AUTREV-01798; No of Pages 9

Autoimmunity Reviews xxx (2015) xxxxxx

Contents lists available at ScienceDirect

Autoimmunity Reviews
journal homepage: www.elsevier.com/locate/autrev

Review

2Q1

Vitiligo: Pathogenesis, clinical variants and treatment approaches

a r t i c l e

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Article history:
Received 1 December 2015
Accepted 16 December 2015
Available online xxxx

b
c

Organi di Senso Department, Sapienza University of Rome, Viale del Policlinico 151, 00161 Rome, Italy
First Dermatology Division, Institute Dermopatico dell'Immacolata (I.D.I.) IRCCS, Via Monti di Creta 104, 00167 Rome, Italy
Department of Clinical Immunology, Sapienza University of Rome, Viale dell'Universit 37, 00161 Rome, Italy

i n f o

a b s t r a c t

Vitiligo is a common chronic acquired disease of pigmentation whose etiology is unknown, which usually occurs
with asymptomatic whitish patch or macule. Although several hypotheses have been proposed in the literature,
the leading theory is still the auto-immune etiology linked to specic genetic mutations. Vitiligo can also be associated with several autoimmune diseases, including autoimmune thyroid diseases, alopecia areata, and halo
nevi.
Sensorineural hearing loss was reported in several vitiligo patients due to a reduction in the number of melanocytes contained in the membranous labyrinth of the inner ear. Because of its complexity, several therapeutic
options are available to treat this systemic disease.
2015 Published by Elsevier B.V.

Keywords:
Vitiligo
Autoimmune diseases
Hearing loss
Oxidative stress
NB-UVB
Prednisolone

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5.

Introduction . . . . . . . . . . .
Epidemiology . . . . . . . . . .
Genetic features in vitiligo . . . . .
Etiopathogenesis . . . . . . . . .
4.1.
Autoimmune theory . . . .
4.2.
Adhesion defect theory . . .
4.3.
Biochemical theory. . . . .
Classication and clinical features .
5.1.
Classication . . . . . . .
5.2.
Skin features . . . . . . .
5.3.
Ocular features . . . . . .
5.4.
Audiological abnormalities .
5.5.
Vitiligo and melanoma . . .
Histopathology . . . . . . . . . .
Diagnosis and differential diagnosis.
Therapy . . . . . . . . . . . . .
8.1.
Topical steroids . . . . . .
8.2.
Calcineurin inhibitors. . . .
8.3.
Systemic therapy. . . . . .

N
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5Q3
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R
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Giannicola Iannella a, Antonio Greco a, Dario Didona b, Biagio Didona b, Guido Granata c, Alessandra Manno a,
Benedetta Pasquariello a, Giuseppe Magliulo a,

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Abbreviations: APS, Autoimmune polyglandular syndromes; TRP-1, Tyrosinase one; TRP-2, Tyrosinase two; MART-1, Melanoma antigen recognized T cells 1; TREGs, Regulatory T cells;
TNF-, Tumor necrosis factor-; IFN-, Interferon-; NSV, Non-segmental vitiligo; DDR1, Discoidin domain receptor-1; SOD, Superoxide dismutase; NOS, Nitric oxide synthase; NADPH,
Nicotinamide adenine dinucleotide phosphate oxidase; MAO-A, Monoamine oxidase A; 6-BH4, (6R)-L-erythro 5,6,7,8-tetrahydrobiopterin; SV, Segmental vitiligo; MV, Mixed vitiligo; RPE,
Retinal pigment epithelium; TCs, Topical corticosteroids; TCIs, Topical calcineurin inhibitors; NB-UVB, Narrow-band UVB; PUVA therapy, Phototherapy with UVA; MEL, Monochromatic
excimer light.
All authors declare no conicts of interest, grants or other founding supports.
Corresponding author at: Via Gregorio VII n.80, Rome 00165, Italy.
E-mail addresses: giannicolaiannella@hotmail.it (G. Iannella), antonio.greco@uniroma1.it (A. Greco), dario.didona@gmail.com (D. Didona), b.didona@idi.it (B. Didona),
guido.granata@alice.it (G. Granata), alessandramanno@hotmail.it (A. Manno), benedetta.pasquariello@gmail.com (B. Pasquariello), giuseppemagliuloorl@yahoo.com (G. Magliulo).

http://dx.doi.org/10.1016/j.autrev.2015.12.006
1568-9972/ 2015 Published by Elsevier B.V.

Please cite this article as: Iannella G, et al, Vitiligo: Pathogenesis, clinical variants and treatment approaches, Autoimmun Rev (2015), http://
dx.doi.org/10.1016/j.autrev.2015.12.006

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G. Iannella et al. / Autoimmunity Reviews xxx (2015) xxxxxx

8.4.
Physical therapy
8.5.
Surgical therapy
9.
Conclusions. . . . . .
Take-home messages . . . .
References. . . . . . . . .

