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Vitiligo

Article · June 2015

DOI: 10.1038/nrdp.2015.11

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 PRIMER
Vitiligo
Mauro Picardo1, Maria L. Dell’Anna1, Khaled Ezzedine2, Iltefat Hamzavi3, John E. Harris4,
Davinder Parsad5 and Alain Taieb2
Abstract | Vitiligo is an acquired depigmenting disorder that affects 0.5% to 2% of the world population.
Three different forms are classified according to the distribution of lesions; namely non-segmental, segmental
and mixed vitiligo. Vitiligo is associated with polymorphisms in genes involved in the immune response and
in melanogenesis. However, environmental factors are required for the development of manifest disease.
In general, the diagnosis is clinical and no laboratory tests or biopsies are required. Metabolic alterations are
central to current concepts in pathophysiology. They induce an increased generation of reactive oxygen
species and susceptibility to mild exogenous stimuli in the epidermis. This produces a senescent phenotype
of skin cells, leads to the release of innate immune molecules, which trigger autoimmunity, and ultimately
causes dysfunction and death of melanocytes. Clinical management aims to halt depigmentation, and to
either repigment or depigment the skin, depending on the extent of disease. New therapeutic approaches
include stimulation of melanocyte differentiation and proliferation through α-melanocyte-stimulating
hormone analogues and through epidermal stem cell engineering. Several questions remain unsolved,
including the connection between melanocyte depletion and stem cell exhaustion, the underlying
degenerative mechanisms and the biological mediators of cell death. Overall, vitiligo is an excellent model
for studying degenerative and autoimmune processes and for testing novel approaches in regenerative
medicine. For an illustrated summary of this Primer, visit: http://go.nature.com/vIhFSC

Correspondence to M.P.
e-mail: picardo@ifo.it
Cutaneous Physiopathology,
San Gallicano Dermatologic
Institute, IFO IRCCS, via Elio
Chianesi 53, 00144 Rome,
Italy.
Article number: 15011
doi:10.1038/nrdp.2015.11
Published online
4 June 2015
Vitiligo is an acquired, chronic depigmenting dis­order
of the skin. Although the exact cause is still under
debate, the disease results from the selective loss of mel-
anocytes, which in turn causes pigment dilution in the
affected areas of the skin and/or mucosa. Melanocyte
precursors can be found in the hair follicle bulge; dif-
ferentiated, pigment-­producing melanocytes reside in
the basal layers of the epidermis and the hair matrix
(FIG.  1) . Depending on the disease course, skin and
hair are affected to different degrees. Clinically, skin
lesions present as milky white, non-scaly patches with
distinct margins1,2.
According to international consensus3,4, vitiligo
is classified into three major forms; namely, non-­
segmental vitiligo (or simply, vitiligo), segmental viti-
ligo and mixed vitiligo (BOX 1). Non-segmental vitiligo
is the most common form and is characterized by sym-
metrical, bilateral white patches. The lesions are typically
distri­buted in an acrofacial pattern (hands and feet, peri­
orificial facial involvement) or scattered symmetrically
over the entire body, and evolve unpredictably over time.
The hairs on the involved skin remain pigmented initially
but after a prolonged time, leukotrichia (whiteness of the
hair) might develop. The involvement of non-cutaneous
melanocytes such as ocular and cochlear melanocytes
is controversial3,5–9. Segmental vitiligo accounts for 5%
to 16% of overall vitiligo cases10,11 and shows unilateral
distribution, which totally or partially matches a cutane-
ous segment, of recognizable but difficult to interpret
pattern12. The onset is usually at an earlier age than for
non-segmental vitiligo and rapidly involves the follicu-
lar melanocyte reservoir (FIG. 1), which results in hair
whitening 12,13. The course of non-segmental vitiligo is
unpredictable, whereas that of segmental vitiligo is typi-
cally of sudden onset with rapid stabilization over a few
months after partial or complete depigmentation of the
affected segment. Mixed-type vitiligo shows segmental
involvement initially, but a second phase with the onset
of bilateral vitiligo patches usually follows4.
In this Primer article, we summarize the clini-
cal presen­tation and management of vitiligo, and we
highlight underlying degenerative and inflammatory
p­rocesses that lead to melanocyte degeneration.
Epidemiology
Vitiligo is the most common depigmenting disorder
worldwide (TABLE 1). The largest epidemiological study
was performed in 1977 on the island of Bornholm in
Denmark, where the disease was found to affect 0.4%
of the population14. In the predominantly black popu-
lation of the French West Indies, similar results were
obtained15. Overall, the estimated worldwide preva-
lence is 0.5% to 2% but peaks of up to 8.8% have been
reported in India, possibly relating to the inclusion

