,
with lasting effects on self-esteem.6 The obvious goal of
vitiligo treatment is to obtain complete and permanent
repigmentation of the affected areas, although this is not
always possible.
As there is no gold standard treatment for vitiligo, a wide
range of therapeutic options are available. When choosing a
therapeutic modality, one has to take into consideration the
clinical type of vitiligo, the age of the patient, the surface of
skin affected by the disease, the previous experiences with
the chosen therapeutic modality, the specifities of the area
of vitiligo to be treated, and the possible side-effects of the
chosen therapy. Children and adolescents with genital vitiligo
often hide their disease from their parents, and they often
postpone their complaints because of shame and fear of being
ridiculed by their peers. Treatment option for periocular and
International Journal of Dermatology 2007, 46, 986989
Leite and Leite
genital vitiligo are not broad. Children and adolescent skin
characteristics make this area prone to local therapy side-
effects. Topical corticosteroids are the first line of therapy
for child and adolescent vitiligo.5 Children treated with
corticosteroids should be monitored for local side-effects, like
teleangiectasias, cutaneous atrophy, or striae.5
However, more studies with large number of patients are
needed to characterize pimecrolimus cream as a first-line
therapeutic option for vitiligo. Because pimecrolimus has
been shown to be a safe treatment to atopic dermatitis, even
with recent concerns about carcinogeneis, and its side-effect
profile is poor,1921 it could be an interesting option for focal
vitiligo treatment, mainly when there is serious concern about
local side-effects as in periocular and genital areas in children.
References
1 Lerner AB. Vitiligo. J Invest Dermatol 1959; 32: 285
310.
2 Osborne GE, Francis ND, Bunker CB. Synchronous onset of
penile lichen planus and vitiligo. Br J Dermatol, 2000; 143:
218219.
3 Zhang XJ, Chen JJ, Liu JB. The genetic concept of vitiligo.
J Dermatol Sci 2005; 39: 137146.
4 Schaffer JV, Bologna JL. The treatment of hypopigmentation
in children. Clin Dermatol 2003; 21: 296310.
5 Njoo MD, Westenhof W, Bos D, et al. The development of
guidelines for the treatment of vitiligo. Arch Dermatol 1999:
135: 15141521.
6 Kovacs SO. Vitiligo. J Am Acad Dermatol 1998; 38: 6768.
7 Grimes PE, Soriano T, Dytoc M. Topical tacrolimus for
repigmentation of vitiligo. J Am Acad Dermatol 2002; 47:
789791.
8 Coskun B, Saral Y, Turqut D. Topical 0.05% clobetasol
propionate versus 1% pimecrolimus ointment in vitiligo.
Eur J Dermatol 2005; 15: 8891.
9 Odom RB, James WD, Berger TG. Andrews Diseases of the
Skin: Clinical Dermatology, 9th edn. Philadelphia, PA: W.B.
Saunders Company, 2000: 10651066.
10 Moelmann GE, Krass P, Halaban R, et al. On the subject of
serum antibodies to melanocytes in vitiligo. J Invet Dermatol
1985; 84: 333.
11 Yu HS, Chang KL, Yu CL, et al. Alterations in IL-6, IL-8,
GM-CSF, TNF-, and IFN-release by peripheral
mononuclear cells in patients with active vitiligo. J Invest
Dermatol 1997; 108: 527529.
12 Honda Y, Okubo Y, Koga M. Relationship between levels of
soluble interleukin-2 receptors and the types of activity of
vitiligo. J Dermatol 1997; 24: 561563.
13 Caixia T, Hongwen F, Xiran L. Levels of soluble interleukin-
2 receptor in the sera and skin tissue fluids of patients with
vitiligo. J Dermatol Sci, 1999; 21: 5962.
14 Grimes PE, Morris R, Avaniss-Aghajani E, et al. Topical
tacrolimus therapy for vitiligo: therapeutic responses and
skin messenger RNA expression of proinflammatory
cytokines. J Am Acad Dermatol 2004; 51: 52 61.
2007 The International Society of Dermatology
Leite and Leite
15 Consensus Conference Management of atopic dermatitis in
children. Recommendations (short version). Eur J Dermatol
2005; 15: 215230.
16 Lepe V, Moncada B, Castanedo-Cazares JP, et al. A double-
blind randomized trial of 0.1% tacrolimus vs. 0.05%
clobetasol for the treatment of childhood vitiligo. Arch
Dermatol 2003; 139: 651654.
17 Grimes PE. Therapeutic trends for the treatment of vitiligo.
Cosmet Dermatol 2002; 15: 2125.
18 Schreiber SL, Crabtree GR. The mechanism of action of
cyclosporin A and FK506. Immunol Today 1992; 13: 136142.
2007 The International Society of Dermatology
Periocular and genital vitiligo in children Pharmacology and therapeutics 989
19 Papp K, Staab D, Harper J, et al. Effect of pimecrolimus
cream 1% on the long-term course of pediatric atopic
dermatitis. Int J Dermatol 2004; 43: 978983.
20 Grassberger M, Steinhoff M, Schneider D, et al.
Pimecrolimus-an anti-inflammatory drug targeting the skin.
Exp Dermatol 2004; 13: 721730.
21 Staab D, Pariser D, Gottlieb AB, et al. Low systemic
absorption and good tolerability of pimecrolimus,
administered as 1% cream (Elidel) in infants with atopic
dermatitis a multicenter, 3-week, open-label study. Pediatr
Dermatol 2005; 22: 465471.
International Journal of Dermatology 2007, 46, 986 989