13 Chapter 76 :: Vitiligo
:: Khaled Ezzedine & John E. Harris
AT-A-GLANCE
■ Vitiligo is a common autoimmune disease of the
skin that causes depigmentation through T-cell–
mediated destruction of melanocytes.
■ Pathogenesis is multifactorial, including genetic
Part 13
predisposition, autoimmunity, and environmental
factors.
■ Vitiligo can cause significant social stigma, with
serious implications for mental health.
::
■ Correlates with increased risk of other autoimmune
Melanocytic Disorders
diseases, but decreased risk of skin cancer.
■ Clinical signs of lesional activity include confetti,
trichrome, and inflammatory lesions, as well as
koebnerization.
■ Reversible with treatment, but only in areas with
normally pigmented hair.
■ Effective treatments include topical and oral
immunosuppressants, phototherapy, and chemical
depigmenting agents.
■ Emerging treatments include targeted
immunotherapy and melanocyte-stimulating
hormones.
DEFINITION AND HISTORY
Vitiligo, an acquired skin disease of progressive mela-
nocyte loss, is clinically characterized by well-defined
milky-white macules that may also include white
hairs, or poliosis. The term vitiligo initially appears in
the first century, although clinical features consistent
with vitiligo were described in ancient medical texts
during the second millennium before Christ.1-3 His-
torically, vitiligo has been confused with leprosy, an
infectious disease of the skin that results in ill-defined
hypopigmentation. Some texts sought to differentiate
the 2 diseases, while others conflated them. As early as
1500 bc, the Ebers Papyrus listed 2 diseases that affected
skin color—one associated with “swellings,” which
may have been leprosy, and another that exclusively
affected the color, which was likely vitiligo. In the book
of “Leviticus” in the Bible, also dated between 1500
and 1400 bc, a number of skin diseases could make
one “unclean” and required examination by the priest
to determine whether isolation was warranted. Skin
swelling, lightening, poliosis, and evolution of lesions
over time were assessed to make this determination.
This protocol may have been designed to distinguish
vitiligo from leprosy or other skin diseases. In India,
vitiligo was described in the Atharva Veda (1400 bc) and
the Buddhist Vinay Pitak (224 to 544 bc) under the term
Kang_CH076_p1330-1350.indd 1330
“Kilas,” a Sanskrit word “derived from kil,” meaning
white.3-5 Hippocrates (460 to 355 bc) did not discrimi-
nate between vitiligo and leprosy. In fact, he included
lichenoid eruptions, leprosy, psoriasis, and vitiligo
under the same category. Still, today, in geographic
areas with high incidence of leprosy, the 2 diseases are
often confused.
EPIDEMIOLOGY
PREVALENCE
There have been very few studies conducted in the gen-
eral population that aim to determine the prevalence
of vitiligo. This is a difficult task, because unlike other
diseases that cause significant morbidity and mortal-
ity, affected patients may not present to a medical facil-
ity to be counted. Thus, most estimates of prevalence
are based on prospective surveys, retrospective obser-
vational studies, and prospective studies in selected
populations, which may underestimate or overesti-
mate the prevalence, depending on the approach. The
largest epidemiologic study was performed in 1977
in Denmark, on the island of Bornholm, with a cal-
culated prevalence of 0.38%.6 A study in black people
from the French West Indies found it to be similar to
established data for white people.7 However, peaks
of prevalence have been reported in subpopulations
in India (8.8%) in relationship to chemically induced
depigmentation.8,9 Similarly, higher incidences of vitil-
igo in Mexico and Japan have been reported.9 Although
the different prevalence rates of vitiligo in various pop-
ulations could certainly be the result of genetic or envi-
ronmental differences, one potential reason could be
the different social and/or cultural stigmas that influ-
ence reporting.9 In light of these challenges, the preva-
lence of disease is typically stated to be similar all over
the world, estimated at 0.5% to 1%.10,11
PATIENT DEMOGRAPHICS
Vitiligo can begin at any age, although it usually starts
before the third decade of life with almost half of
patients presenting before the age of 20 years, and a
third before the age of 12 years.9,10,12-14 The segmental
variant of vitiligo, affecting only 1 side of the body, tends
to occur earlier in life.14 A study in Jordan reported that
the prevalence of vitiligo gradually increases with age
(0.45% younger than age 1 year; 1% aged 1 to 5 years
old, 2.1% aged 5 to 12 years old).15 Males and females
appear to be affected equally, although females may
seek treatment more frequently.10,11
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 QUALITY OF LIFE Distribution of vitiligo
13
Vitiligo is frequently dismissed as “cosmetic,” how- Hypomelanosis
of hairr
ever it is often psychologically devastating for
patients.16 Numerous studies show that patients with
vitiligo feel stigmatized, have low self-esteem with
poor body image, and suffer a considerable psycho-
social burden.17,18 Thus, vitiligo may have a significant
impact on quality of life, and patients reportedly have
mental impairment similar to psoriasis and atopic
dermatitis.19 Differences in Dermatology Life Quality
Index (DLQI) scores have been noted in various cul-
tural groups, which may reflect different social stig-

Chapter 76 :: Vitiligo
mas of having the disease. For example, the mean of
Dermatology Life Quality Index scores was 4.95 in a
Belgian population, whereas Indian patients experi-
enced a mean of 7.06 in patients with a successful treat-
ment outcome, and 13.12 in those who failed treatment.20

CLINICAL FEATURES Figure 76-1 Distribution of vitiligo. (From Wolff K,

Johnson R, Saavedra AP, et al. Fitzpatrick’s Color Atlas and
PRESENTATION PATTERNS Synopsis of Clinical Dermatology. 8th ed. New York, NY:
McGraw-Hill; 2017, with permission.)
Typically, vitiligo lesions are asymptomatic, white,
nonscaly macules and patches with distinct margins
that fluoresce when illuminated by Wood lamp exami- In Mucosal vitiligo, the oral and/or genital mucosae
nation. Although a number of patterns have been are primarily involved (Fig. 76-3). When strictly lim-
described, most can be grouped together, except for ited to the mucosa, the differential diagnosis of lichen
the segmental variant of vitiligo, which follows a dif- sclerosus et atrophicus should be carefully considered
ferent disease course and experiences a different treat- (see also section “Differential Diagnosis”). Further-
ment response. Thus, we will describe these forms more, both conditions in the same patients are reported
separately and highlight differences important to rec- to coexist.21
ognize when developing a management plan. Focal vitiligo consists of small, isolated lesions. In a
Vitiligo lesions may involve any part of the body, recent report, long-term followup of 53 cases of focal
usually with a symmetrical distribution (Figs. 76-1 vitiligo have shown that almost 50% of these cases
and 76-2). The disease can start at any site of the body, progress to involve larger areas without any clinical
although the face, as well as acral and genital loca- sign that might predict this progression.22
tions, are often the initial sites. A number of specific The segmental variant of vitiligo is seen in 10% to 15%
clinical patterns have been defined, which include of vitiligo patients who present to the clinic. It is charac-
acrofacial, mucosal, generalized, universal, mixed, and terized by a unilateral and segmental, or block-shaped,
rare forms. However, this distinction is not often easy
to make, as there is often overlap among these forms,
or evolution from one to another. Because many clini-
cians are familiar with these forms and describe vit-
iligo accordingly, we briefly describe each one.
Acrofacial vitiligo is reportedly more common in
adults and typically involves the hands, feet, and face,
particularly the orifices. This form may evolve to typi-
cal generalized vitiligo.
Vitiligo universalis is a rare form of widespread
disease. It is usually seen in adults, although cases
in children have been reported.14 The form is named
“universalis” because it affects a large proportion
of the body, frequently defined as greater than 80%
of the body surface area. Despite this widespread
involvement, hairs may be spared. Classically, vitiligo
universalis results from longstanding disease that
steadily progresses to nearly complete whitening of Figure 76-2 Symmetrical patchy depigmentation of 1331
the skin. vitiligo.