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PRIMER
Author addresses
1
Cutaneous Physiopathology, San Gallicano Dermatologic Institute, IFO IRCCS,
via Elio Chianesi 53, 00144 Rome, Italy.
2
Service de Dermatologie et Dermatologie Pédiatrique, Centre de référence pour les
maladies rares de la peau, INSERM 1035, Université de Bordeaux, Bordeaux, France.
3
Multicultural Dermatology Center, Department of Dermatology, Henry Ford Hospital
Detroit, Michigan, USA.
4
Division of Dermatology, Department of Medicine, University of Massachusetts
Medical School, Worcester, USA.
5
Department of Dermatology, PGIMER, Chandigarh, India.
of chemically induced depigmentation16,17. Reports
from Mexico and Japan also indicate high incidences
of vitiligo17. A study, which included a large Chinese
population 18 and, therefore, possibly bypassed the
selection bias of hospital-based studies, confirms an
overall prevalence of 0.6%, with lower prevalence of
the segmental form (2.5% of the total prevalence) and
higher prevalence of focal vitiligo (36%) than reported
in other studies. Differences in disease classification,
lack of simple laboratory tests, varied populations and
inconsistent reporting by patients could account for this
variability in epidemiological data. Moreover, discrep-
ancies between prevalence and incidence data might
be attributable to a higher reporting rate in countries
in which the social and cultural stigma is considerable
or the population has darker skin and, therefore, more
prominent lesions19–23.
Most cases of non-segmental vitiligo occur sporadi-
cally. Between 15% and 20% of patients have one or more
first-degree relatives with vitiligo24. Adults and children
of both sexes are equally affected, even if women seek
treatment more frequently, probably as a consequence
Epidermis
Epidermal
melanocyte
Sebaceous gland
Bulge
(keratinocyte and
Dermis
melanocyte stem cell)
Hair
Bulb Bulb melanocyte
Dermal
papilla
Figure 1 | The hair follicle unit.  The anatomical distribution
Nature of differentiated
Reviews and
| Disease Primers
immature melanocytes is shown. The melanocyte stem cells reside in the bulge of the
hair follicle, which is located next to the sebaceous gland, whereas differentiated
melanocytes are located in the papilla and the epidermis.
2 | 2015 | VOLUME 1 www.nature.com/nrdp
© 2015 Macmillan Publishers Limited. All rights reserved
of greater social burden19,20. The prevalence increases
with age (0.5% in children <1 year of age; 1% of 1- to
5‑year-olds, 2.1% of 5- to 12‑year-olds)20. This finding
was confirmed in a review that reported prevalence
rates of 0.06% to 2.3% in the general population and 0%
to 2.2% in children21. Vitiligo usually occurs in young
people between the age of 10 years and 30 years17,18,22,23,
although it can develop at any age (TABLE 1). Almost half
of all patients present before the age of 20 years, and
nearly 70% to 80% before the age of 30 years17. Onset
before the age of 12 years is common, with 32% to 37%
of patients in this age category 23,25, although earlier stud-
ies reported 25%26–28. Segmental vitiligo tends to occur
at a younger age25–29, before the age of 30 years in 87% of
cases and before the age of 10 years in 41.3%.
Mechanisms/pathophysiology
Vitiligo is characterized by the loss of functional melano­
cytes3,30–32, and multiple mechanisms might contri­bute
to this loss, including metabolic abnormalities, oxida-
tive stress, generation of inflammatory mediators, cell
detachment and autoimmune responses. The overall
contribution of each of these processes is still under
debate. Our unified view considers the intrinsic defect in
melanocytes as the initial event. In this model, oxidative
stress in the melanocytes leads to a local inflammatory
response and the activation of innate immune pro-
cesses, which, in subjects with a genetic pre­disposition
to develop autoimmunity, generates melanocyte-specific
cytotoxic immune responses (FIG. 2). Several processes
might be involved in the progressive loss of melanocytes
and they either involve immune attack, or cell degener­
ation and detachment. The pathogenetic mechanisms
underlying non-segmental and segmental vitiligo were
thought to be distinct owing to their different clini-
cal patterns. Accordingly, for the segmental form, a
neuronal hypothesis or somatic mosaicism have been
favoured. However, recent data indicate over­lapping
inflammatory pathogenesis for segmental and non-
segmental vitiligo. Both are caused by a multistep pro-
cess, which includes initial release of proinflammatory
cytokines and neuropetides, triggered by external or
internal injury, with a subsequent vascular dilatation
and immune response33.
Oxidative stress
The pathogenetic role of oxidative stress is supported
by increased levels of reactive oxygen species (ROS)
in lesional and non-lesional skin both in vitro and
in vivo31,34–38. ROS also lead to impaired expression or
activity of the antioxidant system. Epidermal catalase
levels are low, probably as a result of H2O2-mediated
deactivation of the nicotinamide adenine di­nucleotide
(NADH)-binding site of the enzyme, as catalase
mRNA expression is unchanged34–38. Other antioxidant
enzymes, including thioredoxin reductase and thio­
redoxin, glutathione peroxidase, glutathione reductase,
superoxide dismutases, and the repair enzymes methio-
nine sulf­oxide reductases A and B, are also altered in vit-
iligous skin31,39–41, which indicates that ROS generation
causes widespread alteration of the antioxidant system.
 PRIMER

