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Vitiligo: A Review About Causes, Clinical Aspects, and Therapies

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 JOURNAL OF CLINICAL DERMATOLOGY REVIEW ARTICLE

Vitiligo: A Review About Causes, Clinical Aspects, and

Therapies
Gionata Buggiani, Francesca Prignano, Alena Krysenka, Leonardo Pescitelli and Torello Lotti
Affiliation: Second University Unit of Dermatology, University of Florence School of Medicine, Florence, Italy

A B S T R A C T

Vitiligo is a common, acquired, idiopathic and, in the majority of cases, progressive disorder of the skin characterized by the onset of

C
depigmented patches of unknown etiology and poorly understood pathogenesis. It shows milky-white patches involving up to all body
surfaces depending on clinical subsets. It is one of the most common dermatological diseases with an esteemed prevalence of 0.5%
2% of
the population worldwide. Its occurrence is influenced by neither sex, age, nor ethnic roots. Vitiligo is too often erroneously considered only

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an esthetical problem. On the contrary, it is more correct to refer to vitiligo as a complex syndrome, given its high rates of association with
autoimmune diseases such as thyroiditis, gastritis, diabetes mellitus type I, and autoimmune surrenalitis, among others. Moreover, people
affected by vitiligo have a largely decreased quality of life, mainly caused by the color contrast between the healthy pigmented skin and the
depigmented vitiligo patches, which give the patients’ skin a leopard-like appearance. The recent acquisitions as regards both pathogenetic
mechanisms and therapeutic approaches give us increasing resources to understand and manage vitiligo patients and their disease.
Currently, we have many therapeutic options to reach excellent results in vitiligo treatment; however, vitiligo remains a challenging disease.
al,
Keywords: Vitiligo, hypopigmentation, autoimmunity, treatments

Correspondence: Gionata Buggiani, Piazza dell’Indipendenza, 11, 50129 Florence, Italy. Tel: 39 055 6939637; Fax: 39 055 5038506;
dic
e-mail: gionata.buggiani@unifi.it

INTRODUCTION CLINICAL FEATURES

The original description of vitiligo comes from the remote Vitiligo is a primitive chronic disorder of pigmentation,
Me

past of humanity, since the Egyptians, the Indian Vedas and
the Holy Bible all spoke about it.1,2 As regards the root of the
word ‘‘vitiligo’’ itself, it seems to be related to the Latin word
for calf (vitelium) or again for the Latin word for a blemishing
fault (vitium),1,2 the latter giving reason to what vitiligo
represented in most populations and cultures in the past: a
terrible bearing indicating a divine punishment, a shame.
as
characterized by the presence of round-like, well-defined
hypo-amelanotic cutaneous and mucous patches, variable in
dimensions, and with defined edges (Figure 1). External
edges of the patch, in rare cases, can be hyperpigmented or
erythematous and itchy, determining the so-called inflamma-
tory vitiligo in which the borders could be even raised, related
to an intense lymphocytic and histiocytic dermal infiltrate. In

This irrational and absurd belief is still strong currently, for
example, in some subsets of Indian populations a woman
suffering with vitiligo will never be married. This awful
discrimination probably derives also from the likeliness of
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some cases there can be a third color, between the normal
skin and the amelanotic area, defining the trichromic, four-
chromic, or even pentachromic vitiligo. The color of the patch
is uniform, but small pigmented spots can persist on its

vitiligo white patches to those occurring during leprosy and
syphilis, two diseases with a strong impact on humanity so
that awareness against them is justified.3
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context especially near hair follicles where melanocytes may
have a particular phenotype, which should give them more
strength against the noxae that causes loss of epidermal
melanocyte activities and thus vitiligo.5,6

Only near the end of the 19th century were the histopatho-
logical features of vitiligo described by Brocq and Kaposi
among others. But pathogenesis was still obscure and so
remained despite the many hypotheses built in a century,
from emotional stressors to traumatic factors and unex-
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Initial manifestations of vitiligo usually set up in childhood
and adolescence in
50% of cases. They are a few white skin
lesions, often localized to the exposed areas of the face, neck,
and limbs, then they tend to expand (74% of all cases)

plained connections with the nervous system. Currently many
acquisitions, by increasingly interested researchers, contrib-
uted to the knowledge about vitiligo, but its pathogenesis and
etiology are still partially unknown in spite of the fact that
clinical manifestations of vitiligo are considered the prototype
of the hypomelanotic disorders.4
depending on the different clinical features; however, only a
few cases tend to spontaneously recede (1.3%). Vitiligo
involves, in particular, the face and periorificial areas, the
neck, armpits, groin and genitals, knees, elbows, hands, feet,
but all body surfaces can be involved. Subjects with darker
phototype (Fitzpatrick III or more) are more likely to develop