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1. Introduction

3. Genetic features in vitiligo

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Vitiligo is a common chronic acquired disease of pigmentation. Its

etiology is unknown, but it is characterized by destruction of melanocytes in the skin that causes hypopigmented and asymptomatic macules
with sharply demarcated margins (Fig. 1) [1]. However, recent clinical
and experimental studies suggest that there is a systemic destruction
of melanocytes, especially in the mucous membranes, eyes, and the
membranous labyrinth of the inner ear. Indeed, several authors reported an association between vitiligo, ocular manifestation, hearing loss
and autoimmune diseases [2,3]. Hearing loss is one of the most common
associated symptoms with an incidence estimated in a range from 4% to
20% of vitiligo patients [2,3].
The term vitiligo derives from latin and was rst used by Celsus in his
De Medicina [4]. However, in the nineteenth century both Brocq and
Kaposi described the clinical features of vitiligo [5]. Furthermore, Kaposi
showed that in the basal layer cells of the epidermis affected by vitiligo
there were no pigment granules [5].
According to Ezzedine et al. [1], a segmental vitiligo which is the
commonest form, and a non-segmental vitiligo can be distinguished.
However, several subsets of this condition have been reported in the literature, including localized, generalized and universal types [1].
Although several hypotheses have been described in the literature,
the leading theory is still the autoimmune one [69].

Vitiligo is a complex genetic disease. Fifty genes at least have already

been evaluated in order to identify a link with vitiligo. However, only a
few genes present a clear association with vitiligo. On the one hand,
there are non-HLA genes, including DDR1, XBP1, NLRP1, PTPN22 and
COMT [14]; on the other hand, there are HLA-associated genes, including HLA-A2, HLA-DR4 and HLA-DR7 alleles [1517].
The DDR1 gene, on the chromosome region 6p21, is involved in melanocyte adhesion to the basal layer through integrin CCN3. Indeed, recent papers highlighted that mutations in this gene generated a
reduction of melanocyte adhesion in the basal membrane [18,19].
The XBP1 gene, mapped on 22q12 locus, is implicated in the expression of MHC class II genes. Recently a paper has demonstrated an elevation in the expression of XBP1 in lesional skin of carriers of a particular
XBP1 (allele C of rs2269577 polymorphism) [20].
It was shown that some variants of NLRP1, on chromosome region
17p13, were associated with the risk of generalized vitiligo and several
autoimmune diseases associated with vitiligo [21]. Furthermore, the
NLRP1 gene was the rst to be related to American vitiligo families [21].
The PTPN22 gene, located on 1p13.3-p13.1 locus, has been recently
demonstrated as an inherited risk factor to generalized vitiligo by several studies [22,23].
The COMT gene, on 22q11.1-q11.2 locus, has been related to rising
oxidative stress in vitiligo, because of its involvement in the metabolism
of some catecholamines [24].
The factors mentioned above are collectively responsible of the high
inherent risk of vitiligo. Indeed, it has been reported in the literature
that up to 20% of vitiligo patients show at least one rst-degree relative
with vitiligo [13]. Furthermore, the relative risk of developing vitiligo in
rst-degree siblings has been found up to tenfold higher than in general
population [25].

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4. Etiopathogenesis

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2. Epidemiology

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By far, vitiligo is the most frequent disorder of pigmentation.

India shows the highest incidence in the world (up to 8.8%) [10]. In
the U.S.A. the incidence is about 1% [11]. However, the largest epidemiological study was conducted in 1977 in Denmark, showing an
incidence of 0.38% [12]. In addition, it is reported in the literature
that about 1% of the world's population has vitiligo [1]. Vitiligo affects both genders equally, although is a common observation that
women complain earlier and more frequently about vitiligo, possibly
because in some places vitiligo is considered as a stigma or a cosmetic problem [13]. Vitiligo can develop at any age. However, in 70%
80% of cases it arises before the age of 30 [13]. Furthermore, an
onset before the age of 12 years is common, affecting up to 37% of
patients [1].

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Fig. 1. Hypopigmented macules of vitiligo with sharply demarcated margins.

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Although the etiology of vitiligo remains unclear, several theories 131

have been developed. However, the autoimmune hypothesis remains 132
the leading one.
133
4.1. Autoimmune theory

134

It is widely known that vitiligo can be associated with several autoimmune diseases, including autoimmune thyroid diseases, alopecia
areata, halo nevi, and Addison's disease. Indeed, in the literature an association has been reported between vitiligo and autoimmune diseases
affecting up to 20% of Caucasian patients [8,11]. Furthermore, it has been
shown that autoimmune thyroid diseases, especially Hashimoto thyroiditis, are the most common vitiligo-associated disorders [11,26]. In
addition, vitiligo could be present in all the autoimmune polyglandular
syndromes (APS), especially APS-3 [27]. Finally, it was reported that
Addison's disease, systemic lupus erythematosus, and inammatory
bowel diseases were all associated with vitiligo, although these were
an uncommon event [11].
Although the role of anti-melanocyte antibodies in vitiligo is still not
well known, high levels of circulating autoantibodies have been found
in about 10% of patients, especially against tyrosinase one and two
(TRP-1 and TRP-2) [2831]. However, their detection could be linked
to the damage of keratinocytes and melanocytes [9]. In addition, other

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Please cite this article as: Iannella G, et al, Vitiligo: Pathogenesis, clinical variants and treatment approaches, Autoimmun Rev (2015), http://
dx.doi.org/10.1016/j.autrev.2015.12.006