Box 1 | Vitiligo Global Issues Consensus Conference classification

Vitiligo can be classified into three main types: non-segmental, segmental and mixed
vitiligo (see the figure, silhouettes in parts a, b and c, respectively).
Non-segmental vitiligo can have different patterns; it can occur in mostly acrofacial,
mucosal (at more than two sites) and generalized patterns. Generalized patterns involve
most of the body (vitiligo universalis). Segmental vitiligo can be uni- or bisegmental.
The mixed type has an onset that is the same as segmental vitiligo but it then evolves into
non-segmental vitiligo.
a b c keratinocyte adhesion, which depends on desmosomes,
This imbalance of the pro-oxidants and antioxidant
status in vitiligo has been indicated to cause increased
sensitivity of melanocytes to external pro-oxidant
stimuli37,43,44 and, over time, to induce a pre-senescent
status. Stress-dependent melanocyte detachment has
been observed at the borders of lesions48,49. This find-
ing possibly explains the Koebner phenomenon (that
is, the induction of new lesions by minor skin trauma)
observed in patients with vitiligo49. Unlike keratinocyte–­
melanocyte–keratinocyte interaction does not involve
specific adhesive structures but simple adhesion mol-
ecules such as integrins and cadherins. In clinically
normal-appearing skin of patients with vitiligo, the
expression of cadherins is decreased and the anti-
adhesion molecule tenascin increased48. In vitiligo skin,
chronic friction can activate epithelial cells. These cells
sense the mechanical forces and convert them into bio-
chemical signals49, which p­roduce intracellular stress and
altered cadherin expression50.

Metabolic profile in non-lesional skin. Several sources

for ROS generation have been identified (BOX 2) but
Consequences of oxidative stress. Oxidative stress the key reason for the oxidative stress in vitiligo is not
compromises the function of cellular proteins and understood completely. Considering that a general
membrane lipids42,43. One of the affected proteins is intrinsic defect occurs in vitiligo cells, the biological
tyrosine-related protein 1 (TRP1, also known as DHICA phenotype and metabolic properties of cells derived
oxidase), which is important for melanin synthesis. from normal-appearing skin might help to clarify
Oxidative stress-driven modification of the TRP1–­ pathogenesis. Overall, unaffected epidermis in patients
calnexin complex can lead to reduced TRP1 stability is characterized by deregulation of the bi­o pterin
with subsequent production of toxic melanin inter­ metabolism 45, mainly due to increased production
mediates5-44. Modifications of the active (binding) site of of 6‑­tetrahydrobiopterin and 7‑tetrahydrobiopterin
the cytosolic enzyme dihydro­pteridin reductase45 lead to (FIG. 2b). This could lead to inhibition of antioxidant
altered biopterin synthesis and recycling (see below)31,45. enzymes activities and of melanin synthesis, and to an
Modification and inactivation of acetyl­cholinesterase increased production of c­atecholamines, which further
further promotes and maintains skin oxidative d­amage46. favours oxidative stress51–53.
Redox alterations of membrane lipids affect lipid Melanocytes from non-lesional skin show aberrant sig-
rafts, which compromises the function of membrane nal transduction, including hyperactivation of mitogen-­
receptors, and e­lectron t­ransfer and ATP production activated protein kinase (MAPK) and cyclic AMP
in mitochondria42,47. response element-binding protein (CREB), and modifi-
cations of their membrane lipids42,47,54. Moreover, prob-
ably as a consequence of the intracellular oxidative stress,
Table 1 | The epidemiology of vitiligo they overexpress p53 (REFS 54,55) and some of its target
Parameter Value Comments genes. This expression induces a senescence-­associated
secretory phenotype (SASP), which is character­ized by
Prevalence
the production of interleukin‑6 (IL‑6), matrix metallo-
General population 0.06–2.28% Values vary depending on study proteinase 3, cyclooxygenase‑2, and insulin-­like growth
Children 0–2.6% Onset before 12 years factor-binding protein 3 (IGFBP3) and IGFBP7 (REF. 54)
India 8.8% High value probably due to the inclusion (FIG. 2c). This pre-senescent profile could be melanocyte-
of chemical and toxic depigmentation specific, which might explain the absence of clinically
Sex ratio manifest ageing of the entire skin. The current hypoth-
esis for vitiligo pathogenesis postu­lates that degenerative
Female:male prevalence 1:1 – damage leads to the specific impairment or loss of mel-
Female:male treatment 2:1 More treatment requests in women, anocytes alone. Interestingly, the p53 deregulation corre-
requests probably due to greater social stigma lates with a protection from non-melanoma skin cancer 55.
Onset p53 might facilitate DNA damage repair, which maintains
Childhood and early onset 70–80% 10–30 years old genome stability, and can induce the production of POMC
vitiligo (pro-­opiomelanocortin) which can modulate, along with
Non-segmental vitiligo Any age – SIRT1 (NAD-dependent protein deacetylase sirtuin 1)
and FOXO1 (forkhead box protein O1), the energy bal-
Segmental vitiligo Young Onset before 12 years
ance and cell metabolic processes56. Indeed, patients with