www.slm-dermatology.com 1 DERMA 2011; 000:(000). Month 2011

Journal of Clinical Dermatology
dic
Figure 1. Vitiligo patches involving face and neck of a middle-aged woman.
Some spots of repigmentation can be seen in the context of the amelanotic
lesions.
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vitiligo (84%). Mucosal and palm-plantar lesions seem to be
more likely to darker people on a racial basis.5,6 Vitiligo
fulminans, which develops in few weeks involving the whole
body surface, is still a very rare event.
as
Köbner isomorphic phenomenon is reported in about 30%
of cases in which vitiligo follows a local skin trauma, this is
particularly relevant in cosmetic dermatology because sub-
jects with active or latent vitiligo could develop chronic
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achromic lesions following chemical peelings, depilation,
etc.5,6
Leucotrichia (9%
45%), iritis (10%
40%), choroid altera-
tions, retinal alterations, hearing defects, alopecia areata
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(0.4%), halo nevi (7.2%) can be associated with vitiligo. Even
autoimmune diseases such as Hashimoto’s thyroiditis, per-
nicious anemia, Addison’s disease, Diabetes mellitus type 1,
atrophic autoimmune gastritis, and Vogt-Koyanagi-Harada
syndrome7
12 can be associated with vitiligo.
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Cutaneous neoplasms such as actinic keratoses, basal cell
carcinoma, and squamous cell carcinoma are less likely in
vitiligo patients versus controls, while incidence of malignant
melanoma seems to be slightly increased, yet the patient
survival is higher than in control patients.8
DERMA 2011; 000:(000). Month 2011
CLASSIFICATION
There are two major forms of vitiligo, generalized and
localized/segmental. This clinical classification, which is the
most commonly recognized, is based on both the extension
and the localization of the involved areas. This sharp
distinction could even suggest that perhaps the two main
forms of vitiligo could represent two different entities with
similar clinical features.4
1. Generalized vitiligo: Depigmented macules involving
both sides of the body in a symmetrical pattern, or
patches diffused on most parts of the body surface. It
is the most common type of vitiligo in both adulthood
and childhood. It tends to have spontaneous progres-
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sion during the years, with periods of stability or
occasional partial repigmentation, followed by unex-
pected progression.13,14 Thus, generalized vitiligo has
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the worst prognosis.14 Mucosal involvement occurs in
about 70% of patients; when vitiligo involves the lips
or the genitals, progression is more common.13 There
are three subtypes of generalized vitiligo, which seem
to represent three subsequent stages in the progression
al, of the disease regarding the extension of the cutaneous
involvement:
a. Acro-facial vitiligo: It involves the face in particu-
lar, mainly periorificial areas, and distal limbs.
b. Vitiligo vulgaris: It is characterized by multiple
lesions involving photo-exposed areas, periorifi-
cial areas, folds, and physiologically pigmented
skin such as mammary areolas and external
genitals. Rubbing is considered a main event in
causing micro-traumas, thus the development of
vitiligo lesions in body areas in contact with
underwear or belts or areas over bone protuber-
ances such as sacral-iliac area, knees, shoulders,
shinbones, malleola, dorsum of the hands and
feet. Even the scalp can be involved and a white
lock of hair may grow. Untimely graying of the
hair occurs quite frequently and seems to have a
sort of familial inheritance.15,16
c. Vitiligo universalis: In this form, depigmentation
involves almost all body surfaces, sparing a few
areas of ‘‘normal’’ skin, thus appearing hyper-
pigmented and ‘‘abnormal.’’
2. Localized/Segmental vitiligo. These lesions appear only
in a limited area of the body surface.5,6,15 Vitiligo can be
defined as localized when the depigmented macules have
a random distribution, while it can be defined as
segmental when they are limited to one or more
dermatomes or localized areas.11 Segmental vitiligo
represents about 16% of all vitiligo cases and has
distinctive characteristics such as the earlier setting
up during childhood and the rapid extension in an
area of the skin that can be approximately attributable
to a dermatome. Depigmentation involves only one
dermatome-like area in about 90% of cases, however,
2 www.slm-dermatology.com