Kang_CH076_p1330-1350.indd 1331 07/12/18 2:23 pm

13
Figure 76-3 Mucosal vitiligo, limited to the lips.
Part 13
::
distribution of the lesions (Fig. 76-4). Typically, a single
contiguous segment is involved, although 2 or more
Melanocytic Disorders
segments with ipsilateral or contralateral distribution
have been described.23 Mixed vitiligo is a rare form of
vitiligo that refers to the occurrence of a clear exam-
ple of segmental vitiligo plus additional macules or
patches that do not fit the segment (Fig. 76-5). These
additional patches may be remote from the segmental
involvement and are bilateral and symmetrical, affect-
ing the contralateral side.24 In segmental vitiligo, there
is frequently early involvement of the follicular mela-
nocyte reservoir, resulting in poliosis. The disease usu-
ally spreads over the segment within 6 to 12 months,
and then stabilizes.25 Although this may initially be dif-
ficult to distinguish from focal vitiligo, the rapid pro-
gression of segmental disease usually makes it clear
within a few weeks to months.
1332 Figure 76-4 Unilateral, block-like depigmentation of the
segmental variant of vitiligo.
Kang_CH076_p1330-1350.indd 1332
Figure 76-5 Mixed vitiligo, made up of a segmental lesion
on the back plus additional bilateral lesions in remote
areas.
CLINICAL MARKERS OF
DISEASE ACTIVITY
In addition to recognized anatomical patterns of vit-
iligo, there are lesional patterns that indicate disease
activity, which are important to recognize when deter-
mining the best treatment approach for patients. These
patterns include the Koebner phenomenon, trichrome
lesions, confetti-like depigmentation, and inflamma-
tory lesions. For example, one study reported that the
Koebner phenomenon in vitiligo patients was associ-
ated with higher body surface area involvement in
vitiligo and poorer response to treatment.26 Disease
activity also has been partially quantified through
scoring systems such as the vitiligo disease activity
score (VIDA), which relies on patient recall, and the
Koebner phenomenon in vitiligo score (K-VSCOR),
which is focused on clinical signs.
The Koebner phenomenon, also called the isomorphic
response, describes the observation that depigmenta-
tion occurs readily at the site of skin trauma in patients
with active vitiligo. This can be recognized as linear
marks of depigmentation where the skin has been
scratched, lacerated, or burned, or nonlinear macules
and patches at the site of known skin injury, such as
erosions and abrasions (Fig. 76-6).
Trichrome vitiligo is characterized by blurring of lesional
borders because of the presence of a hypopigmented
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Figure 76-6 Linear depigmentation in locations of skin
trauma.
zone between the depigmented and normally pig-
mented border. This results in the appearance of 3 dis-
tinct colors: the depigmented skin, normally pigmented
skin, and hypopigmented skin (Fig. 76-7). This pattern is
associated with active, rapidly spreading vitiligo.27
Confetti-like depigmentation consists of multiple
small macules of depigmentation clustered together,
often at the edge of existing vitiligo lesions (Fig. 76-8).
One study used serial photography to demonstrate
that these small macules grew and coalesced into
larger depigmented areas after just a few weeks,
Figure 76-7 Trichrome vitiligo comprised of normal pig-
mentation, depigmentation, and a zone of hypopigmen-
tation between them.
Kang_CH076_p1330-1350.indd 1333
13
Chapter 76 :: Vitiligo
Figure 76-8 Multiple scattered macules of confetti depig-
mentation in vitiligo.
identifying this sign as an important marker of dis-
ease activity.28
Inflammatory vitiligo is a very rare form of vitiligo
characterized by the presence of erythema, scale, and
itch at the border of hypopigmented or depigmented
lesions (Fig. 76-9). This inflammatory phase is typi-
cally transient, lasting just a few weeks to months but
rapidly progressing to involve large areas of the body.
Early histologic studies in vitiligo were done on inflam-
matory lesions, where the immune infiltrate could be
readily observed.29
Figure 76-9 Inflammatory vitiligo characterized by ery-
thema and scaling at the margin of the depigmented 1333
lesion. (Used with permission from Dr. Shyam Verma.)
07/12/18 2:23 pm
13 The VIDA score is a 6-point scale that was devel-
oped with the aim of assessing and monitoring
vitiligo activity.30 Because this scoring is based on
the patient’s recollection of disease activity, it may
be subject to recall bias. Active vitiligo is defined as
the spread of existing lesions or onset of new lesions.
The VIDA scores range from +4 (activity lasting 6
weeks or less) to −1 (vitiligo stable for 1 year or more
with spontaneous repigmentation). One of the limita-
tions of the VIDA score is that different lesions can
have different scores, making it difficult to use in
daily practice.
Finally, the K-VSCOR uses the Koebner phenomenon
and anatomical location of lesions to determine disease
Part 13
activity in vitiligo patients.31 It is based on the presence
or absence of vitiligo lesions at 6 different areas of the
body (forehead + scalp areas, eyelids, wrists, genital +
belt areas, knees and tibial crests) as well as disease
::
duration. The K-VSCOR ranges from 0 to 56, with 56
Melanocytic Disorders
corresponding to the highest likelihood of having the
Koebner phenomenon, which serves as an indicator
of disease activity in the clinic. Further validation is
needed to predict the extension of lesions over a longer
period of time.
DISEASE ASSOCIATIONS
Vitiligo is an autoimmune disease of the skin that is
associated with a number of other autoimmune dis-
eases in other organs through increased incidence of
type 1 diabetes, autoimmune thyroiditis, pernicious
anemia, Addison disease, lupus, and alopecia areata,
in both vitiligo patients and their family members.32,33
This strongly implicates inherited factors that predis-
pose patients and their family members to a group
of autoimmune diseases, and the breadth of diseases
found in this overlap suggests that the predisposi-
tion is toward autoimmunity in general, rather than
specific diseases themselves. Up to 20% of vitiligo
patients have at least 1 additional autoimmune dis-
ease, and most of these patients (13% to 19%) have
autoimmune thyroid disease. This increased risk
has prompted some to advocate testing thyroid-
stimulating hormone (TSH) in all patients with
vitiligo, because the pretest probability of finding a
positive result is higher in this patient population.
Others suggest, however, that this is unnecessary,
because many patients will develop thyroid disease
much earlier or later than the onset of vitiligo, and
recommend that the presence of symptoms should
drive TSH screening.34
There has always been some concern that vitiligo
patients have a higher risk of skin cancers than the
general population because of their loss of pigment in
the skin. Although this makes some intuitive sense, the
data do not support this hypothesis. Two large stud-
ies, one of 1307 participants35 and another of 10,040
participants,36 reported that vitiligo patients have close
1334 to 3-fold lower risk of developing melanoma, basal cell
carcinoma, and squamous cell carcinoma compared to
Kang_CH076_p1330-1350.indd 1334
controls. This protection was maintained even when
factors like reduced sun exposure and/or increased
exposure to phototherapy were factored in. Controls
included partners of patients in one study and vascular
surgery patients in another. The remarkable agreement
between these 2 studies strongly suggests that the data
are representative, despite the individual weaknesses
of each study. Protection from melanoma is least sur-
prising, as immune surveillance against neoplastic
melanocytes should be heightened in vitiligo patients,
and because genetic risk alleles for vitiligo are simul-
taneously protective against melanoma.37 However,
why the incidence of basal cell carcinoma and squa-
mous cell carcinoma are also lower in vitiligo patients
is not clear.
DISEASE COMPLICATIONS
Melanocytes are found not only in the epidermis of the
skin, but also in the mucous membranes, hair follicles,
uveal tract, retinal pigment epithelium, membranous
labyrinth of the inner ear, heart, and meninges of
the brain. Typically, these sites are spared in vitiligo
patients, with the exception of hair follicles, which
can be involved when present within lesions. How-
ever, some studies report hearing changes in vitiligo
patients, with sensorineural hearing loss present with
a wide range of prevalence (20% to 60%), depending
on the study.38-40 However, sensorineural hearing loss
frequently goes undetected by the patient, and is only
observed with formal testing. Ocular abnormalities
have been reported in vitiligo patients as well, includ-
ing pigment changes, scarring, and even uveitis in
up to 5% of patients.41,42 Vogt-Koyanagi-Harada syn-
drome (VKHS) and Alezzandrini syndrome represent
severe, rare forms of vitiligo that affect organs other
than the skin. VKHS results in skin depigmentation
with prominent poliosis, as well as hearing loss, visual
changes, meningitis, and flu-like symptoms. The skin
manifestations occur after the systemic ones, so those
with classic vitiligo are not known to progress to
VKHS.43 Alezzandrini syndrome has been described in
7 patients, and is characterized by segmental vitiligo
(unilateral depigmentation) on the face with poliosis,
plus ipsilateral hearing loss and visual changes.44-46
ETIOLOGY AND
PATHOGENESIS
COMPETING HYPOTHESES
AND THE CONVERGENCE
THEORY
Vitiligo is an autoimmune disease of the skin in which
CD8+ T cells target melanocytes and destroy them,
leaving areas without pigment production, which is
07/12/18 2:23 pm
 clinically manifest as white macules and patches. The
pathogenesis has been debated for many years, with
multiple hypotheses offered as alternative explana-
tions as to what lies at the root of the disease. These
alternative hypotheses include cellular stress caus-
ing degeneration of melanocytes, chemical toxicity
causing melanocyte death, and neural changes that
influence melanocytes or their ability to produce
melanin. The reason for these alternative explana-
tions were research observations over the years sug-
gesting that much more than simply autoimmune
targeting of perfectly normal melanocytes was
occurring in vitiligo.
Early clinical observations that other autoimmune
diseases occurred frequently in vitiligo patients and
their family members hinted, through guilt by asso-
ciation, that vitiligo was itself an autoimmune disease.
Additionally, antimelanocyte antibodies appeared to
be elevated in vitiligo patients compared to healthy
controls, also implicating immune responses in disease