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© 2015 Macmillan Publishers Limited. All rights reserved

PRIMER

a Healthy
UV
Macrophage
Chemical damage

Mitochondrion

Citric acid FADH2

cycle
ATP ROS
III
I II 6BH4
NADH IV V
Electron
transport chain 7BH4

Metabolic efficiency Melanocyte Adaptive response

and ability to counteract Dendritic
dangerous noxious ROS cell

b Metabolic defects and immune activation Membrane

debris
UV Genetic background

Chemical damage

Alteration of membrane lipids New CXCL10

antigen
ROS
Misfolded T cell
ROS DAMPs protein
III
I II 6BH4
IV V

ROS Damaged
7BH4 melanocyte

Metabolic defects
CB8+ TReg
T cell cell
c Metabolic defects and cell degeneration

UV Genetic background

Chemical damage SASP

■ IL-6
■ MMP3
■ COX-2
■ IGFBP3
■ IGFBP7
ROS Autophagy
ATP
III
I II 6BH4
IV V

ROS 7BH4 p53

Metabolic defects Degenerative process

Nature Reviews | Disease Primers

vitiligo have a low incidence of skin cancer 57,58, despite
light or absent pigmentation of their lesions, whereas
individuals with fair skin or albinism are more prone to
d­eveloping non‑melanoma skin cancers57.
Mitochondria. A wide range of metabolic pathways lead
to the uncontrolled generation of ROS (BOX 2), but the
site of ROS production is unclear. Mitochondria have
been suggested as a key source of ROS, as they mediate
oxidative stress-related ageing and control apop­tosis in
healthy cells (FIG. 2a). How mitochondrial defects impact
metabolism and cell fate in vitiligo is under debate.
Several lines of evidence suggest that mitochondria
are key in mediating melanocyte dysfunction42,47,59,60:
inhibitors of mitochondrial transition pores reduce
ROS levels and cell death, transmembrane potential is

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© 2015 Macmillan Publishers Limited. All rights reserved