multiple lesions can occur. Poliosys and mucosal
involvement in the referring dermatome can occur;
however, none of these factors influence the prognosis
of the disease. Progression of segmental vitiligo stops
in most cases after about 1 year, then the disease is
referred to as stabilized.14 Segmental vitiligo is the most
common vitiligo subtype in childhood and it differs
from other forms of vitiligo in many ways: it has a
weaker response to common therapies, an earlier
setting up, and Köbner phenomenon is less common
(5%). Eventually, it has a weaker association with
autoimmune diseases (3.4%).14,15
HISTOPATHOLOGY
The histological features of stable vitiligo patches are
represented by the loss of pigmentation that is, following
the two major hypotheses, due to functional inactivation of
epidermal melanocytes or to the loss of epidermal melano-
cytes in the involved areas of the skin,16
18 giving birth to a
long-standing controversy over whether melanocytes are lost
or dormant in the context of vitiligo lesions. Obviously, both
pathogenetic hypotheses and therapeutical approaches de-
pend on this issue.
After hematoxylin/eosin dying, the absence of melanocytes
can be seen in all the long-standing depigmented patches,
dic
together with the absence of melanin. Histochemical proce-
dures for the identification of melanocytes (DOPA-reaction)
result negative, even if abnormal DOPA-positive cells can be
seen, perhaps representing inactivated melanocytes. Also,
residual activity of the melanocyte-specific enzyme tyrosinase
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can be seen in lesional vitiligo patches, maybe representing
an index of the presence of residual melanocytes.16,17
Another subpopulation of dermal melanocytes is the
melanocytic reservoir in hair follicles. These cells are inactive
and DOPA-negative, but they still could be stimulated by
as
targeted treatments to proliferate and migrate to the dermal-
epidermal junction to repigment the lesions in a complex
context of cell maturation.18,19
Histopathological features of perilesional skin are quite
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different. It seems that melanocytes and melanin granules are
present in the basal layer of peripheral epidermis, even if
melanocytes are reduced in number and with some alterations
such as an increase in size and with long dendritic
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processes.18 Some authors demonstrated pre-apoptotic altera-
tions in peripheral melanocytes, which should be then
phagocytized by keratinocytes, thus resulting in a lack of
inflammation at the borders of vitiligo patches.20,21
In vitiligo lesions, not only melanocytes are altered.
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Keratinocytes abnormalities are seen at the edges of the
patches. It has been reported a ‘‘ballooning’’ degeneration
(vacuolization) in basal dermal keratinocytes associated to
spongiosis and the presence of a mononuclear and lympho-
histiocytic infiltrate.20,21
www.slm-dermatology.com
A review about causes, clinical aspects, and therapies
Recent experimental data underline the complex interac-
tions that exist between melanocytes and other cells found in
the skin. Among these cells, keratinocytes are able to
influence both the survival and the functional activity of
melanocytes. In functional and ultrastructural research,
keratinocytes from perilesional skin show the features of
damaged cells; besides considering the achromic patch as the
terminal event of a chain of biological processes that take
place in the perilesional skin, these data raise the question
whether keratinocytes more than melanocytes have a role of
primary importance in vitiligo development.21
Not all authors agree with the increase in the number of
Langerhans cells in the dermal layers. However, recent
studies suggest that the death of melanocytes in lesional
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skin from vitiligo patches will led to an increase in
Langerhans cells.22
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A significant increase in lymphocytes in superficial dermis
and epidermis can be demonstrated by immunohistochemical
studies of perilesional skin,23 showing that the infiltrate is
largely composed of activated T-cells. Lesional T-cells can
play an important role in the hypothesis of an autommune
destruction of melanocytes. Using immunofluorescence (IF)
al,
and immunoperoxidase, focal gaps in perilesional skin basal
membrane are seen with lymphocytes infiltrating between
basal membrane cells.23
Using electron microscopy, degenerative changes affecting
nerve endings have also been reported in vitiligo lesions such
as the increase in thickness of Schwann cells basal mem-
brane, minor axonal degeneration (ie, edema and swelling),
and nerve regeneration (perhaps as a reaction to damage).
Moreover, an increased metabolic activity, with a raise on
mitochondrial density and an augmentation of rough en-
doplasmic reticulum, may suggest a possible role of neural
factors in vitiligo pathogenesis.24
PATHOGENESIS
Vitiligo pathogenesis is only partially known, and many
experimental hypotheses are trying to explain the cause of
melanocyte destruction or functional inactivation. However, it
seems that there are many mechanisms causing vitiligo spots.
Thus, vitiligo has to be considered as a syndrome with
different causal factors, which can act alone or in a
synergistic way to make pigmentation disappear in genetically
predisposed subjects. On this basis of genetic predisposition,
several hypotheses have been developed to explain the
occurrence of vitiligo patches.
GENETICS OF VITILIGO
Vitiligo is an acquired disorder, but there is evidence for
familial inheritance because up to 20%
40% of vitiligo
patients have one or more relatives suffering from vitiligo.
Genetic factors are relevant for the predisposition or devel-
opment of vitiligo,25 though not in a Mendelian way. In fact,
incomplete penetrance, multiple susceptibility loci, and
3 DERMA 2011; 000:(000). Month 2011
Journal of Clinical Dermatology
genetic heterogeneity are more appropriate to describe the
pathways of vitiligo inheritance.
The genetic associations of vitiligo and alleles of major
histocompatibility complex (MHC) loci are strong in patients
(and families) where vitiligo is associated to other auto-
immune diseases versus subjects with vitiligo alone. More
and more authors are trying to parallel vitiligo and a number
of different genes and genetic locuses; that is, catalase gene
(Cat) damage,26 chromosome 2 locus (Vit-1 gene),27 chromo-
some 1 locus (AIS1),28 specific HLA aplotypes,29 and a
mutation in GTP-cyclohydrolase the rate-limiting enzyme
for 6-BH4 synthesis.30 In particular, genome-wide linkage
analyses in recent years identified multiple linkages to
vitiligo31 on chromosome 1p (AIS1), 7p (AIS2), 8p (AIS3),
and 17p (NALP1/SLEV1). Autoimmune susceptibility locus
(AIS): AIS1 and AIS2 were identified from families with
vitiligo-related autoimmune disorders, while AIS3 was pri-
marily identified from nonautoimmunity-associated families.
The NALP1 encodes for a protein called NACHT, which is part
of cytoplasmic complexes that regulates the activation of
caspases, and mutations in NALP1 were found in subjects
with variable associated autoimmune features.
Eventually, despite the fact that vitiligo is equally wide-
spread in different areas of the world, different ethnic roots
may express genetic heterogeneity with little or no overlap
dic
between susceptibility loci in different populations.32
PATHOGENETIC HYPOTHESIS 1: THE
AUTOIMMUNE HYPOTHESIS
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The autoimmune theory postulates that either melanocytes
are killed by an immune-mediated mechanism involving
autoantibodies directed against melanocyte surface antigens,
or memory cytotoxic T-cells because of tolerance break-
down.33 Many clinical and experimental studies suggest the
role of autoimmunity in the pathogenesis of vitiligo. Most of
as
these studies focus on the involvement of autoantibodies and
self-reactive T-lymphocytes directed against antigens of
melanocytes and/or keratinocytes. This implies the possibility
of mentioning vitiligo as an autoimmune cutaneous disease.
uc
This hypothesis is supported by the frequent association
between vitiligo and autoimmune diseases such as Hashimo-
to’s thyroiditis,34 Basedow’s disease,34 Addison’s disease,35
pernicious anemia,36 diabetes mellitus type 1,37 and alopecia
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areata.38 In particular, vitiligo is a common manifestation
(10%
15% of all cases) of the so-called polyglandular
autoimmune syndromes characterized by the various associa-
tions of autoimmune thyroiditis, autoimmune surrenalitis,
pernicious anemia, diabetes mellitus type 1, and chronic
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mucocutaneous candidiasis.39 Moreover, in vitiligo patients
and their unaffected first-degree relatives, organ-specific
antibodies are much more common (20%
30%) than in
controls; in particular, there are antibodies against thyroid
and gastric mucosa.40 A 10-year follow-up of asymptomatic
relatives of vitiligo patients showed the subsequent appear-
ance of cutaneous manifestations in up to 11.3% of subjects
DERMA 2011; 000:(000). Month 2011
with antithyroid and antigastric antibodies versus 0.9% of
subjects with no antibodies.41,42
Last, but not least, the effectiveness of immunomodulatory
agents such as corticosteroids and calcineurin inhibitors in
the treatment of vitiligo43 marks another point in favor of this
pathogenetic hypothesis.
Up to 80% of patients suffering from nonsegmental vitiligo
have antibodies against melanocytic antigens,44 while only
about 10% of normal controls are positive for such autoanti-
bodies. These antibodies are mainly IgG (class 1, 2, 3), but also
IgA have been reported.45 Vitiligo antibodies have the func-
tional capacity of killing pigmented cells through complement-
dependent cytotoxicity and antibody-dependent cellular cyto-
toxicity (ADCC).46 Autoantibody cytotoxicity can be considered
C
the initial cause of melanocyte damage, but some authors have
also suggested that it could be a secondary reaction to
melanocyte damage induced by other mechanisms.47
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Indirect immunofluorescence studies, immunoblotting, and
ELISA have demonstrated the presence of specific antibodies
directed against melanocyte superficial antigens in 50%
95%
of patients.48 In approximately 85% of patients with active
al,
vitiligo, antibody levels parallel the activity and extension of
the disease and levels decrease with successful therapy. They
are present in about 44% of patients with clinically inactive
vitiligo. These antibodies are known as ‘‘vitiligo antibodies,’’
and they have the faculty of ‘‘killing’’ pigmented cells. Vitiligo
antibodies bind to antigens expressed by melanocytes and
play an important role in the pathogenesis of the disease.
They recognize many target antigens such as surface antigens
(VIT) with a molecular weight of 35, 40
45, 75, 90, and 150
kD.48 Two antigens with molecular weight, respectively, of
165 and 68 kD were found in melanoma patients using
antibodies from the sera of patients affected by vitiligo.49 The
most common antibodies are directed against antigens of 40