pathogenesis. However, others found that melano-
cytes cultured from vitiligo patients, and thus sepa-
rated from immune influences, were abnormal—they
did not grow well, were susceptible to exogenous oxi-
dative stress, and appeared to have elevated cellular
stress. This was manifest by the presence of reactive
oxygen species and a dilated endoplasmic reticulum, a
marker of activation of the unfolded protein response
which is involved in stress responses.47-52 But histologic
studies revealed that CD8+ T cells infiltrated lesional
epidermis and were found next to dying melanocytes,
strongly supporting T-cell–mediated cytotoxicity as
the key event in vitiligo.29,53 Finally, one group reported
that CD8+ T cells isolated from lesional skin of a patient
and then coincubated with nonlesional skin from that
same patient resulted in melanocyte targeting and
death, demonstrating that CD8+ T cells were both nec-
essary and sufficient to cause melanocyte destruction
in vitiligo patient skin.54
These seemingly unrelated and conflicting observa-
tions were later tied together by the convergence the-
ory, which suggested that all of these pathways may
synergize to cause vitiligo in patients.55 Now it appears
that melanocytes in vitiligo patients are indeed abnor-
mal and are more sensitive to cellular processes like
melanogenesis and energy consumption. This results
in the production of reactive oxygen species and acti-
vation of the unfolded protein response, which initiate
the secretion of signaling intermediates from mela-
nocytes that act as danger signals to alert the innate
immune system. Next, innate immune cells activate
and recruit adaptive immune CD8+ T cells to the skin,
where they find the abnormal melanocytes and kill
them. Thus, cellular stress within the melanocyte and
autoimmunity work together to cause what we see
clinically as vitiligo.56,57
Additional studies have now revealed that cer-
tain chemicals, typically phenols, induce the cellular
stress response in melanocytes by acting as analogs
of tyrosine, also a phenol.56 Thus, these chemicals act
as exogenous environmental agents that induce and
exacerbate vitiligo by initiating the cellular stress
Kang_CH076_p1330-1350.indd 1335
response in otherwise well-compensating melano-
cytes. Consequently, the “chemical theory” can be
13
incorporated into the inclusive convergence theory
as well. Finally, the neural hypothesis was based on
the clinical appearance of segmental vitiligo, misin-
terpreting the unilateral nature of disease for being
associated with dermatomes, which is not the case.58-60
Others reported that catecholamines were increased in
the urine of vitiligo patients; however, catecholamines
are also secreted by melanocytes, which is a more
likely source in vitiligo. Case reports of vitiligo clear-
ing after unilateral nerve injuries suggested nerves as
important players in disease pathogenesis, but further
observations noted the opposite result as well, elimi-
Chapter 76 :: Vitiligo
nating this as strong evidence. The role of emotional
stress in worsening vitiligo has been offered as evi-
dence, yet this is common in many diseases that do
not appear to be influenced by nerves. Finally, some
animals control their pigmentation through innerva-
tion (primarily fish), but this has never been observed
in mammals. Thus, the “neural hypothesis” remains
unsupported by evidence and should be discarded for
now.58
T CELLS AND CYTOKINES IN
AUTOIMMUNITY
As mentioned above, CD8+ T cells play a critical role
during the progression of vitiligo, serving as the pri-
mary immune effectors that destroy melanocytes.
Studies using human tissues and a mouse model of
vitiligo have revealed that interferon (IFN)-γ is a key
cytokine that drives the disease.61-64 IFN-γ is secreted
by melanocyte-reactive autoimmune CD8+ T cells, and
induces the production of CXCL10 and other chemo-
kines from keratinocytes, which promote the further
recruitment of additional T cells that progressively
destroy more melanocytes as the disease spreads.64,65
Multiple groups have found that IFN-γ–induced che-
mokines are elevated in the serum and skin of vitiligo
patients, and these may serve as useful biomarkers
of disease activity in the future.64,66-68 In addition, tar-
geting the IFN-γ–chemokine axis during disease may
be an effective novel treatment strategy (see section
“Emerging Therapies”).69
THE SEGMENTAL
VARIANT OF VITILIGO,
A SPECIAL CASE
As mentioned above, segmental vitiligo was initially
thought to mirror the distribution of nerves via der-
matomes, which led to the “neural hypothesis.” Close
inspection, however, reveals that segmental vitiligo
lesions rarely, if ever, follow dermatomes, and fre- 1335
quently cross these zones in a perpendicular direction.
07/12/18 2:23 pm
13 Depigmented blocks of segmental vitiligo also do
not appear to follow blaschkoid lines, especially on
the trunk, which are narrow and S-shaped.59,60 So, the
question arises, what defines a segment of vitiligo,
and what is the pathogenesis of this variant, consider-
ing that immune-mediated disorders do not typically
respect the midline? One hypothesis that is gaining
acceptance is that segmental vitiligo results from a
general autoimmune predisposition combined with
melanocytes that have acquired a postzygotic muta-
tion that alters their susceptibility to autoimmune
attack, like activation of the cellular stress pathways
discussed above. This has the potential to explain
(a) why it is unilateral (melanocytes migrate from the
Part 13
neural crest and do not cross the midline), (b) its rapid
evolution and stabilization (normal melanocytes cre-
ate the stable border of the lesion), (c) its resistance to
treatments (abnormal melanocytes are unstable and
::
have an impaired ability to repigment the skin), and
Melanocytic Disorders
(d) the successful response to surgical therapies (nor-
mal melanocytes transplanted from another region are
stable and resistant to autoimmune attack).70
RISK FACTORS IN VITILIGO
Similar to other autoimmune diseases, a number of
factors influence the risk of developing vitiligo. These
include both genetic factors and environmental fac-
tors. Vitiligo is more common in family members of
affected patients, as 15% to 20% of patients have a fam-
ily member with the disease, strongly suggesting that
genetics influences the risk of getting disease. While
the prevalence of vitiligo in the general population is
close to 1%, the prevalence in first-degree relatives is
7%, and the prevalence in identical twins of affected
individuals is 23%, clearly demonstrating a role for
genes in disease. However, the fact that concordance
between identical twins is not 100% also clearly dem-
onstrates nongenetic influences in disease, which may
represent environmental factors, stochastic influences
(those that occur by chance), or both.
Modern genome-wide association studies have iden-
tified approximately 50 genetic loci that contribute to
the risk of developing vitiligo, clearly demonstrating
that it is inherited in a polygenic fashion with a com-
plex interplay among multiple genes that contribute to
the total risk. Of these loci, the majority are involved
in regulating the immune system, representing key
molecules in both innate and adaptive immunity, and
thus strongly support the conclusion that disease is
immune-mediated. Others appear to influence cellu-
lar apoptosis pathways and still others direct melano-
cyte function, including melanogenesis, supporting a
role for the melanocyte in conferring risk for disease.
Importantly, those genes involved in melanogenesis
also influence the risk of developing melanoma, but
in the opposite direction, suggesting that immune
responses in vitiligo may be protective against mela-
1336 noma, and thus may have evolved to protect against
the development of this devastating cancer.37
Kang_CH076_p1330-1350.indd 1336
In addition to genetic influences, environmental
influences are important in vitiligo. The first chemical
exposure to be definitively linked to the onset of vit-
iligo occurred in a group of leather factory workers in
1939. A large proportion of these workers developed
depigmentation on their hands and lower arms, and
monobenzyl ether of hydroquinone, or monoben-
zone, was implicated as the cause. Because some of
the workers also developed depigmentation at sites
remote from the exposure, depigmentation was not
simply the result of direct toxicity to the melanocyte,
but an exacerbation of the autoimmune destruction.71
Other chemicals have been similarly implicated
since then, including 4-tert-butyl phenol and 4-tert-
butylcatechol.72 An outbreak of vitiligo occurred in
Japan in 2013, when a cosmetic company created a new
skin lightening cream that resulted in more than 18,000
users getting vitiligo at the site of application and in
remote areas.72 Another study revealed that the use of
permanent hair dyes may increase the risk of getting
vitiligo by as much as 50%.73 The common character-
istic of implicated chemicals is that they are phenols
with a chemical structure that resembles the amino
acid tyrosine, also a phenol. Mechanistic studies reveal
that these chemicals act as tyrosine analogs, which are
taken up by melanocytes instead of tyrosine, interact
with tyrosinase, and induce cellular stress pathways
that then activate immune inflammation to initiate or
exacerbate vitiligo.56,74-76
DIAGNOSIS
CLINICAL EXAMINATION
The diagnosis of vitiligo is usually a clinical one, as
there is usually no need for additional laboratory
or histologic testing to confirm the diagnosis. On
physical examination it is important to differentiate
vitiligo from its segmental variant, as these 2 forms
have different clinical course, prognosis, and treat-
ment responses. Vitiligo is usually characterized by
well-defined, symmetrical depigmented lesions that
can be distributed on any part of the body, but with
a preference for the face (particularly periorificial
areas), genitals, and acral areas. Wood lamp exami-
nation in a dark room is helpful in differentiating the
depigmentation of vitiligo from hypopigmentation
seen in other diseases. The disease is also charac-
terized by cycles of flares and stabilization that are
unpredictable, which can be distressing for patients.
Additional clinical signs that may help with the diag-
nosis of vitiligo are the presence of multiple halo nevi
and poliosis. The presence of repigmentation can be
recognized as perifollicular pigmented macules from
pigmented hairs at hair-bearing sites (Fig. 76-10) or
convex patterns of pigment at lesional borders in
glabrous skin (Fig. 76-11). Hair-bearing sites with-
out poliosis repigment easily, whereas glabrous skin
and lesions containing mostly white hairs respond
poorly.
07/12/18 2:23 pm