◀ Figure 2 | The melanocyte and its environment.  a | In healthy skin, mitochondria
produce energy efficiently, and metabolic pathways — including those of biopterin
metabolism — are modulated according to demand and are well balanced. After external
stress — for example, ultraviolet (UV) radiation exposure or chemical damage — reactive
oxygen species (ROS) are produced in a tightly regulated manner and serve as useful
intracellular messengers. Melanocytes adapt to these stresses without activating immune
cells; they initiate physiological changes, such as melanin production or kinases activation,
and their survival is not affected. b | In vitiligo, melanocytes exhibit metabolic defects,
which unbalance the steady-state equilibrium and make handling additional stressors
difficult. Elevated ROS levels, which are a hallmark of deregulation of energetic pathways,
damage key enzymes and further compromise important metabolic pathways, for
example, in the mitochondrion. Biopterin synthesis and recycling is also affected, leading
to further oxidative stress and cell damage. These changes, in the context of a susceptible
genetic background, activate a signalling cascade that starts with ROS hyperproduction,
activate the unfolded protein response (which identifies and responds to the
accumulation of unfolded or misfolded proteins) and unmask oxidatively modified
antigens. Membrane debris and damage associated molecular patterns (DAMPs) are
released and activate macrophages and dendritic cells, and this is followed by cytokine-
and chemokine-driven activation of T helper 17 (TH17) cells and dysfunction of T regulatory
(TReg) cells. c | Melanocyte degeneration can also affect autophagic processes and cause
the release of ATP and induce, through p53 overexpression, a senescence associated
secretory phenotype (SASP), including interleukin‑6 (IL‑6), matrix metalloproteinase 3
(MMP3), cyclooxygenase‑2 (COX‑2), and insulin-like growth factor-binding
protein 3 (IGFBP3) and IGFBP7). These SASPs activate dendritc cells. CXCL10, CXC
chemokine-ligand 10; FADH2, flavin adenine dinucleotide; NADH, nicotinamide adenine
dinucleotide; 6BH4, 6 tetrahydrobiopterin; 7BH4, 7 tetrahydrobiopterin.
lost, cardio­lipin pattern and respiratory chain complex
expression are altered, and the mitochondrial mass
is increased.
In other degenerative diseases, mitochondrial dys-
function has been connected to cell damage61–63. A role for
the B cell lymphoma 2 (BCL‑2) protein family as modu-
lators of cell survival, metabolism and mitochondrial
dynamics is emerging 64–68. Downstream, cytochrome C
participates both in electron transfer and ATP produc-
tion, and activates caspases during apoptosis. Sirtuins
are another example of the crosstalk between metabo-
lism and cell fate (they can influence both metabo­lism
and apoptosis)63,68–71. Damaged mitochondria modulate
the pathway involving SIRT1, phosphoinositide 3‑kinase
(PI3K), –AKT (protein kinase B), protein kinase A,
mammal­ian target of rapamycin (mTOR), and then
nuclear PPARγ co-activator 1 (PGC1α), CREB and
FOXO1, restoring normal cellular metabolic status70. As
some of the key steps linking mitochondria to cell fate
are defective in vitiligo cells, this evaluation of cell
m­etabolism can illuminate our understanding of vitiligo.
Keratinocytes and fibroblasts. Some of the alterations
observed in melanocytes have also been described in
other skin cells, suggesting that vitiligo leads to general­
ized degeneration. Keratinocytes and fibroblasts also
exhibit oxidative stress, phosphorylation of p38, over-
expression of p53 and a senescent phenotype72–74. These
changes could be the basis for altered secretion of solu-
ble growth factors supporting melanocyte survival and
homeostasis. In non-lesional skin from vitiligo patients,
p53 overexpression, downstream stress signalling and
aberrant expression of p16, which regulates the cell
cycle, have been confirmed in both melanocytes and
keratinocytes by immunohistochemistry 72,74. However,
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PRIMER
melanocytes might be more sensitive to these changes,
as they have a physiologically low renewal rate and are
selectively lost owing to stem cell exhaustion and the
continuous exposure to toxic insults75–77. In lesions,
apoptotic keratinocytes have been described 76,77.
Keratinocytes support melanocyte survival and melanin
production via growth factors, including bFGF (basic
fibroblast growth factor) and SCF (stem cell f­actor).
Lesional keratinocytes show apoptotic markers and
reduced SCF production, which might contribute to
the melanocyte defects77. The dermal–epidermal net-
work ensures optimal cell proliferation and differenti­
ation through direct cellular contact and the secretion
of soluble factors78–80.
Melanocyte stem cells. Oxidative stress can affect
melano­cyte stem cells in the hair follicle and in the der-
mis, which might explain the higher incidence of early
hair greying in patients with vitiligo and their relatives81.
The maturation and function of hair follicle stem cells
are regulated by dermal cells, including adipocytes,
dermal papilla cells and fibroblasts, and it is conceiv-
able that metabolic impairment of dermal cells will
affect stem cells. In mice, increased expression of p53
is associated with a defect of the stem cell reservoir in
hair follicles and sebaceous glands, and with impaired
skin renewal81,82. A decreased number of dermal stem
cells has been reported in the dermis of non-lesional
vitiligous skin, and this seems to be also associated
with inflammation.
Immune activation
Stressed melanocytes might initiate immune responses
through several mechanisms83–85. Vitiligo is associ-
ated with other autoimmune diseases, including auto­
immune thyroiditis and type 1 diabetes mellitus, which
all involve cellular stress, innate immunity and adaptive
T cell responses. The role of autoimmunity in vitiligo is
supported by the presence of antibodies against melano-
cytes, the association with polymorphisms at immune
loci, the presence of prominent T cell perilesional infil-
trates and cytokine expression, and by the association
with other autoimmune diseases86.
Activation of innate immunity. In vitiligo, the process
is likely to begin with the activation of innate immune
cells that sense exogenously or endogenously induced
stress signals released from melanocytes and possibly
keratinocytes31,87 (FIG. 2b). Natural killer cells infiltrate