45, 75, and 90 kD, known as VIT 40, VIT 75, and VIT 90. The
VIT 90 is expressed in 35%
45% of vitiligo patients and only
in 0%
4% of controls; VIT 40 and VIT 75 are, respectively, in
74%
76% and 57%
72% of vitiligo patients and in only 4%

14% and 4%
8% of controls.48 These three antigens are
partially defined and expressed on the melanocyte surface.48
The enzyme tyrosinase is recognized by a specific intracel-
lular vitiligo antibody that is currently very difficult to search in
patients. Other melanogenic enzymes are referred to as
‘‘tyrosinase related protein-1’’ (TRP-1)50 and ‘‘tyrosinase
related protein-2’’ (TRP-2).51 They have antigenic activity and
are recognized by specific autoantibodies, which can be found
in the serum of some vitiligo patient52 but not in controls.
Stating the actual information (prevalence of specific
circulating T-lymphocytes with a cytotoxic activity against
melanocytes in a high number of vitiligo patients and
prevalence of lymphocytes strictly in contact with melano-
cytes), many authors consider a primitive or secondary
immune cell-mediated reaction as the most probable patho-
genetic mechanism of vitiligo.53 Cytotoxic T-lymphocytes are
reported just near apoptotic melanocytes in vitiligo patches,54
with a considerably increased CD8/CD4 ratio.55 In the
4 www.slm-dermatology.com