Figure 76-10 Perifollicular repigmentation. Note the lack
of repigmentation from white hairs.
In the segmental variant of vitiligo, the lesions are
unilateral, typically do not cross the midline, and are
organized into block-like patterns, in contrast to the
dermatomes of zoster or blaschkoid lines of keratino-
cyte disorders like segmental Darier disease. These
blocks of depigmentation may represent zones of skin
that have been affected by postzygotic mutations that
create a mosaic distribution of abnormal melanocytes
(discussed under section “Segmental Variant Special
Case” above).59,60 The evolution of segmental vitiligo is
distinct in that the onset is usually acute with rapid pro-
gression over 6 to 12 months before it becomes stable
and unchanging for the remaining life of the individual.
Figure 76-11 Marginal repigmentation in glabrous skin.
Kang_CH076_p1330-1350.indd 1337
LABORATORY TESTING
13
Because vitiligo is associated with other autoimmune
diseases such as thyroid diseases, clinicians should
consider laboratory testing for these other diseases
when patients’ symptoms warrant them. TSH is com-
monly tested to rule out concomitant Hashimoto thy-
roiditis, although in the absence of symptoms this
testing may not be necessary.34 Complete blood count
and antinuclear antibody testing can be considered
in the context of light sensitivity, as phototherapy is a
standard in vitiligo treatment. During followup, clini-
cians should consider testing for other autoimmune
Chapter 76 :: Vitiligo
markers whenever patients have suggestive signs and
symptoms.
HISTOLOGY
When the history and physical examination are con-
sistent with vitiligo, there is usually no need for skin
biopsy to confirm the diagnosis. However, when the
presentation is unusual, biopsy may help to rule out
other disorders of pigment abnormalities that fall
within the differential diagnosis (discussed below).
When performed, histologic examination and immu-
nohistochemical studies reveal a complete loss of
melanocytes within the epidermis,55 and biopsy near
the lesional border during progression may demon-
strate an inflammatory infiltrate of CD4+ and CD8+
T cells in an interface pattern, with primarily CD8+
T cells infiltrating the epidermis.77
DIFFERENTIAL DIAGNOSIS
The differential diagnosis of vitiligo is broad and is
presented concisely in Tables 76-1 and 76-2. In gen-
eral, inherited hypomelanoses are present at or within
a few months after birth, whereas vitiligo is rarely, if
ever, present that early. Wood lamp examination helps
to differentiate the depigmentation of vitiligo from
hypopigmentation of most other diseases. Specifi-
cally, vitiligo and its segmental variant have different
considerations when thinking about differential diag-
noses, because the former is symmetric, often more
widespread, and progressive, whereas the latter is
focal, unilateral, and stable.
The differential diagnosis of vitiligo includes
inflammatory, postinflammatory, neoplastic, and
genetic (mostly congenital) disorders of depigmen-
tation. The first helpful step is to determine whether
the lesion or lesions are congenital, remembering
that in fair skin, lesions may not become apparent
until after the first few months of life, often after
the first sun exposure. A number of genodermato-
ses may be initially misdiagnosed as vitiligo, but
the most frequent are piebaldism and tuberous
sclerosis. In piebaldism, the combination of white 1337
forelock, anterior body midline depigmentation,
07/12/18 2:23 pm
13 TABLE 76-1
Differential Diagnoses for Nonsegmental Vitiligo
CONDITION DISTINGUISHABLE FEATURES