normally pigmented skin of patients with vitiligo,
which suggests that these cells are early responders to
melanocyte stress87,88. In addition, chemically induced
stress causes human melanocytes to secrete exosomes
that contain melanocyte-specific antigens and damage-
associated molecular pattern molecules (DAMPs). These
exosomes activate nearby dendritic cells and induce their
maturation into efficient antigen-presenting cells89–91.
Vitiligo melanocytes and chemically stressed normal
melanocytes release inducible heat shock protein 70
(HSP70) (REF. 92), which alerts infiltrating dendritic
cells and worsens depigmentation in a mouse model
PRIMER
Box 2 | Possible sources of ROS in the epidermis
• Transforming growth factor-β, epidermal growth
factor and platelet-derived growth factor
• X‑rays, ultraviolet A (UVA) and UVB radiation
• Orthoquinols and paraquinols
• Phenols
• Tumour necrosis factor
• Nicotinamide adenine dinucleotide phosphate
(NADPH) oxidase
• Nitric oxide synthases
• Monoamine oxidase A
• Aromatic steroids, oestrogens, progesterone
and androgens
• Xanthine oxidase
• Biopterin photooxidation
• Phenylalanine hydroxylase
• Tyrosine hydroxylase
• Electron transport chain
ROS, reactive oxygen species.
of vitiligo87,89. Nitrosactive stress-driven alteration of
mitochondrial DNA triggers pro-inflammatory signals
capable of activating immune responses90. Moreover,
stressed melanocytes accumulate unfolded proteins in
the endoplasmic reticulum, which activates the unfolded
protein response (UPR) through three pathways: s­erine/
threonine-­protein kinase/endoribonuclease IRE1,
eukaryotic translation initiation factor 2‑alpha kinase 3
(EIF2AK3), and cAMP-dependent transcription factor
ATF6α. This homeostatic response mitigates damage
and promotes cell survival; however, during prolonged
stress, the cells still die or release immunostimulatory
signals that disrupt immune tolerance91,92.
Adaptive immunity. Melanocyte-specific, cytotoxic
CD8+ T  cells have been strongly implicated in the
destruction of melanocytes. Patients with vitiligo have
higher numbers of cytotoxic CD8+ T cells in the blood
compared with healthy controls; these numbers corre-
late with disease activity, and isolated CD8+ T cells from
vitiligo patients can identify and kill normal human
melanocytes in vitro92–94. Furthermore, high numbers of
CD8+ T cells are found in lesions and these cells are both
necessary and sufficient to kill melanocytes94. Infiltrating
T cells isolated from biopsies of vitiligo lesions show an
enrichment of cells that recognize melanocyte antigens,
and when these cells were reintroduced in non-lesional,
normally pigmented skin from the same patient, they
migrated to the melanocytes and induced apoptosis95,96.
CD8‑depleted T  cells were unable to kill melano­
cytes, whereas CD8‑purified populations were even
more potent 96.
CD8 + T  cells from cutaneous lesions produce
interferon-γ (IFNγ) and tumour necrosis factor (TNF),
among other cytokines97–100. IFNγ is also expressed in
lesions97, which suggests that this cytokine is impor-
tant in driving autoreactive T cell responses and the
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© 2015 Macmillan Publishers Limited. All rights reserved
destruction of melanocytes. In a transcriptional profile
of lesional skin from vitiligo patients, the IFNγ‑induced
CXC chemokine-ligand 9 (CXCL9), CXCL10 and
CXCL11 were the most highly expressed genes, whereas
other chemokine pathways were silent 97,99. In addi-
tion, the common receptor of these chemokines, CXC
receptor type 3 (CXCR3), is expressed on melanocyte-­
specific blood CD8+ T cells from patients with viti-
ligo and on lesion-infiltrating T cells. CXCL10 is also
elevated in patient serum101–104. Functional studies in
mice confirmed the crucial role of the IFNγ–CXCL10–
CXCR3 axis in both the progression and maintenance
of de­pigmentation in vitiligo97,98. Taken together, these
results support investigation of therapies that interrupt
this pathway and that target IFNγ, the IFNγ receptor, the
downstream signalling proteins Janus kinase 1 (JAK1),
JAK2 and signal transducer and activator of transcrip-
tion 1 (STAT1), and the chemokine CXCL10 and its
receptor CXCR3 (FIG. 3).
The role, if any, that other cytokines have in depig-
mentation is unclear. Some studies have reported
expression of IL‑6 and IL‑17 in lesions and patient
serum, although the contribution of these cytokines to
pathogenesis has not been determined100. The increased
n­umber of circulating T helper 17 (TH17) cells correlates
with the extent of the disease101,102. The importance of
regulatory T (TReg) cells in controlling autoimmunity in
vitiligo is based on observations made in patients102–108
and on functional experiments in mouse models104.
TReg cell-mediated suppression of human melanocyte-­
specific CD8+ T cells in vitro causes decreased prolifera-
tion, cytokine production and T cell receptor affinity,
and increased susceptibility to apoptosis, expression of
cell surface markers CC-chemokine receptor 7 (CCR7)
and cytotoxic T‑lymphocyte antigen 4 (CTLA4) of the
CD8+ T cells105. However, this pheno­type is only induced
in melanocyte-specific CD8+ T cells from healthy sub-
jects, but not in those from patients with vitiligo, which
suggests that TReg cells are indeed important in control-
ling the development of autoimmunity, and that their
function might be abnormal in patients with vitiligo106,107.
Indeed, in vitiligo, TReg cells are decreased or function-
ally defective, and they show deficient skin homing
and low expression of transforming growth factor‑β and
CC-chemokine ligand 21 (CCL21) (REF. 106). Consensus
on changes and dysfunction of TReg cells in vitiligo has
not yet been established108–112.
Melanocyte death. The exact mechanism responsible for
the death of melanocytes in lesions is controversial113.
Apoptotic mechanisms have been suggested, including
over-expression of ribonuclease T2, which facilitates
the pro-apototic activity of TNF receptor-associated
factor 2114, deregulated expression of SIRT1 (REF. 115),
increased release of inducible HSP70116, and apopto-
sis induced by perilesional CD8+ T cells117. However,
most of these studies rely on in vitro data — clear evi-
dence of apoptosis in vivo is still lacking. An alterna-
tive hypothesis is that decreased expression of adhesion
molecules and oxidative stress lead to melanocytorrhagy
(d­etachment and loss of melanocytes)49,50,118,119.