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G. Iannella et al. / Autoimmunity Reviews xxx (2015) xxxxxx

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levels, that leads to inhibition of the phenylalanine hydroxylase enzyme 214

and causes a marked reduction in L-tyrosine synthesis resulting in an 215
impairment of melanin production [55].
216

175

antigenic proteins have been detected in vitiligo, including glycoprotein

100 (gp100) and melanoma antigen recognized by T cells 1 (MART-1)
[6]. Several papers showed CD4 + and CD8 + lymphocytes in the
dermalepidermal junction of areas of skin near a vitiligo lesion,
highlighting the activation of cell-mediated immunity [32,33]. A recent
in vitro study identied the presence of cytotoxic T lymphocytes, that
kills melanocytes in perilesional skin [34], and now it is known that
HLA-A2 restricted, melanocyte-specic CD8+ T lymphocytes detected
in vitiligo patients are related to disease activity [35]. Furthermore, in
the literature there are several reports about regulatory T cells
(TREGs), which play an important role in the pathogenesis of vitiligo.
More specically, it was demonstrated that a reduction of TREGs in
the peripheral blood and their dysfunctional activity raised the damage against melanocytes [3638]. However, there are many unclear
essential points about the loss of self-tolerance in the pathogenesis
of vitiligo as already reported for the genesis of other autoimmune
diseases [3941].
Cytokines also have been studied in vitiligo, which is considered a
Th1-related disease. Indeed, it has been reported that there is a signicant increase in tumor necrosis factor- (TNF-), interferon- (IFN), and IL-10 [42,43]. IL-17 also has been found at higher levels in the
blood and tissues of patients. Its activity inuences the production of
TNF-, which is also elevated in vitiligo [44]. In addition, it has been
shown that the persistence of vitiligo is related to IL-17 levels [44].

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217

5.1. Classication

218

Vitiligo is divided clinically into two main forms, segmental vitiligo

(SV) and non-segmental vitiligo respectively. The latter also includes
three major subsets, namely generalized vitiligo, acrofacial vitiligo,
and universal vitiligo [1]. Recently, mixed vitiligo (MV) has been
described as an initial SV, which later (usually several months) spreads
bilateral NSV patches [56]. However, because the progress of vitiligo is
unpredictable, it is not uncommon for NSV to evolve over time, modifying its extension and distribution. Despite this clear classication, two
unclassied forms are reported in the literature, namely focal vitiligo
and mucosal vitiligo [57]. Focal vitiligo is characterized by few, small,
and isolated white macules without a segmental distribution that fails
to progress to NSV after a couple of years from onset. Mucosal vitiligo
is identied by the presence of only oral or genital mucosa involvement.
However, when vitiligo affects a mucosa in the context of an NSV, it is
considered a true NSV.
The different subtypes of vitiligo are summed up in Table 1.

219

4.2. Adhesion defect theory

5.2. Skin features

235

The most typical skin lesion is an asymptomatic whitish macule or

patch, with regular borders and sharp margins, surrounded by normal
or a hyperpigmented skin (Fig.2). Rarely, patches have inamed borders
with pruritus [1]. The onset of the lesions is insidious and the development of the disease in unpredictable. Hairy areas also can be affected.
In this case, the hair follicles are typically white. An early age of onset
is associated with familial occurrence and often determines a more
severe disease (Fig.3) [11]. In NSV, lesions usually arise on areas exposed to a chronic trauma, especially the hands or the arms (Fig.4). Indeed, it has been observed that vitiligo lesions may be related to
repeated rubbing during daily activities, like personal care or occupation
activities. Macules can also appear in areas submitted to pressure from
tight-tting clothes. These kinds of stimuli are responsible for
koebnerization. However, scientic evidences regarding the Koebner

236

Table 1
Classication of vitiligo.

t1:1
t1:2

198

In 2003 Gauthier et al. postulated that non-segmental vitiligo

(NSV) could be caused by a chronic detachment of melanocytes provoked by trauma, mainly a mechanical rubbing of healthy skin [45].
This concept is now known as melanocytorrhagy theory. Indeed,
it was reported that vitiligo patients showed that the Kebner phenomenon in up to 31% of the Caucasian population [46]. For this reason, koebnerization in vitiligo is now considered as a migration of
melanocytes through the epidermal basal skin layer [45]. Furthermore, Gauthier et al. hypothesized that an autoimmune activation
could be provoked by dendritic cells or memory T cells detecting
auto-antigens during melanocytorrhagy through the epidermis
basal layer [47].
As a result of the above ndings, some adhesion proteins have been
studied to explain the loss of melanocytes. Le Poole et al. [48] highlighted that tenascin, an extracellular matrix molecule involved in adhesion,
was increased in vitiligo patients, thus reducing melanocyte adhesion.
Discoidin domain receptor-1 (DDR1), which is a domain implicated in
the adhesion of melanocytes to the basal skin, has also been demonstrated to be reduced in vitiligo lesional skin [18]. In addition, it has
also been postulated that vitiligo is a disease that affects not only melanocytes, but also the whole epidermis. Indeed, DDR1 expression was
found to be reduced in all lesional epidermis [18].