Inherited Hypomelanoses
Piebaldism (KIT mutation)
(Fig. 76-12)
Waardenburg syndrome
(PAX3 mutation)
Tuberous sclerosis (TSC1 and
TSC2 mutations) (Fig. 76-13)
Ito hypomelanosis
Part 13
White forelock, anterior body midline depigmentation and bilateral shin depigmentation present at birth (with
absence of melanocytes); autosomal dominant
White forelock, white skin macules, hypertelorism, heterochromic or hypoplastic blue irides, deafness, early graying,
± Hirschsprung disease
Hypomelanotic macules (ash leaf ) present within the first years of life; angiofibromas at age 3-4 years; ungual fibro-
mas; cephalic and lumbar (shagreen patch) fibrous plaques; and hypopigmented “confetti” macules appearing in
childhood to early adolescence; seizures; autosomal dominant
Hypopigmented skin macules and patches along Blaschko lines in a linear pattern, unilateral or bilateral pattern;

usually develops within the first 2 years of life; sporadic; chromosomal or genetic mosaicism
Infectious Disorders
Tinea versicolor Well-demarcated finely scaling patches in highly sebaceous areas; yellow-green fluorescence on Wood light
::

(Fig. 76-14)
Melanocytic Disorders

Treponematoses (syphilis and
pinta)
Leprosy (tuberculoid/
borderline forms) (Fig. 76-15)
Postinflammatory Hypopigmentation
Discoid lupus erythematosus,
scleroderma, lichen sclerosis
et atrophicus, psoriasis
Paramalignant Hypomelanoses
Mycosis fungoides (Fig. 76-16)
Cutaneous melanoma
Idiopathic Disorders
Idiopathic guttate
hypomelanosis
Progressive macular
hypomelanosis
Postinflammatory pigment loss
Melasma
Postinflammatory hypopigmented/depigmentated patches) on the neck on trunk, limbs. Positive testing for
serologic treponemal infection
Mainly hypopigmented patches; localized anesthesia
History of preexisting condition
Scattered irregular hypopigmented patches on non–sun-exposed areas. Atrophic epidermal surface. Plaque
and tumor lesions of mycosis fungoides may be present concurrently. Histology: epidermotropism of atypical
lymphocytes
Dyschromic lesion combining pigmented areas with depigmentation around or within the tumor
Hypopigmented well-circumscribed macules, sharply defined and small in size. Usually localized on photoexposed
areas, especially the legs. Very slowly progressive and nonconfluent
Nummular, nonscaly hypopigmented spots lesions of the trunk, often confluent. Punctiform red fluorescence on
Wood lamp
History of preceding eruption/injury
Hyperpigmented macules and patches, often limited to the face. The contrast between lighter and darker skin may
appear hypopigmented; dermoscopy may show capillary network

bilateral shin depigmentation, and large islands of
sparing are hallmarks of the disease. Family history
will often make the diagnosis of piebaldism straight-
forward, as it is most often dominantly inherited.
TABLE 76-2
Differential Diagnoses for Segmental Vitiligo
CONDITION DISTINGUISHABLE FEATURES
Nevus anemicus Poorly demarcated white macule surrounded by
erythema, which disappears with diascopy.
Nevus Well-delimited hypopigmented macule usually
depigmentosus present at birth with irregular, saw-toothed
border. Hairs within the lesion generally remain
pigmented. The lesion is stable in size but will
expand in proportion to growth with age. In
fair skin types, parents may note the lesion
1338 after first photoexposure of the child
Distinguishing vitiligo from tuberous sclerosis relies
on the hypopigmented nature of ash-leaf spots, as
well as their stability over time. Of course, the pres-
ence of seizures or other cutaneous symptoms that
may appear later, such as shagreen patches or angio-
fibromas, should prompt further investigation for
tuberous sclerosis.
If the lesions in question are acquired, the most
common differential diagnoses are pityriasis versi-
color and postinflammatory hypopigmentation, such
as pityriasis alba. Here, a Wood lamp examination is
quite helpful, as lesions of vitiligo are depigmented
and enhance, while others are hypopigmented and
do not. In addition, neoplastic hypomelanoses, in par-
ticular hypopigmented mycosis fungoides, should be
ruled out. Hypopigmented mycosis fungoides is dis-
tributed in sun-protected areas and is hypopigmented,
rather than depigmented. Isolated genital involvement
should be carefully differentiated from the diagnosis

Kang_CH076_p1330-1350.indd 1338 07/12/18 2:23 pm

 13

Figure 76-14 Scaly, hypopigmented macules of tinea

Chapter 76 :: Vitiligo
versicolor.