perilesional skin of vitiligo patients, lymphocytes express
high levels of the common activation markers as stated by the
increased expression of HLA-DR (class II) antigens and of the
IL-2 receptor (CD25) near the areas of melanocytic depletion.
Even keratinocytes and melanocytes show alterations with
an increased expression of HLA-DR II e ICAM-1, respec-
tively.56 Pigmented cells are primary targets of T-cell
mediated cytotoxicity, but they also show a phagocytic activity
and they can act as antigen-presenting cells (APC) to T-cells
expressing MHC-II.56 The increase in ICAM-1 on the
melanocyte surface seems the cause of the increased adhesion
between lymphocytes and melanocytes thus simplifying
cytotoxicity. The levels of many inflammatory and/or
immunomodulating cytokines such as IL-2, IL-6, TNF-a,
and GM-CSF seem altered during vitiligo.57
59
In vitiligo patients, a significant increase in circulating
T-lymphocytes expressing a specific ‘‘homing receptor’’ for
the skin on their surface has been reported. Lymphocytes
with this antigen, known as CLA (cutaneous lymphocyte-
associated antigen), can recognize and destroy melanocytes
expressing HLA-A*201Melan-A/Mart-1.60 It has been
recently proposed that the hypotheses of melanocyte destruc-
tion could occur by apoptosis, perhaps invoked by cytokines
(IL-1, IFN-g, and TNF-a) released by lymphocytes, keratino-
cytes, and melanocytes.61
dic
Eventually, research in the 1980s and 1990s on animal
models of vitiligo seem to show that the initial phase of the
autoimmune process is antibody-dependent, and only in the
following stages is melanocytic destruction due to cell-
mediated mechanisms.42 It is still unclear whether the
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specific immune alterations in vitiligo are a major step in
pathogenesis or, on the contrary, only a consequence of the
disease. Thus, are these alterations directly causing melano-
cyte destruction, only increasing the damage already pro-
voked by other factors, or are they simply an interesting
epiphenomenon.
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PATHOGENETIC HYPOTHESIS 2: THE
BIOCHEMICAL HYPOTHESIS
The biochemical hypothesis considers an autocytotoxic
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mechanism as the main factor for vitiligo development. In
unaffected skin, levothyroxine is the common substrate
for the synthesis of melanin in melanocytes and for the
synthesis of catecholamines in keratinocytes. Levothyroxine
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production from L-phenylalanine by the action of phenylala-
nine-hydroxylase is limited by the co-factor (6R)-5,6,7,8
tetrahydrobiopterine (6-BH4). The 6-BH4 is generated by
4a-OH-BH4 through the action of the enzyme 4a-hydroxy-
BH4 dehydratase. In vitiligo patients, it seems that 4a-
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hydroxy-BH4 dehydratase activity is lower than normal, thus
increasing the levels of the isomer 7-BH4 and of H2O2 in
epidermis,62 probably the effectors of melanocyte damage.
Moreover, the increasing level of 6-BH4 and 7-BH4 acts as a
powerful inhibitor of phenylalanine-hydroxylase and tyrosi-
nase, thus inhibiting melanin synthesis.63 Recent studies
seem to show that autocytotoxicity could be provoked by
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A review about causes, clinical aspects, and therapies
the intracellular storage of reactive oxygen intermediates
(superoxide anion radicals, hydrogen peroxide, hydroxyl
radicals) and not by the intermediate products of melanin
synthesis.64
Increased levels of pro-oxidants as well as decreased levels
of antioxidant agents have been reported in the blood of
patients with vitiligo.64 Other studies indicated the presence
of oxidative stress-induced damage within the epidermis of
vitiligo lesions.65
PATHOGENETIC HYPOTHESIS 3: THE NEURAL
HYPOTHESIS
According to the neural theory, which fits best to segmental
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vitiligo subset, some chemical mediators released from
peripheral nerve endings cause a decreased production of
melanin.66 A significant increase in urinary catecholamine
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metabolites, homovanillic acid, and vanilmandelic acid has
been reported at the onset and during the progression of
vitiligo.67 This results from a release of catecholamines by
autonomic nerve endings and keratinocytes in the skin that
contributes to melanocyte damaging.68 In addition to a direct
al,
cytotoxic effect, these molecules could exert an indirect action
through the activation of the a-adrenergic receptors of skin
arterioles that eventually results in a remarkable vasoconstric-
tion. Severe and/or repeated attacks of hypoxia cause toxic
oxygen radicals to accumulate leading to depigmentation.67
The activation of the sympathetic nerve fibers following major
stressors may contribute to the periodical worsening of
vitiligo following these particular life events. Eventually,
some studies have reported ultrastructural evidence of axonal
damage in the nerve fibers from lesions of segmental vitiligo
supporting this hypothesis.67
PATHOGENETIC HYPOTHESES 4: FROM THE
OLDER TO THE NEWER ALTERNATIVES
Many other factors are supposed to play a role in vitiligo
pathogenesis. The alterations of calcium uptake/release
from keratinocytes and melanocytes seem to influence
melanogenesis through the alteration of calcium-dependent
L-phenylalanine intracellular transport, and the turnover of
L-phenylalanine to L-tyrosine from which melanin is synthe-
sized.69 More than 40% of vitiligo patients have a signifi-
cantly slower phenylalanine metabolism compared to healthy
controls.69
Another hypothesis has arisen in the past, proposing a viral
etiology for vitiligo particularly claiming CMV and EBV as
possible causative pathogens.70,71 However, the extremely
diffused infections by CMV in population makes it difficult to
assess its direct association to vitiligo, and studies using PCR
techniques have not so far demonstrated direct evidence for
CMV, HSV I/II, or VZV in skin biopsies or sera of patients.72
However, ‘‘hit and run’’ mechanisms, even through mole-
cular mimicry activating autoimmunity, cannot be excluded as
shown in animal models.73 Isolated case-control observations
proposed an association between vitiligo and HCV infection74
5 DERMA 2011; 000:(000). Month 2011
Journal of Clinical Dermatology
and stressed the role of HIV as a precipitating factor in
vitiligo.75 More studies on these issues are needed.
Currently, it is thought that several associated factors, in
part mentioned in each of the previously discussed pathoge-
netic theories, can synergistically induce hypopigmentation of
the skin in genetically predisposed individuals. Recently, the
novel ‘‘eclectic hypothesis’’ takes place from the observation
of the complex interactions that exist between melanocytes
and other cutaneous cells such as keratinocytes, Langerhans
cells, endothelial cells, fibroblasts, and mast cells.76
80
These data support and complete the concept of the
epidermal-melanic unit proposed by Fitzpatrick and Breath-
nach,81 as it attributes to the melanocyte a central role in
receiving a series of stimulating and/or inhibiting signals
produced by keratinocytes, mast cells, fibroblasts, lympho-
cytes, macrophages, and nerve endings. A biochemical
imbalance (related to growth factors, cytokines, inflammatory
mediators, adhesion molecules) that does not permit mela-
nocytic survival in the epidermal environment would induce
the early death of melanocytes by apoptosis and the formation
of the achromic lesions.
In a recent paper,82 the role of keratinocyte dysfunction and
apoptosis in vitiligo lesions due to cytokine microenviron-
ment alterations was assessed by means of evaluating the
presence of keratinocyte-derived mediators involved in pig-
dic
mentation. In particular, stem cell factor (SCF) and endothe-
lin-1 (ET-1) mRNA were significantly reduced in lesional as
compared to perilesional epidermis, and the expression of
mRNA for tumor necrosis factor (TNF)-alpha and interleu-
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kin-6 (IL-6), two pro-inflammatory cytokines that inhibit
pigmentation, was increased in lesional skin, whereas their
expression was practically undetectable in the skin of control
subjects.
In a novel work from Prignano et al,21 functional and
ultrastructural analyses of healthy, perilesional and lesional
as
skin of vitiligo subjects were performed, putting in evidence,
among other observations, major morphological and func-
tional alterations of mitochondria in keratinocytes from
perilesional skin. The mitochondrial activity plays a crucial
uc
role in normal cell functionality, thus the alteration of these
organelles could lead to cell death (mainly by apoptosis
mechanisms). To corroborate this hypothesis, the authors
assessed mitochondrial activity and membrane permeability,
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and biochemical assays were performed in order to evaluate
the presence of oxidative stress that could lead to cell
dysfunction. Keratinocytes from perilesional skin appeared
to be damaged indeed; thus, it is possible that they are not
able to produce adequate quantities of growth factors
Sa
necessary for melanocyte survival such as stem cell factor
(SCF),83,84 cytokines, and growth factors implied in the
correct differentiation of melanocytes and in the maintenance
of their homeostasis in the epidermis. The reduced produc-
tion of all these factors could trigger the apoptotic process in
the melanocytes and cause their disappearance in vitiligo
lesions.61
DERMA 2011; 000:(000). Month 2011
These data give to keratinocytes a role of primary impor-
tance in vitiligo development, shifting (partly) the attention of
research from melanocytes to keratinocytes in the develop-
ment of future strategies to understand and fight against
vitiligo.
DIAGNOSIS
In most cases, diagnosis of vitiligo is quite simple for a
dermatologist as it is based on the inspection of the skin. It is
important to recollect the clinical history of the patient, to
inquire about other dermatological or systemic pathologies
such as autoimmune diseases that can be related to vitiligo in
patients and their relatives. Complete examination of the skin
is mandatory, using a Wood’s lamplight if necessary (ie, for
C
lighter phototypes). Laboratory screening is needed to
evaluate autoimmunity, thyroid function, and plasma markers
of atopy. Eventually, in controversial and selected cases,
LL
biopsies of lesional and perilesional skin may help to get an
histology-confirmed diagnosis.
TREATMENTS
al,
Too many physicians and dermatologists, even currently,
tell their patients that there is no treatment for vitiligo; it is
not true and we should consistently react against this
prejudice. Vitiligo treatment should have the aim to reset
complete skin appearance and function and to manage
internal associated diseases. Melanocytes usually respond
slowly to treatments, so it may take up to 6
12 months to
reach acceptable results.
Both nonsurgical and surgical treatments for vitiligo are
available. Nonsurgical repigmentation therapies are well
established and include narrow-band UVB irradiation; psor-
alen plus ultraviolet A (UVA); broadband UVB; topically, oral,
and intralesional administered corticosteroids; and other less
popular and/or effective treatments. Surgical methods should
only be considered for stable vitiligo once medical treatments
have failed.
Recently, combination therapies have been introduced in
the treatment of vitiligo. We would like to mention here, for
example, potent topical corticosteroids plus UVA or UVB
irradiation and calcipotriol ointment 50 mg/g plus UVB,
among others. Simultaneously, the clinical effects of focused
phototherapy have been studied using UVB-targeted micro-
phototherapy (broad-band, narrow-band 308 nm and 311 nm)
and laser-targeted therapy with good results and excellent
compliance, thanks both to the lack of hyperpigmentation of
the unaffected skin and to a lowered risk of premature skin
aging and possible cancerization related to total body
irradiation.
Corticosteroid therapy
Topical steroids are still considered by most dermatologists
the first-line treatment for vitiligo. Advantages of topical
corticosteroid therapy for vitiligo include relatively low cost,
ease of application, and ability to use at home. Topical
corticosteroids are considered a treatment option for children
6 www.slm-dermatology.com