199

4.3. Biochemical theory

200

It has been speculated that an alteration of redox balance in

vitiliginous skin could lead to melanocyte damage and cause
hypopigmented macules [43,49]. It was also demonstrated that patients
with vitiligo had a raised level H2O2 [50]. Indeed, an increment in superoxide dismutase (SOD) activity was reported by several authors [51,52].
However, there may be several reasons why a rise in H2O2 level can be
raised in several ways in vitiliginous skin. Firstly, an increase of nitric
oxide synthase (NOS) and nicotinamide adenine dinucleotide phosphate oxidase (NADPH) oxidase activities [53]; secondly, an increase
in monoamine oxidase A (MAO-A), that causes a direct and an indirect
cytotoxic action by increasing catecholamine production [54]. This
could explain why mental stress facilitates the appearance of vitiligo
macules by activation of the hypothalamicpituitaryadrenal axis [55].
Thirdly, a rise in (6R)-L-erythro 5,6,7,8-tetrahydrobiopterin (6-BH4)

178
179
180
181
182
183
184
185
186
187
188
189
190
191
192
193
194
195
196
197

201
202
203
204
205
206
207
208
209
210
211
212
213

R
O

173
174

171
172

169
170

167
168

165
166

163
164

161
162

159
160

N
C
O

158

5. Classication and clinical features

156
157

220
221
222
223
224
225
226
227
228
229
230
231
232
233
234

237
238
239
240
241
242
243
244
245
246
247
248
249

NOMENCLATURE SUBSET

NOTES

t1:3

Non-segmental
vitiligo

Usually limited to face, head, hands, and

feet
Symmetrical macules, mainly hands,
ngers, face, and trauma-exposed areas
Involvement of the oral and/or genital
mucosae with other sites of skin
involvement
Depigmentation affects 80%90% of body
surface.
One or more depigmented macules
distributed on one side of the body
Two segmental lesions distributed either
unilaterally or bilaterally
Multiple segmental lesions distributed
either unilaterally or bi-laterally
SV followed by NSV with a delay of at
least 6 months. At least 20% of a
dermatomal segment affected by SV.
Isolated macules that do not have a
segmental distribution. No evolution into
NSV after at least 2 years
Exclusive involvement of the oral or
genital mucosae

t1:4

Acrofacial
Generalized
Mucosal (at least
two sites involved)
Universal

Segmental
vitiligo

Unisegmental
Bisegmental
Plurisegmental

Mixed vitiligo

Occurrence of SV
and NSV

Unclassied
vitiligo

Focal vitiligo

Mucosal vitiligo
(only one site
involved)

Please cite this article as: Iannella G, et al, Vitiligo: Pathogenesis, clinical variants and treatment approaches, Autoimmun Rev (2015), http://
dx.doi.org/10.1016/j.autrev.2015.12.006

t1:5
t1:6

t1:7
t1:8
t1:9
t1:10
t1:11

t1:12

t1:13

G. Iannella et al. / Autoimmunity Reviews xxx (2015) xxxxxx

253

The choroid and retinal pigment epithelium (RPE) are similar to the
skin in that they display the presence of well differentiated melanocytes, with a common origin: the neural crest. In the eye, these melanocytes contribute to retinoid production and protection against UV rays.
In the literature few papers have dealt with ocular ndings in vitiligo.
However, the association between ocular diseases and vitiligo is well
known, because vitiligo is a feature of both VogtKoyanagiHarada syndrome [58] and of sympathetic ophthalmia [59]. Indeed, the association
between vitiligo and uveitis is well known by far [60]. Furthermore,
Nordlund et al. [60] reported a small but statistically signicant

C
E
R
R

262

260
261

258
259

256
257

254
255

R
O

5.3. Ocular features

252

phenomenon in vitiligo are not clear. As far as SV is concerned, the occurrence of the Koebner phenomenon is still disputed [1].

Fig. 4. Unisegmental vitiligo of the arm.

251

250

Fig. 2. Typical skin lesion of the hands with asymptomatic whitish macule, regular borders
and sharp margins.

Fig. 3. Plurisegmental vitiligo in early age.

percentage of vitiligo patients with idiopathic uveitis. In the same

paper the authors also highlighted that, in contrast to the usual asymptomatic ocular involvement, their patients were referred to an ophthalmologist because of the presence of anterior uveitis symptoms,
including photophobia, lacrimation, and pain [60].
Regarding the wide spectrum of ocular diseases that can affect vitiligo patients, Biswas et al. [61] demonstrated several ocular features in a
sample of 100 vitiligo patients, including hypopigmented spots on the
iris (23%), pigmentation on the anterior chamber (18%), chorioretinal
degeneration (11%), RPE hypopigmentation (9%) and uveitis (5%). In
addition, two studies conducted on large series reported that more
than 40% of vitiligo patients had noticeable areas of hypopigmentation
affecting the choroid or retinal pigment epithelium [62,63]. In particular, Albert et al. [63] reported a rise in the incidence of RPE
hypopigmentation not caused by ocular inammation in patients with
vitiligo.
As a whole, vitiligo patients should be evaluated for ocular diseases
because uveitis and several other pathological ndings have been clearly documented.