diagnosis. However nevus depigmentosus is usually

congenital or recognized within a few months of life
and is stable in size, growing only in proportion to the
child. In contrast to its name, it is typically hypopig-
mented rather than depigmented, and the border is
frequently jagged rather than smooth, both notable
differences from vitiligo. When biopsy is performed,
histology displays normal or a slightly decreased
number of melanocytes with reduced melanin content,
Figure 76-12 Piebaldism. Note large central midline patch rather than absence of melanocytes. Nevus anemicus is
of depigmentation with islands of sparing. another to condition to rule out and is usually present
at birth. Clinically, nevus anemicus corresponds to a
poorly demarcated white macule surrounded by ery-
of lichen sclerosus et atrophicus as this diagnosis can thema, which, contrary to segmental vitiligo, does not
be quite destructive and often is irreversible. Lichen
sclerosus is often symptomatic, following a figure-of-
eight pattern around the anus and introitus in women,
frequently with signs of atrophy and fissuring of the
skin. In longstanding cases, it may be accompanied by
resorption of normal structures like the labia minora as
well as narrowing of the introitus. A complicating fac-
tor in the differential diagnosis includes reports of con-
comitant genital lichen sclerosus and vitiligo. Biopsy
can be helpful in difficult cases.
For segmental vitiligo, nevus depigmentosus is
the most common consideration in the differential

1339
Figure 76-13 Ash-leaf macules in tuberous sclerosis. Figure 76-15 Hypopigmented patches of leprosy.

Kang_CH076_p1330-1350.indd 1339 07/12/18 2:23 pm

13
Part 13
::
Melanocytic Disorders
Figure 76-16 Hypopigmented patches of mycosis
fungoides.
show accentuation when examined with Wood lamp.
It also disappears with diascopy, or other gentle pres-
sure on the skin.
CLINICAL COURSE
AND PROGNOSIS
Vitiligo has an unpredictable course with a disposition
toward cycles of flares and phases of stability. Early
whitening of the hairs is unusual, although this may
appear later in the course of the disease. Repigmenta-
tion in hair-bearing locations is likely, and may either
occur spontaneously, after specific therapeutic inter-
vention, or following sun exposure. However, lesions
in glabrous skin are much slower to respond, as they
improve from slower marginal repigmentation that is
limited to only a few millimeters total, despite long-
term treatment. There is some evidence that episodes of
stress may trigger disease onset and/or relapse. In con-
trast, the course of segmental vitiligo is rapid but self-
limited, with rapid stabilization and rare progression
after this has occurred. The early involvement of hairs
makes segmental vitiligo less responsive to treatment,
although if caught early good results may be obtained.
MANAGEMENT
When developing a management plan for vitiligo
1340 patients, multiple factors should be considered. A thor-
ough examination of patients under natural and Wood
Kang_CH076_p1330-1350.indd 1340
lamp light is important to assess the extent of disease.
In addition, social and demographic details, family
history of the patient, as well as the patient’s relevant
medical history, should be elicited at the initial consul-
tation. The skin phototype, presence of halo nevi, dis-
ease duration and extent, and activity are key items in
guiding therapeutic management. Scoring of disease
activity by evaluating the probability of Koebner phe-
nomenon also can be considered.31
As of this writing most therapies that are effec-
tive for vitiligo were developed for other inflamma-
tory skin diseases and are thus used off-label. The
management plan for patients with vitiligo will vary
according to disease activity and extent. For example,
if a patient presents during active progression, com-
bination therapy that includes oral antiinflammatories
may be important to halt the progression of disease, as
other therapies, such as phototherapy, may take weeks
to months to become effective. If the disease is stable,
monotherapy is an option as the likelihood of progres-
sion while the responses slowly develop is minimal.
TOPICAL THERAPIES
Topical therapies may be used as monotherapy when
there is limited surface involvement (less than 5%
body surface area); however, they are often used in
combination with phototherapy. Two main classes of
topical drugs are used in vitiligo: topical steroids and
topical calcineurin inhibitors.
The advantages of topical corticosteroids are good
efficacy, ease of application, high compliance rate, and
low cost. The drawbacks of topical corticosteroids are
their side effects, which include skin atrophy, telangi-
ectasia, hypertrichosis, acneiform eruptions, and striae,
as well as increased intraocular pressure (exacerbation
of glaucoma) when used around the eyes. Typically,
ultrapotent formulations are required for reliable effi-
cacy, and most published studies have evaluated the
class I steroid clobetasol. They should be applied twice
daily and can be used in a discontinuous scheme, such
as cycles of 1 week on treatment followed by 1 week
off treatment for up to 6 months, to avoid side effects.
For childhood vitiligo, a class II potency steroid with a
good safety profile, like mometasone, is a good choice.
Lower-potency steroids do not have strong evidence to
support their use.
Advantages of topical calcineurin inhibitors include
their good efficacy and excellent safety profile.78 They
can be used on areas that are not ideal for steroids,
such as on the face, neck, intertriginous areas, and
on children. Of note, warnings have been placed on
the long-term use of topical calcineurin inhibitors in
relation to an increased risk of cancer; however, these
concerns are based on risks associated with oral dos-
ing of these drugs and have not been observed with
topical use. A recent systematic review and meta-
analysis concluded that the use of topical steroids
and calcineurin inhibitors was unlikely to increase the
risk of lymphoma in patients with atopic dermatitis.79
07/12/18 2:23 pm
 Although some concerns about the combining of pho-
totherapy with these drugs promotes skin cancer have
13
been raised, the combination of light therapy with
topical calcineurin inhibitors increases their efficacy80
and there is no clinical data that supports these con-
cerns for increased cancer risk. Thus, clinicians should
proceed with these treatments but with caution, and
patients should be counseled of these facts when
prescribed these therapies, at least until these warn-
ings are removed from the packaging. A recent report
tested topical tacrolimus as maintenance therapy in
patients who achieved repigmentation through other
methods.81 In this randomized controlled study of
35 patients, more than 90% of those treated with tacro-
A

Chapter 76 :: Vitiligo
limus 0.1% only twice weekly maintained their pig-
mentation without a relapse of their vitiligo, whereas
only 60% did so in the placebo group. A small number
of studies have compared topical calcineurin inhibi-
tors and topical steroids without significant difference
in efficacy between the 2 groups.82