of all ages in many (but not all) cutaneous sites but only in
limited skin areas. Topical high potency corticosteroids are
particularly suited for treatment of limited areas, and they are
most effective for lesions on the face (excluding eyelids),
elbows, and knees.85
The most efficient steroids seem to be class III steroids
(betamethasone valerate 0.1%
0.2%) and class IV steroids
(clobetasol propionate 0.05%), applied 1
2 times daily for 2
4
months. These therapeutic protocols reach discrete results in
30%
84% of cases. Topical steroids should only be used for
limited times and only in the case of localized vitiligo (B10%
total body surface) but not in segmental vitiligo. When
treating the face, eyelids, and folds, class I and II steroids
are preferred considering their less evident side effects. When
no sign of improvement is seen after about 3 months, the
treatment should be discontinued to avoid well-known side-
effects such as acneiform eruptions, epidermal atrophy,
teleangectasis, erythema, striae distensae, hypertrichosis,
itch, and rosacea particularly in pediatric patients. The
association of topical steroid (fluticasone propionate) and
UVA phototherapy has reached good results.86
Oral corticosteroids have been proposed but are not
recommended because of the possible occurrence of well-
known serious adverse events.87 Mini-pulse-therapy with per
os betamethasone or dexamethasone 2 days per week has
been proposed in patients with rapidly spreading vitiligo,
dic
obtaining good results with significantly lower side effects.88
Other topicals
The use of creams/ointments containing pseudocatalase
seems to stop vitiligo progression and induce repigmenta-
Me
tion.89 In fact, the low levels of catalase demonstrated in the
epidermis of vitiligo patients have been related to increased
hydrogen peroxide (H2O2) levels in melanocytes and impaired
melanogenesis.90 Pseudocatalase acts as a substitute for
impaired levels of catalase, degrading excessive hydrogen
peroxide, and thereby allowing recovery of enzyme activities.
as
Narrow-band UV-B-activated topical pseudocatalase may be
effective for vitiligo treatment but, although some repigmen-
tation can be observed in about 60% of patients treated with
this modality, further studies are needed in order to evaluate
uc
the degree of contribution of the UV-B radiation to these
results.91
Some authors report positive results after the topical
administration of tacrolimus ointment 0.1% particularly on
nL
sun-exposed areas of the skin (face and neck).92 Tacrolimus
seems to selectively work by inhibiting T-lymphocyte activa-
tion, thus blocking the production and secretion of proin-
flammatory cytokines such as TNF-a, which levels are
increased in vitiligo skin but not in healthy controls.93 This
Sa
suggests that repigmentation could be in part associated to
TNF-a levels reduction in affected skin. The association of
tacrolimus ointment with the Excimer Laser 308 nm seems an
effective treatment for vitiligo,94 but the possibility of
unexpected burns has to be considered. Pimecrolimus cream
seems similarly active in the treatment of vitiligo patches,
mainly in the management of childhood vitiligo.95
www.slm-dermatology.com
A review about causes, clinical aspects, and therapies
A possible approach to the treatment of vitiligo is based on
the long-time known concept that UV rays induced melano-
genesis is partly due to the UV-induced turnover of membrane
phospholipids generating prostaglandins (PGs) and other
products and may be representing the activating signal for
repigmentation. Some authors96 observed an improvement in
the clinical conditions of vitiligo patients with a skin
involvement B5%, treated with a topical gel formulation
containing 166.6 mg/g prostaglandin (PG)-E2 applied in the
evening to depigmented skin for 6 months. Of the 24 patients
evaluated at the end of the study period, 15 reported marked
(50%
75%) to complete repigmentation (6 focal vitiligo,
7 vitiligo vulgaris, 2 segmental vitiligo), while 6 patients
showed 25%
50% improvement and 6 showed minimal or no
improvement. The observed side effects were episodes of
C
mild irritation after exposure to sunlight. Different mechan-
isms could explain the repigmentation process following
LL
topical PGE2 administration including (1) its influence on
melanocyte responsiveness to neuronal stimulation, (2)
melanocyte proliferation, and (3) direct or second messen-
ger-mediated interaction with melanocytes through the
stimulation of tyrosinase activity. In addition, other mechan-
isms, not directly involving melanocytes, have been proposed:
al,
one of the most interesting is focused on the immunosup-
pressive role of PGE2, in vitro and in vivo.97 Other trials
should be performed to evaluate the correct use of topical
prostaglandin analogues in vitiligo.
Patients with vitiligo exhibit reduced levels of intracellular
calcium in both keratinocytes and melanocytes.98 The
decrease in calcium levels parallels increased thioredoxin
levels, which could inhibit the tyrosinase activity and thus
melanogenesis. Derivatives of vitamin D act on melanocyte
receptors for 1,25-dihidroxy-vitamin D, modifying the altered
calcium homeostasis and thus permitting a more rapid
repigmentation both when used alone and when associated
with classical PUVA treatment.98
Cucumis melo extracts have shown relevant super-oxide-
dismutase and catalase-like activities when associated to
selective UVB therapy.99 Both in vitro and experimental data
show the most interesting performance of this vegetal extract,
which is especially well accepted by vitiligo patients and by
the family members of the children affected by the disease.
Excellent results have been observed in association with
focused UVB narrow-band treatment, showing that the
association represents a safe and effective treatment, well
tolerated, and accepted by the patients.100
Ultraviolet A photochemotherapy (PUVA)
Photochemotherapy began in 1948 when El Mofty101
reported the successful treatment of vitiligo with an extract
from the plant Ammi majus linnaeus, applied topically and/or
taken orally, together with either UV light or natural sunlight.
Bergapten (5-MOP) and 8-MOP were shown to represent two
of the major active compounds derived from this plant.
Treatment then evolved with high-intensity UVA photother-
apy units102 and then, in 1997, with the use of the narrow-