263

5.4. Audiological abnormalities

282

The membranous labyrinth of the inner ear contains melanocytes

and pigmented cells are also present in the scala vestibuli. Despite the
fact that the specic functions of otic melanocytes are still unclear, clinical and experimental studies suggest that melanin has semi-conductive
properties, responding to acoustic and electrical stimulations. Furthermore, these cells have the ability to convert energy states into molecular
rotation and vibration as well as reversing the process. In addition, the
melanin is reported to have a protective role against environmental
damage [3,6466]. Several authors studied the association between vitiligo and hearing loss, which was detected in a range from 4% to 20% of
vitiligo patients [3,65,67]. Akay et al. [3] in a clinical study, compared 53
patients with vitiligo and 50 age-matched and gender-matched non-

283

Please cite this article as: Iannella G, et al, Vitiligo: Pathogenesis, clinical variants and treatment approaches, Autoimmun Rev (2015), http://
dx.doi.org/10.1016/j.autrev.2015.12.006

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265
266
267
268
269
270
271
272
273
274
275
276
277
278
279
280
281

284
285
286
287
288
289
290
291
292
293
294

G. Iannella et al. / Autoimmunity Reviews xxx (2015) xxxxxx

Normal total

t2:4
t2:5
t2:6
t2:7
t2:8
t2:9

Focal
Segmental
Vitiligo vulgaris
Acrofacial
Universal
Total

7
1

11

7
0
1
9

11
1
20
1

33

15
1
34
2
1
53

331

5.5. Vitiligo and melanoma

332
333

Some papers reported that vitiligo was linked to a reduction in the

risk of melanoma [70,71]. In addition, it was shown that vitiligo was a
good prognostic factor for melanoma patients [7274]. Indeed, it was
reported that the immune response against melanocytes could be
responsible for the decrement in the prevalence of melanoma in vitiligo
patients [75,76].
Nowadays, it is widely known that melanoma cells share several antigens with normal melanocytes, including tyrosinase TRP-1, TRP-2,
gp100, and MART-1 [77]. Furthermore, autoantibodies against tyrosinase, TRP-1, and TRP-2 were found both in melanoma and vitiligo [78,
79]. In this regard, it was highlighted that serum antibodies of vitiligo
patients were capable of destroying melanocytes and melanoma cells
in vitro [8083].
On the other hand, it was also reported that CD8 T cells from vitiligo
lesions were capable of killing melanoma cells in vivo [8486]. In

308
309
310
311
312
313
314
315
316
317
318
319
320
321
322
323
324
325
326
327
328

334
335
336
337
338
339
340
341
342
343
344
345
346

306
307

304
305

302
303

300
301

N
C
O

298
299

296
297

6. Histopathology

329
330

vitiligo patients. Sensorineural hypoacusis was found in 20 patients

(37.7%). Nine of the 20 patients showed unilateral minimal hearing
loss (N30 dB), while the other 11 demonstrated bilateral hearing loss
(N30 dB) over a large range of frequencies (20008000 Hz). Hypoacusis
was observed in eight (16%) control patients (chi-square = 23.1, p =
0.00). Sensorineural hypoacusis was more frequently observed in vitiligo vulgaris than in the other clinical types, although this was statistically
not signicant (p = 0.407). Abnormal pure tone thresholds were found
in 8 patients out of 20 (38.09%) in a study conducted by Mahdi et al.
[66].
No differences in the hearing loss were present among all clinical
types of vitiligo although hypoacusis prevalence in vitiligo vulgaris
patients was reported (Table 2) [3]. In addition, comparing the ndings
of audiometric examination to age, duration of disease and sex, no statistical correlation was found [2,66,67]. This could be explained by the
hypothesis that otic melanocytes are damaged at the early stage of vitiligo and then stabilized. However, this theory is in contrast with the
data reported by Aslan et al. [68] and Ardie et al. [69], who found a statistically signicant association between the duration of vitiligo and
hearing loss. In addition, some authors performed auditory brain stem
responses (ABR) in patients with vitiligo [64] [67]. The sequences of
peaks in an ABR recording reected the synaptic activity of consecutive
nuclei along the afferent auditory pathways in the brainstem. The analysis of ABR conducted by Mahdi et al. [67] revealed that 10 patients
(47.61%) had an abnormal increase in the latency of wave III and 6 patients (28.57%) had an abnormal prolongation of the inter-peak latency
(IPL) between wave I and III. Usually, wave III is associated with neural
activity that mainly originates from the superior olivary complex (SOC)
within the brainstem. The increased IPL of waves IIII can be attributed
to abnormal synaptic activity and transmission of the action potential
from the auditory nerve to the lower brain stem [66]. Similarly, other investigators [3,64,69] found a statistically signicant increases in wave III
latency and IPL of waves IIII in both ears and a signicant increase in
wave V latency in the right ear of patients with vitiligo compared with
control subjects. They suggested that this nding might be a result of
delayed synchronization of action potentials in the brainstem nuclei [3].