PHOTOTHERAPY AND
COMBINATION THERAPIES
Because of its efficacy, ease of use, and relatively good
safety profile, full-body phototherapy should be con-
sidered the first treatment option in patients with more
B
than 5% of the body surface area affected, especially if
the disease is rapidly spreading (Fig. 76-17). For those Figure 76-17 Excellent response after about 1 year of
with more limited, focal disease, targeted photother- narrowband ultraviolet B phototherapy; (A) before and
apy can be considered because of its very high effi- (B) after therapy.
cacy. However, phototherapy is time-consuming and
devices may not be readily accessible to all patients.
When this is the case, home phototherapy can be con-
associated with adverse effects that include nausea,
sidered, where units are prescribed and purchased
ocular damage, and phototoxic reactions, as well as an
for use in the patient’s home. Although the strength
increased risk of skin cancer.84 A 2015 Cochrane review
of home units does not match those in the physician’s
reported that the efficacy of PUVA was inferior to
office, the convenience of getting phototherapy at
nbUVB in achieving greater than 75% repigmentation
home often results in excellent responses.83 Most units
in vitiligo patients.85 In another study, color matching
require a prescription from a dermatologist, who must
of treated areas with normal skin was inferior in PUVA
provide ongoing codes to enable continued use of the
compared to nbUVB.86 In addition, nbUVB treatment
unit after regular in-office assessments. Because some
has fewer short-term (painful erythema) and long-term
patients with vitiligo have circulating antinuclear
(epidermal thickening, atrophy, and photocarcinogen-
antibodies that could sensitize them to light, screen-
esis) adverse reactions than PUVA.56 Thus, PUVA is
ing for antinuclear antibodies prior to phototherapy
no longer first-line therapy for vitiligo, and has been
can be considered, particularly if there is a history of
largely replaced by nbUVB. However, PUVA may be
sun sensitivity. Overall, the risk-to-benefit profile of all
considered in patients who fail to repigment with other
treatments should be considered when developing a
modalities.86-88 Like other methods of phototherapy,
management strategy for each patient.
PUVA is typically administered 2 or 3 times weekly.
Historically, phototherapy has been administered
using different sources, including oral or topical pso-
ralen plus ultraviolet A (PUVA), broadband ultraviolet B,
narrowband ultraviolet B (nbUVB), and targeted pho- NARROWBAND ULTRAVIOLET B
totherapy with excimer laser. These are outlined below:
nbUVB has largely replaced other modalities because
of its efficacy and better safety profile. It provides 2
PSORALEN AND ULTRAVIOLET A particular benefits: (a) repigmentation and (b) stabili-
zation, which is important in those who have active
PUVA was the first phototherapy treatment reported to disease. Njoo and colleagues achieved greater than 1341
be effective for vitiligo; it has since, however, become 75% repigmentation in 53% and stabilization in 80%

Kang_CH076_p1330-1350.indd 1341 07/12/18 2:23 pm

13 of children with twice-weekly nbUVB.89 Increased
benefit has been reported with the addition of topical
corticosteroids and calcineurin inhibitors. The 2015
Cochrane update for interventions in vitiligo reported
that 35 of 96 randomized controlled trials used nbUVB
as either monotherapy or in combination with other
treatments.90 nbUVB has potent immunosuppressive
effects locally and is able to induce melanocyte differ-
entiation and melanin production.91
Treatment with nbUVB should be 2 to 3 times weekly,
starting with a dose of 200 millijoules (mJ) with an
increase of 10% to 20% increments until reaching the
minimal erythema dose, which corresponds to the low-
est dose resulting in asymptomatic, visible erythema on
Part 13
depigmented skin that lasts less than 24 hours. A total of
9 to 12 months or more of treatment is required to achieve
full repigmentation, with at least 6 months of therapy
before determining that the disease is nonresponsive.86
::
When used on its own, nbUVB has been reported to
Melanocytic Disorders
induce repigmentation rates ranging from 40% to 100%,
depending on the location of the lesion.89,92-95
TARGETED ULTRAVIOLET B
PHOTOTHERAPY
Targeted UVB phototherapy is achieved using excimer
lasers and lamps. They reportedly are equally effec-
tive, although excimer lamp induces more erythema.96
Because of their small treatment size, targeted photo-
therapy is indicated in patients with limited, focal vitiligo
(less than 5% of the body surface area affected with stable
disease).97 Targeted phototherapy is also reportedly the
treatment that achieves highest efficacy for segmental
vitiligo in its early phase (ie, disease onset of less than
6 months to 1 year). It is also reportedly safe and effective
for long-term treatment of pediatric vitiligo patients.98
COMBINATION THERAPIES
In the most recent update of the Cochrane review, combi-
nation therapies using any type of light were considered
the most effective treatment for vitiligo. Even though not
necessarily synergistic or even additive, the additional
benefit of adding topical therapies when undergoing
phototherapy appears to be worthwhile. If large areas
are involved, sites that are important to the patient, such
as the face and hands, may be selected for adjuvant topi-
cal therapy. The combination of oral steroid pulse ther-
apy, such as dexamethasone on weekends or prednisone
on alternate days, with light therapy is reportedly help-
ful in controlling rapidly spreading vitiligo until photo-
therapy achieves a therapeutic dose.99
PSYCHOLOGICAL
INTERVENTIONS
1342 The psychological impact of vitiligo includes poor
self-perception, low quality of life, poor interpersonal
Kang_CH076_p1330-1350.indd 1342
relationships, depression, and anxiety.100-104 Thus, psy-
chological interventions such as cognitive-behavioral
therapy and hypnosis have been shown to improve
quality of life, reduce anxiety, improve coping
with disease, and even enhance repigmentation in
vitiligo.101,105-107 Importantly, adolescents with vitiligo
are uniquely susceptible to social pressure and stigma,
and thus should be screened for psychological impair-
ment and referred for management.
COSMETICS
Cosmetic camouflage, especially on visible areas such
as the face and the hands, can improve quality of life
in patients with vitiligo.108,109 There are now several
water-resistant camouflage dyes and creams that are
available with a wide range of color and shades cover-
ing all skin types.
DEPIGMENTATION
THERAPY
Ever since the observation that monobenzone potently
induced and exacerbated vitiligo in exposed indi-
viduals, it has been used as a treatment for vitiligo to
depigment the skin, removing the remaining pigment
and evening out the tone.110 In fact, it is the only Food
and Drug Administration–approved medical therapy
for vitiligo. For patients with widespread disease that
would be difficult to reverse with the conventional
treatments discussed above (many suggest greater than
80% body surface area or significant poliosis), mono-
benzone can be prescribed as a 20% topical cream to be
applied 1 to 2 times daily. It can take 1 to 2 years for com-
plete depigmentation, and it even affects areas remote
from the site of application, so it cannot be used for just
local depigmentation. Up to 20% of patients develop a
contact dermatitis to the cream, which is located only in
pigmented skin and may limit treatment. If this occurs,
the strength can be decreased to 10%, and concurrent
use of topical steroids may limit the reaction. Hair, eyes,
and other locations where melanocytes are found are
typically spared during depigmentation therapy with
monobenzone. Even though this is a drastic and perma-
nent approach to therapy, patients are typically happy
with the result. They must be counseled that their skin
will be sun-sensitive for the rest of their lives, and sun
protection must be strictly followed.
NONTRADITIONAL
TREATMENTS
There are numerous nontraditional treatments that
have been suggested for vitiligo. Of these, khellin,
ginkgo biloba, vitamins and nutritional supplements,
07/12/18 2:23 pm
 Polypodium leukotomos, topical and systemic phe-
nylalanine, topical calcipotriene, and pseudocatalase
cream have been used. Current evidence for their effi-
cacy is weak at best and adding them to a therapeutic
strategy should be carefully considered in light of this
lack of evidence.
SURGICAL THERAPIES
Surgical therapies for vitiligo can be very successful;
however, a key part of surgical therapy is patient selec-
tion. Surgery in vitiligo should be reserved for patients
with highly stable disease, which has been defined
as the absence of new or growing lesions for 1 to
2 years.111 Segmental vitiligo patients are well suited
for this approach because their disease stabilizes
quickly, but those who do not have this variant have
much-less-successful outcomes.
Several techniques for surgical treatment exist for
vitiligo, which can broadly be divided into tissue graft-
ing and cellular grafting. Tissue grafts include thin and
ultrathin split-thickness skin grafts, suction blister
epidermal grafts, mini punch grafts, and hair follicle
grafts. These approaches all use solid-tissue grafts
whose size is matched to the donor site in a 1:1 ratio.
Alternatively, cellular grafts include noncultured epi-
dermal cell suspension, cultured “pure” melanocytes,
cultured epithelial grafts, and autologous noncultured
extracted hair follicle suspension. These approaches
A B
Figure 76-18 Surgical therapy of segmental vitiligo using the melanocyte keratinocyte transplant procedure; (A) before
and (B) after therapy.
Kang_CH076_p1330-1350.indd 1343
transplant suspensions of keratinocytes and melano-
cytes and can cover larger surface areas with up to a
13
1:10 ratio of donor-to-recipient area.
Each technique has advantages and disadvantages.
In general, tissue grafts are easier to perform than
cellular grafts, but are limited by the need to harvest
tissue in a 1:1 ratio to the donor site. Split-thickness
grafting is easy and inexpensive, but frequently results
in color mismatch and occasional failure of the graft
to take. Punch grafting is easy to perform and inex-
pensive but should be used in limited areas because
of frequent side effects, such as cobblestoning, which
describes healing at the recipient site with raised grafts
that are visible and palpable, like cobblestones on a
Chapter 76 :: Vitiligo
path.112 Blister grafting gives better cosmetic results
without cobblestoning, but it is time-consuming and
may be more difficult to perform because of handling
and placement of the very thin blister roof graft.113-117
Because of their improved donor-to-recipient-site
ratio, excellent outcomes in percent repigmentation
and color match, as well as improved healing, cellular
grafts are becoming the first-line in surgical manage-
ment of stable vitiligo (Fig. 76-18). The most commonly
used technique, the melanocyte keratinocyte transplant
procedure, creates a suspension of keratinocytes and
melanocytes from donor epidermis that is enzymati-
cally digested and mechanically disrupted into a single
cell suspension. This technique has been optimized and
simplified over the past few years and now requires
minimal laboratory support. It is usually conducted in
2 steps. The first consists of shaving an ultrathin skin
1343
07/12/18 2:24 pm
13 donor graft (Fig. 76-19A), which is rinsed and incubated
in 0.25% trypsin for 30 minutes at 37°C (98.6°F) before
the epidermal fragments to create a cellular pellet
(Fig. 76-19B, C). This pellet is resuspended in lactated
manually removing the epidermis from the dermis, dis- ringers or normal saline in a 1mL syringe. The second
rupting the epidermis mechanically, and centrifuging step consists of applying this cellular suspension over
Part 13
::
Melanocytic Disorders