band UVB (311 nm) light source.103 The earliest sign of
7 DERMA 2011; 000:(000). Month 2011
Journal of Clinical Dermatology
response to phototherapy, as for topical corticosteroids, is
usually perifollicular repigmentation or a hyperpigmented
rim. Cytokines and other inflammatory mediators released
from cells such as keratinocytes because of UV radiation or
PUVA might stimulate inactive melanocytes in the outer root
sheath of hair follicles to proliferate, mature, and migrate to
repopulate the interfollicular epidermis.104 Interfollicular
repigmentation is also often described. The immunosuppres-
sive action of UV radiation on T-lymphocytes may also play a
role in preventing supposed autoimmune mechanisms of
melanocyte destruction.105 A dated left-right comparison
study106 showed that combination therapy with UVA and a
medium potency topical corticosteroid was about three times
more effective than either treatment alone (P B0.001),
suggesting synergy between melanocyte stimulation and
immunosuppressive effects.
While topical psoralen plus UVA (TUVA-therapy) can be
associated to acute adverse events (erythema, blistering,
edema, vesiculation, sunburn-like reactions), PUVA can cause
nausea and vomiting (particularly for 8-MOP) and is asso-
ciated with cataracts. Thus, UV-protective glasses must be
worn at least 12 hours after psoralen tablet ingestion. As
regards long-term side effects, TUVA is associated mainly
with photoaging of the skin and an increased risk of skin
cancer (actinic keratoses and squamous cell carcinomas)
while PUVA, due to its antiproliferative and cytotoxic effects,
dic
can be mutagenic and carcinogenetic.
Until recent years, PUVA therapy represented the first-line
treatment in vitiligo. Currently, alternative methods, more
effective and less dangerous, are preferred when possible,
and PUVA is almost totally replaced by narrow-band UVB.
Me
Moreover, PUVA therapy is not recommended in pediatric
patients, or when it could be difficult to assess the total
amount of radiation absorbed during different cycles of
treatment.107
Ultraviolet B phototherapy
as
Although the precise biological mechanisms through which
ultraviolet (UV) light leads to effective repigmentation are yet
to be precisely confirmed, the efficacy of UV-B light in vitiligo
is probably due to the production of high levels of cis-
uc
urocanic acid, a metabolic product that causes cutaneous
immune suppression. Furthermore, melanogenesis may be
stimulated by UV-B radiation through the activation of nitric
oxide-cGMP-proteinkinase G pathway, by the activation of the
nL
cAMP-pathway by alpha-melanotropin, and/or through mel-
anocyte-stimulating hormone (MSH) receptor-binding activity
and melanocortin receptor-gene expression.108
The first data on the use of UVB in the treatment of vitiligo
(broadband UVB: 280
320 nm) appeared in 1990, while the
Sa
first report on UVB narrow-band therapy (NB-UVB: 31192
nm) appeared in 1997.103 This latter study showed the efficacy
of NB-UVB compared to UVA therapy plus topical photo-
sensitizers in the treatment of vitiligo, with faster repigmen-
tation and less contrast between normal and depigmented
skin. In addition, a combination of UVB with other therapies
such as topical corticosteroids and vitamin D derivatives were
DERMA 2011; 000:(000). Month 2011
considered. No statistical differences in rates of success seem
to exist between PUVA, NB-UVB, or broadband UVB.
Besides the major advantage of avoiding the side effects of
orally assumed or topically applied photosensitizers and the
evidence of less photodamaging due to lower cumulative
doses, the recent guidelines for the treatment of vitiligo show
that UVB narrow-band phototherapy is recommended for
generalized vitiligo,109 pregnant women, and children.
Three recent treatment modalities, UVB Narrow Band
Microphototherapy, Monochromatic Excimer Light, and Ex-
cimer Lasers (the so-called focused UV therapy) took place
from UV-B narrow-band therapy, ameliorating the way to
deliver UVB rays to patients. By means of these therapies, it is
C
possible to reduce the color contrast between healthy and
hypopigmented skin, provide different amount of UV radia-
tions to different body sites (ie, eyelids need less exposure
LL
than feet to repigment), and avoid the side effects associated
to diffuse phototherapy (photoaging, erythema, burns,
among others).
A study, published in 2003, evaluating microphototherapy
in a large number of patients110 showed results that parallel
al,
those obtained in various clinical trials by total body UV-B
irradiation in terms of repigmentation. Focused UV-therapies
seem to be particularly useful in patients affected by
segmental vitiligo and vitiligo vulgaris, when less than 10%
body surface is involved.111
A recent open study investigated the variable rates of clinical
improvement in vitiligo patients following different treatment
modalities. In particular, subjects were treated using UV-B
narrow-band microphototherapy (311 nm) alone or in asso-
ciation with tacrolimus 0.1% ointment, pimecrolimus 1%
cream, betamethasone dipropionate 0.05% cream, calcipo-
triol ointment 50 mcg/g, or 10% L-phenylalanine cream. Each
topical treatment was also given as a monotherapy in
subgroups of patients.112 The study showed the supremacy
of targeted combination therapies over monotherapies with
the highest repigmentation rates obtained with the associa-
tion of topical high potency corticosteroids and photother-
apy; while, when each and every treatment was considered as
monotherapy, UV-B narrow band and 0.05% betamethasone
dipropionate cream still showed the best results.
Oral antioxidant supplementation
The hypothesis that a deficiency of nutritional elements
could contribute in part to the pathogenesis of vitiligo
depigmentation has been proposed, thus giving interesting
therapeutic perspectives: many researches tried to demon-
strate repigmentation after replacement therapy with vita-
mins. Among all these compounds, vitamin B12, folic acid,
ascorbic acid, tocopherol, and vitamin D3 seem to play some
effective role in the pathogenesis of vitiligo.113 However,
further studies are needed in order to receive confirmation on
the real effectiveness of these agents to determine their ideal
minimal dosages and to obtain some treatment protocol. Per
os antioxidants (ie, vitamin E) could perhaps increase the
8 www.slm-dermatology.com