Hypoacusis

Unilateral
Sensorineural

347
348
349
350
351
352
353
354
355
356
357
358
359
360
361
362

Vitiligo is characterized mainly by typical ndings in the dermal

epidermal junction. While borders of white macules still demonstrate
residual melanocytes and a few granules of melanin, the rest of the lesion show no melanocytes and the absence of melanin: sometimes, a
lymphoid inltrate may be evident in the outer active part of the lesion
[92]. Some authors reported that the healthy skin near the
hypopigmented macule showed isolated areas of vacuolization at the
dermalepidermal junction and a moderate presence of mononuclear
cells [92,93]. The histological ndings are also conrmed by ultrastructural examination of vitiligo lesions. Indeed, Galadari et al. [94] did not
observe any melanocytes through electron microscopy. Furthermore,
it has been demonstrated that Langerhans cells replace damaged melanocytes and an alteration of keratinocytes around the border of lesions
has been observed [9597].

363

7. Diagnosis and differential diagnosis

377

Diagnosis is mainly based on clinical features. In fact, there are no

particular tests to identify vitiligo. However, evaluation of the presence
of organ-specic autoantibodies, especially those directed against thyroid and adrenal glands could be useful. A Wood's lamp could be used
for the optimal evaluation of some uncertain lesions.
Differential diagnosis includes some acquired hypopigmented disorders, like pityriasis versicolor, pityriasis alba, lichen sclerosus et
atrophicus, leprosy, tertiary stage of pinta, morphea, and sarcoidosis
[13]. Obviously, chemical leukoderma and post-inammatory
hypopigmentation should be excluded. However, a variety of congenital
diseases could be included in differential diagnosis, including tuberous
sclerosis, piebaldism, nevus depigmentosus VogtHaradaKoyanagi
syndrome, Waardenburg's syndrome and ZiprkowskiMargolis syndrome [98]. A more complete list of pathologies for differential diagnosis is summarized in Table 3 [98105].

378

8. Therapy

393

The aim of the treatment is to obtain skin repigmentation. It is a

common observation that some areas, especially those damaged by a
chronic physical trauma (e.g. the hands), are less responsive to the therapy. However, spontaneous repigmentation occurs in between 1% and
25% of patients [81].

394
395

8.1. Topical steroids

399

Topical corticosteroids (TCs) are still the mainstay of treatment for

localized forms of vitiligo [106]. Although they have several widely
known side effects, such as atrophy or telangiectasia, TCs are considered
as rst-line therapy because of their wide availability, low cost and efcacy [107]. Several papers report that high-potency TCs are more

400
401

R
O

Bilateral
Sensorineural
Hypoacusis

Clinical type

t2:3

295

addition, it has been suggested recently that CD4 T cells could be involved in melanoma-associated vitiligo [87,88]. Therefore, nowadays it
is widely accepted that melanoma-associated vitiligo is mainly provoked by CD8 T cells, with probably little participation of antibodies
and/or CD4 T cells [8588].
Several studies reported that some kinds of immunotherapy used
against melanoma caused high rates of vitiligo [8991]. Indeed,
Boasberg et al. [89] showed that IL-2 and GM-CSF maintenance therapy
caused an improvement of survival rates in those patients who developed therapy-induced vitiligo. In addition, Dudley et al. [90] reported
that their CD8 adoptive T cell therapy regimen produced vitiligo in 5
out of 13 melanoma patients, all of whom had a signicant tumor regression. Therefore, it could be postulated that therapy-induced vitiligo
could act like a protective factor against melanoma, although additional
studies are required.

Table 2
Vitiligo features and hearing loss [3].

t2:1
t2:2

Please cite this article as: Iannella G, et al, Vitiligo: Pathogenesis, clinical variants and treatment approaches, Autoimmun Rev (2015), http://
dx.doi.org/10.1016/j.autrev.2015.12.006

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366
367
368
369
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374
375
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388
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392

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398

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G. Iannella et al. / Autoimmunity Reviews xxx (2015) xxxxxx

t3:1
t3:2

Table 3
Differential diagnosis of vitiligo.