A B

C D

Figure 76-19 Melanocyte keratinocyte transplant procedure. A, Harvesting of thin skin graft. B, Processing of the skin
1344 graft to remove the epidermis and mechanically disrupt it into small pieces. C, Pellet of melanocytes and keratinocytes
after centrifugation. D, Dermabraded skin lesions ready for application of cell suspension.

Kang_CH076_p1330-1350.indd 1344 07/12/18 2:24 pm

 the recipient site that was previously dermabraded or
laser treated to remove the epidermis (Fig. 76-19D). The
recipient site is then covered with an appropriate dress-
ing for 4 to 7 days, depending on the treated area.118,119
TREATMENT ALGORITHM
We propose 2 treatment algorithms, one for vitiligo
(Fig. 76-20) and another for the segmental variant of
disease (Fig. 76-21).
Examples of future targeted therapies include inhi-
bition of Janus kinases (JAKs), which are required for
13
the signaling of many cytokines, including IFN-γ. In
small case studies and series, JAK inhibitors have been
reported to promote repigmentation of vitiligo patients,
including oral tofacitinib, oral ruxolitinib, and topical
ruxolitinib.120-126 Ongoing clinical trials are currently test-
ing JAK inhibitors as new treatments for patients with
vitiligo. In addition, biologics that target other members
of the IFN-γ–chemokine signaling axis may be effec-
tive, such as antibodies against CXCR3 or its ligands,
which have been reported effective in a mouse model of
vitiligo.64,127 Additional cytokine-targeted biologics have
been developed for other diseases and may be repur-

EMERGING THERAPIES
As discussed above, vitiligo is driven primarily by
the destruction of melanocytes by CD8+ T cells that
secrete IFN-γ, which induces chemokines that recruit
additional T cells in an ongoing, positive feedback
loop. Future targeted therapies are likely to target
this and other synergistic cytokine pathways, similar
to recent advancements in the treatment of psoria-
sis. However, psoriasis treatments are ineffective for
vitiligo because the interleukin-23–interleukin-17–
tumor necrosis factor-α cytokine axis that drives pso-
riasis is not active in vitiligo.69
Chapter 76 :: Vitiligo
posed for vitiligo.69 Side effects should be considered
for any immunotherapy, which may include increased
incidence of infections or decreased tumor surveillance.
Finally, in addition to targeted immunotherapy,
treatments that promote melanocyte regeneration,
proliferation, and/or migration could also be effec-
tive treatments, particularly when combined with
immunosuppressive treatments. One example that
has been tested in vitiligo patients is afamelanotide, an
α-melanocyte–stimulating hormone analog, which, in
conjunction with nbUVB, increased the rate and extent
of repigmentation in vitiligo patients.128,129 Side effects
of this treatment included nausea, abdominal pain, and
darkening of the normal skin of patients, which led to

Treatment algorithm for vitiligo

Vitiligo/Nonsegmental Vitiligo

• Avoid triggering factors (trauma inducing Koebner

phenomenon, chemicals)
• Consider screening for other forms of autoimmunity, Unstable/active
including autoimmune thyroiditis disease
• Offer psychological support if needed
• Offer camouflage counseling

Oral minipulse steroids

Stable disease (3 to 6 months) + nbUVB +
topical treatment

Limited involvement Extensive and widespread

(<5% BSA) involvement (>5% BSA)

Topical treatment (TIM for Combination therapies

face/intertriginous areas and
• Topical treatment (TIM for
corticosteroids for body)
face/intertriginous areas and
Excimer laser/lamp sequential potent steroids for
body)
Combination therapies
• nbUVB

Figure 76-20 Treatment algorithm for vitiligo. BSA, body surface area; nbUVB, narrowband ultraviolet B; TIM, topical 1345
immunomodulators.

Kang_CH076_p1330-1350.indd 1345 07/12/18 2:24 pm

13 Treatment algorithm for segmental vitiligo
Segmental
Vitiligo
Unstable disease/disease onset
of less than 6 months to 1 year
Part 13
Oral minipulse steroids
(3 to 6 months) + excimer
lamp + topical treatment
::
Melanocytic Disorders
Figure 76-21 Treatment algorithm for segmental vitiligo. TIM, topical immunomodulators.
dissatisfaction and withdrawal of some participants
from the study owing to the increased prominence of
lesions against the darker background of normal skin.
In summary, recent advances in our understanding
of vitiligo have led to the development of new treat-
ment strategies that may have improved efficacy in our
treatment of patients with vitiligo. As with any new
therapy, safety will have to be monitored and carefully
considered when making recommendations for patients
suffering with this psychologically, but not physically,
debilitating disease. This marks an exciting time for
both patients with vitiligo and their caregivers, who are
gaining deeper insight into their disease, and may have
improved options for management in the near future.
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