protections against oxidative stress, which seem to facilitate
the eruption of vitiligo.114
A recent paper investigated the potential role of oral
supplementation of the natural antioxidant agents curcumin
and capsaicin in protecting keratinocytes from the oxidative
stress and in the inhibition of keratinocyte apoptosis.115
Moreover, pretreatment with such natural antioxidants seems
to increase total cell antioxidant capacity, to repress intracel-
lular ROS generation and lipid peroxidation, and to improve
mitochondrial activity.115 These results may suggest that
antioxidants might represent an alternative approach to
protect against vitiligo progression.
Surgical treatments
Surgery is an option when dealing with patients with stable
vitiligo that is refractory or partially responsive to medical
treatments, or patients who have areas of involvement
B2
3 cm containing depigmented hairs, or involvement of
sites such as the lips or fingers that are unlikely to have a
satisfactory response to medical therapy. There are many
different surgical approaches to vitiligo; therefore, we recom-
mend referring to specific manuals. However, in this paper we
would like to offer some recommendations. It is mandatory
that the disease is stable; in fact, stability is the most critical
factor in the selection of patients with recalcitrant vitiligo as
candidates for surgical repigmentation. Some authors suggest
dic
surgically treating vitiligo patches only if stable during the last
2 years, and/or to perform a mini-grafting test before the graft
to evaluate the positive response and the absence of köbner-
ization at the donor site after 2
3 months follow-up.116 In fact,
active vitiligo gives a higher risk for graft failure, recurrence of
Me
depigmentation, and köbnerization at the donor site.116 Other
important factors affecting graft outcome in vitiligo patients
include the location and type of disease with 95% success rates
for test grafting in segmental or focal vitiligo versus550% in
generalized vitiligo.117 Better surgical results can be obtained
in segmental vitiligo and in subjects under 20 years of age.118
as
Surgical repigmentation techniques can be associated to other
therapeutic protocols such as topical corticosteroids and/or
focused phototherapy in order to obtain better results.119
uc
CONCLUSIONS
Vitiligo is a skin, hair, and general pigmentation disorder
that has important implications not only from a dermatolo-
nL
gical and cosmetological point of view but also regarding
fundamental aspects of patients quality of life such as self-
esteem, relationships, acceptance, and discrimination. In
recent years, dermatologists have made big forward steps to
explain its pathogenesis and to improve its treatment.
Sa
The management of vitiligo is difficult, and not only
patients but also physicians agree that it is hard to deal
with the chronicity, remissions, and flares of a disease with a
strong psychosomatic issue. However, a positive and empa-
thetic approach to the patient is mandatory, in consideration
of the excellent treatments in our hands that can be selected
according to the patients’ needs. An adequate treatment
www.slm-dermatology.com
A review about causes, clinical aspects, and therapies
schedule is based on the clear classification and evaluation of
the course of the disease in each patient. The dermatologist
has then the duty to know and choose the most valid, safe,
and well-tolerated therapy after exhaustive discussion with
the patient and providing him correct information regarding
his realistic expectations about therapy results.
Disclosure: The authors declare no conflict of interest.
Acknowledgements: No financial or material support have been
requested by the authors in performing the present paper. The
authors have performed data collection, analysis, and interpretations
independently and without external sponsorship.
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