t3:3

Inherited or genetical disease

Post-inammatory hypomelanoses

Hypomelanosis and malginancy

Hypopigmentation and
infective disease

Others

t3:4

Griscelli's syndrome

Atopic dermatitis

HermanskiPudlak syndrome

Lichen planus

Acquired macular
hypomelanosis
Leishmaniasis

Melasma

t3:5

Melanoma-associated
depigmentation
Mycosis fungoides

t3:6

Ito's hypomelanosis

Psoriasis

Leprosy

t3:7
t3:8

Menks syndrome

Toxic drug reactions

Onchocerciasis
Pityriasis versicolor

412
413

8.2. Calcineurin inhibitors

415
416

This class of drugs includes two topical immunosuppressants, namely tacrolimus and pimecrolimus. Compared to TCs, topical calcineurin
inhibitors (TCIs) do not provoke skin atrophy [111,112]. Although in
2005 the FDA issued a public health advisory regarding a possible association between TCIs and malignancy (e.g. squamous cell carcinoma,
basal cell carcinoma, T-cell lymphoma), no denite relationship between TCIs and malignant tumors was reported [113115].
On the one hand, a double blind randomized controlled study
highlighted that tacrolimus 0.1% ointment was almost as efcacious as
clobetasol propionate 0.05% ointment [114116]. Furthermore, Choi
et al. [117] found that tacrolimus was equal to upper mid-strength TCs
in promoting repigmentation. In addition, recent reports have shown
that a twice-weekly application of 0.1% tacrolimus ointment prevents
the depigmentation of vitiligo patches that have been previously treated
with success [118].
On the other hand, mixed results were reported regarding
pimecrolimus. A double blind randomized controlled study has demonstrated that pimecrolimus is ineffective on body lesions [119]. Furthermore, Eryilmaz et al. [120] demonstrated that clobetasol propionate
0.05% was superior to pimecrolimus 1% cream for inducing
repigmentation. However, in an open study Lubaki et al. [121] reported
that pimecrolimus works statistically better for the face than for the
upper limbs. Additionally, Coskun et al. [122] reported that
pimecrolimus 1% cream was just efcacious as clobetasol propionate
0.05% ointment.
Another therapeutic approach is to use excimer laser therapy and
TCIs in combination. Kawalek et al. [123], in their double-blind study,
reported that tacrolimus 0.1% ointment plus excimer laser was more effective than placebo plus excimer laser. Furthermore, Nistico et al. [124]
demonstrated that the combination treatment of 0.1% tacrolimus ointment plus 308-nm excimer laser was effective and safe in vitiligo patients. In addition, in a comparative, randomized, single-blinded study
a better outcome was found in groups treated with 1% topical
pimecrolimus associated with excimer laser (308 nm) than laser alone
[125].
Regarding topical tacrolimus, some papers in the literature have
dealt with an association between tacrolimus ointment and UV sources.
In a double-blind study, it was reported that tacrolimus 0.1% ointment
plus narrow-band UVB (NB-UVB) reduced the size of vitiligo lesion
more efcaciously than NB-UVB alone [126]. Majid [127] also reported
that the combination of tacrolimus 0.1% ointment and NB-UVB resulted

429
430
431
432
433
434
435
436
437
438
439
440
441
442
443
444
445
446
447
448
449
450
451
452
453
454
455

427
428

425
426

423
424

421
422

419
420

417
418

Although some different approaches have been attempted in cases

of disseminated vitiligo lesions, steroids still remain the principle therapy. However, a recent study, conducted on six patients, reported that
oral methotrexate was a safe and effective therapy for vitiligo [128]. A
non-comparative study reported that the administration of i.v. prednisolone (0.3 mg/kg/day) guaranteed the control of disease progression
and repigmentation [129]. Radakovic-Fijan et al. [130] also reported
that weekly pulses of 10 mg dexamethasone therapy reduced the progression of vitiligo, but failed to induce repigmentation. In a prospective,
randomized, clinical trial, Seiter et al. [131] reported that i.v. methylprednisolone (8 mg/kg bodyweight) on 3 consecutive days was effective to treat generalized progressive vitiligo. Overall, these ndings
clearly indicate that further studies on this form of treatment are
needed.

414

8.3. Systemic therapy

R
O

410
411

in better repigmentation rates and decreased NB-UVB exposure com- 456

pared to the NB-UVB alone.
457

408
409

effective on small lesions, but some authors prefer low-potency TCs on

exural areas and on the face because of their thinness [108]. Vasistha
et al. [109] proposed the use of intralesional steroids to treat small
lesional areas, but it was reported that upper mid-strength TCs had
higher efcacy [110]. Furthermore, in the same paper the authors emphasized that upper mid-strength TCs had a higher efcacy and produced less atrophy compared to mid-strength TCs [110]. Regarding
the high power TSs, it has been reported that they should be used for
no longer than 24 months [111].

406
407

405

Post-traumatic leucoderma
Occupational and drug-induced
depigmentation

458
459
460
461
462
463
464
465
466
467
468
469
470
471
472

8.4. Physical therapy

473

There are three main types of physical therapy for vitiligo, namely
narrow band UVB, phototherapy with UVA and psoralens (PUVA therapy) and monochromatic excimer light (MEL).
NB-UVB (311 nm) is now considered one of the most effective and
safest types of therapy for vitiligo [106132]. Indeed, many papers
have shown that it is safer and more effective than psoralen UVA
(PUVA) therapy [133135]. It has been widely reported that NB-UVB
reached the same or better results in repigmentation compared to
PUVA [136,137]. In addition, NB-UVB was not found to increase the
risk of melanoma and non melanoma skin cancers [138], while PUVA
slightly increases the risk of both melanoma and non melanoma skin
cancers [139]. NB-UVB alone reaches repigmentation rates between
41.6% and 100% [140,141].
On the other hand, PUVA therapy requires the use of UVA (320
400 nm) and of a photosensitizing drug, commonly 8 methoxypsoralen
per os. Because of its side effects, including a higher risk of squamous
cell carcinoma of the skin, cutaneous phototoxicities, and nausea, NBUVB is now preferred to PUVA therapy [142]. However, some authors
reported good results with PUVA therapy [143,144].
MEL is the best known laser therapy for vitiligo. In particular,
the xenon chloride MEL has a wavelength of 308 nm. Several papers reported high success rates of successful results when it is used alone
[145147]. Indeed, response rates as high as could 95% were achieved
[145147]. It was also highlighted that MEL produced better outcomes
than NBUVB [148].