CXCR3*
JAK1/2*
IFNγ* IFNγ
receptor*
STAT1* CXCL9 CD8+
CXCL10* T cell
Skin
cell
Figure 3 | Treatment target in interferon signalling.  Interferon-γ (IFNγ) is expressed in
Nature Reviews | Disease Primers
vitiligous lesions. It drives autoreactive T cell responses and the destruction of
melanocytes. The IFNγ‑induced CXC chemokine-ligand 9 (CXCL9), CXCL10 and CXCL11
are the most highly expressed. Functional studies100 in a mouse model of vitiligo
confirmed the important role of the IFNγ–CXCL10–CXCR3 (CXC receptor type 3) axis in
both the progression and maintenance of depigmentation. These studies open the
search for targeted therapies (potential targets indicated by asterisks) that interrupt this
pathway, including IFNγ, the IFNγ receptor (IFNγR), IFNγ pathway signalling proteins
Janus kinase 1 (JAK1) and JAK2 (JAK1/2), signal transducer and activator of transcription 1
(STAT1), CXCL10 and CXCR3.
Genetic background
A genetic background for vitiligo development has
been shown in multiple studies (see below); however,
the genetic risk is not absolute. Monozygotic twins,
for example, only have a 23% concordance of disease;
similar percentages have been reported for other auto­
immune diseases such as lupus erythematosus and
type 1 diabetes mellitus, but it is lower than the risk
for psori­asis and atopic dermatitis noted in twins120.
Additional stochastic or environmental factors influence
vitiligo pathogenesis and influence the penetrance of the
genetic p­redisposition to vitiligo.
Genetic studies support immune mechanisms as the
process underlying vitiligo. Mutations in genes involved
in both innate and adaptive immunity increase the risk
for vitiligo120 (TABLE 2). However, polymorphisms in non-
immune genes have also been identified as risk factors,
including in the melanocyte-specific genes TYR (the
gene encoding tyrosinase) and the MC1R (the gene
encoding melanocortin 1 receptor)120. Both are T cell
antigens and participate in melanin production; thus,
mutations of these genes might contribute cellular stress2.
Recently, polymorphic expression of MTHFR (the gene
encoding methylene tetrahydrofolate reductase, which
regulates homocysteine levels), has been described in
patients with vitiligo121. This finding is in agreement with
the elevated plasma level of homocysteine in patients
with vitiligo. The high susceptibility of homocysteine
to oxidative stress can contribute to the melanocyte
d­amage in vitiligo121. XBP1P1 (the gene encoding X‑box
binding protein 1) is also a disease-associated gene122.
It has a central role in mitigating the unfolded protein
response, and might also drive stress-induced inflamma-
tion in vivo120. Several single-nucleotide polymorphisms
have been reported in the catalase gene (CAT), which
might impair the enzyme function34,38,123.
Summary
Interestingly, the risk for vitiligo is inversely correlated
with the risk for melanoma — patients with vitiligo are
relatively protected from developing melanoma57,58,123,
and a subset of patients with melanoma who experi-
ence spontaneous remission or successful response to
NATURE REVIEWS | DISEASE PRIMERS VOLUME 1 | 2015 | 7
© 2015 Macmillan Publishers Limited. All rights reserved
PRIMER
treatment develop vitiligo as a consequence57. Vitiligo
and melanoma share CD8+ T cell antigens, an observa-
tion that has contributed to the development of new,
innovative therapies for melanoma58. Finally, allelic vari-
ants associated with vitiligo directly confer protection
from melanoma, and vice versa124,125. This shows that
immune responses in vitiligo and melanoma are simi-
lar and target similar antigens, and suggests that auto­
immunity in vitiligo develops owing to failed restriction
of inherent mechanisms intended to control melanocyte
proliferation. The importance of immune mechanisms
is further supported by the association of vitiligo with
halo naevus, which is a mole surrounded by a depig-
mented halo-like area accompanied by a dense immune
cell i­nfiltrate in histology 126.
Overall, experimental data support intrinsic damage
and a close link between oxidative stress and immune
responses. For example, histological analysis of develop­
ing lesions shows expression of NALP1 (NACHT, LRR
and PYD domains-containing protein 1), IL‑1 and
catalase127; moreover, the expression levels of haem oxy­
genase 1 in plasma has been linked to the activity phase
of the disease and to IL‑2 levels128,129. All of these factors
are involved both in stress responses and in triggering
of innate immunity. In summary, genetic, experimental
and clinical studies have revealed important pathways
in the pathogenesis of vitiligo and have identified targets
for the development of new therapies.
Diagnosis, screening and prevention
Risk factors
There is a clear genetic risk for the development of viti-
ligo, either in isolation or in combination with immune-
related inflammatory polyendocrine disorders, which
can present with thyroidal autoimmunity, type 1 dia­betes
mellitus and autoimmune gastric atrophy 130. Familial
cases occur in a non-Mendelian pattern that suggests
complex inheritance131,132. The risk of developing vitiligo
for a patient’s first-degree relatives is increased tenfold
compared to unrelated individuals from the general
popu­lation with the same ethnic background; more-­
distant relatives have lower risks120,131. Familial cases
of vitiligo tend to occur at a younger age than sporadic
cases, which further supports the importance of genetic
risks for vitiligo131. Many different risk factors such as
ultraviolet (UV) radiation exposure, repeated mechani-
cal or thermal stress133, and exposure to chemicals
(e­specially phenols or catechols)134 have been p­roposed
for vitiligo, but epidemiologic data remain limited.
Some of the gene variants that are associated with
an increased vitiligo risk also predispose to other com-
mon autoimmune disorders. Many of the vitiligo risk
genes120 (TABLE 2) govern immune and inflammatory
pathways, and a few correspond to pigment cell anti-
gens (see above). Among associated immune-related
inflammatory disorders, thyroid pathologies predomi-
nate (Graves disease and Hashimoto thyroiditis), but
alopecia areata, type 1 diabetes mellitus, psoriasis and
atopic dermatitis are also commonly encountered135,136
in the vitiligo clinic. Other conditions such as pernicious
anaemia, lupus erythematosus, or Addison disease are
PRIMER