474
475

8.5. Surgical therapy

499

Surgical therapy could be useful in patients in whom medical therapy has failed: several surgical techniques are usually employed.
The blister graft technique involves the creation of a subepidemal
bulla from the donor site. The roof of the bulla is then collocated into

500

Please cite this article as: Iannella G, et al, Vitiligo: Pathogenesis, clinical variants and treatment approaches, Autoimmun Rev (2015), http://
dx.doi.org/10.1016/j.autrev.2015.12.006

476
477
478
479
480
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482
483
484
485
486
487
488
489
490
491
492
493
494
495
496
497
498

501
502
503

G. Iannella et al. / Autoimmunity Reviews xxx (2015) xxxxxx

Take-home messages

547
548
549

Vitiligo is a common, but a complex disease, that could arise at any

age.
Its pathogenesis is still not clear although several hypotheses have
been proposed.
The autoimmune theory is now the leading theory.
Vitiligo is mainly a skin disease, but can also involve the eye and the
inner ear.
The association with hearing loss was detected in a range from 4% to
20% of vitiligo patients.
Nowadays, several types of therapy are available. However, topical
medication and NBUVB are the safest and most effective treatment
options for most cases of vitiligo.

527
528
529
530

534
535
536
537
538
539
540
541
542
543

550
551
552
553
554
555
556
557
558
560
562
559
561
563
564
565
566
567
568

525
526

523
524

521
522

519
520

N
C
O

517
518

515
516

546

513
514

544
545

Vitiligo is a common systemic disease that mainly involves the skin.

The majority of the authors favor the theory of an autoimmune
etiopathogenesis, which is further supported by the frequent association of vitiligo with autoimmune diseases.
Ocular and inner ear involvements frequently occur in this disease.
Sensorineural hearing loss is the most frequently reported symptom
and should always be investigated. In our opinion, hearing loss should
be evaluated by pure tone audiometry at vitiligo diagnosis and at least
annually thereafter.
Because of its complexity, nowadays several therapies are available
for obtaining a repigmentation. However, topical therapy and NB-UVB
are the safest and most effective treatment options in most cases of
vitiligo.

511
512

R
O

533

510

9. Conclusions

508
509

References
[1] Ezzedine K, Lim HW, Suzuki T, et al. Revised classication/nomenclature of vitiligo
and related issues: the Vitiligo Global Issues Consensus Conference. Pigment Cell
Melanoma Res 2012;25:E113.
[2] Al-Mutairi N, Al-Sebeih KH. Late onset vitiligo and audiological abnormalities: is
there any association? Indian J Dermatol Venereol Leprol 2011;77:571576.

[3] Akay BN, Bozkir M, Anadolu Y, Gullu S. Epidemiology of vitiligo, associated autoimmune diseases and audiological abnormalities: Ankara study of 80 patients in
Turkey. J Eur Acad Dermatol Venereol 2010;24:11441150.
[4] Nair BK. Vitiligoa retrospect. Int J Dermatol 1978;17:755757.
[5] Kopera D. Historical aspects and denition of vitiligo. Clin Dermatol 1997;15:
841843.
[6] Naughton GK, Eisinger M, Bystryn JC. Antibodies to normal human melanocytes in
vitiligo. J Exp Med 1983;158:246251.
[7] Kasumagic-Halilovic E, Ovcina-Kurtovic N, Jukic T, Karamehic J, Begovic B,
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the recipient area, prepared to allow the uptake of the graft using different techniques to obtain an abraded surface [149,150]. Several procedures to obtain the bulla have been reported in the literature [150,
151]. It was reported that this process determined a complete
repigmentation in up to 90% of patients [152]. However, the Koebner
phenomenon could be a cause of failure of this procedure [153].
The split-thickness skin graft could be used to induce repigmentation
in large areas. A dermatome is needed to obtain a uniform skin graft.
According to Agarwal et al. [153], it is possible to obtain repigmentation
rates up to 100%. Two limiting aspects could be the incompatibility of
colors in the receiving area and the need for an expert surgeon, because
the dermatome is not simple to use [153].
Punch grafting is the simplest and cheapest surgical procedure.
However, it seems to be useful only when small areas are involved
[154]. The recipient site is drilled by multiple punches, allowing the uptake of cylindrical fragments from the donor area. Malakar et al. [155]
reported 90% to 100% repigmentation rates in 74.5% of the patients
treated. In addition, NBUVB could be combined with punch grafting to
obtain even better results [156].
The autologous melanocyte suspension transplant (AMST) is a complex technique, which is composed of three steps: obtaining skin from
the donor area, preparing a suspension of keratinocytes and melanocytes, and transplanting to the recipient site. Van Geel et al. [157]
reported a repigmentation rate of at least 70% in 77% of patients after
12 months. It has been reported that lesions in particular areas, including ngers, legs, and ankles displayed the best results, whereas facial lesions had a poor response [158]. However, this procedure is very
expensive and requires a tissue culture laboratory.

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Please cite this article as: Iannella G, et al, Vitiligo: Pathogenesis, clinical variants and treatment approaches, Autoimmun Rev (2015), http://
dx.doi.org/10.1016/j.autrev.2015.12.006

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