Table 2 | Vitiligo susceptibility loci

Locus Gene Protein Role
1p13.2 PTPN22 Tyrosine-protein phosphatase non-receptor type 22 T cell signalling
1p31.3 FOXD3 Forkhead box protein D3 Neural crest and melanoblast regulator
1p36.23 RERE Arginine-glutamic acid dipeptide repeats protein Lymphoid co‑repressor
2q24.2 IFIH Interferon-induced helicase C domain-containing Innate antiviral immune response
protein 1
2q33.2 CTLA4 Cytotoxic T lymphocyte protein 4 CD80- and CD86‑mediated T cell inhibition
3p13 FOXP1 Forkhead box protein P1 B cell regulator
3q13.33 CD80 T‑lymphocyte activation antigen CD80 T cell priming by B cells, T cells and dendritic cells
3q28 LPP Lipoma-preferred partner Potential co‑activator
4p16.1 CLNK Cytokine-dependent hematopoietic cell linker Positive regulator of mast cells
5q22.1 TSLP Thymic stromal lymphopoietin Cytokine regulator of skin dendritic cells
6p22.1 HLA‑B and HLA‑C Human leukocyte antigen B (HLAB) and HLAC Peptide antigen presentation
6p21.32 HLA‑DRB1 and HLA‑DQA1 Human leukocyte antigens DRB1 and DQA1 Peptide antigen presentation
6Q15 BACH2 Transcription regulator protein BACH2 B cell repressor
10p15.1 IL2RA Interleukin‑2 receptor subunit alpha Interleukin 2‑dependent T cell activation
10q25.3 CASP7 Caspase 7 Apoptotic executor protein
11p13 CD44 CD44 antigen T cell regulator
11q14.3 TYR Tyrosinase Melanogenesis regulator
11q21 Gene desert Not known TYR regulator
12q13.2 IKZF4 Zinc finger protein Eos T cell regulator
14q12 GZMB Granzyme B Cytotoxic T lymphocyte-mediated death
15q12‑13‑1 OCA2 P protein Melanosomal transporter
16q24.3 MC1R Melanocortin 1 receptor Melanogenesis regulator
17p13.2 NLRP1 NACHT, LRR and PYD domains-containing protein 1 Interleukin‑1β‑mediated innate immune
response
22q12.1 XBP1 X‑box-binding protein 1 Major histocompatibility compex class II
regulator
22q12.3 C1QTNF6 Complement C1q tumour necrosis factor-related Immune response to light-induced apoptosis
protein 6
22q13.2 TOB2 Protein TOB2 Cell cycle progression inhibitor, T cell tolerance
Xp11.23 FOXP3 Forkhead box protein P3 T cell activity and development
Based on data from REF. 120.

rarer, but still occur more frequently in patients with Diagnosis

vitiligo than in the general population136. More recently,
a predisposition for atopic diseases has been shown in
childhood-onset vitiligo25. By contrast, as mentioned
above, vitiligo decreases the risk for melanoma and
non-melanoma skin cancer 137. However, the clinical
significance of depigmentation in patients with mela-
noma is not absolutely clear. Patients with melanoma can
show skin whitening before melanoma detection with
a clinical presentation that resembles vitiligo. The only
differential marker is occurrence of antibodies against
melanoma antigen recognized by T cells 1 (MART1) in
melanoma-associated depigmentation but not in viti-
ligo137. The biological connections between vitiligo and
melanoma and other skin cancers is complex, and they
demonstrate the importance of the cutaneous cross-
talk between cells through direct cell–cell contact and
m­ediator release77.
The diagnosis of vitiligo, irrespective of its clinical sub-
type, is straightforward and does not require confirma-
tory laboratory tests in the majority of cases. Melanocytes
are absent from lesions, and this can be assessed non-
invasively by in vivo confocal microscopy, or by a skin
biopsy, which shows a paucity or absence of melano-
cytes, when specific markers are used3. Non‑segmental
vitiligo usually progresses slowly, whereas segmen-
tal vitiligo rapidly progresses, over a time period of six
months, to cover a block-like segment and spontane-
ously stabilizes (BOX 1; FIG. 4). Mixed vitiligo can resemble
the non-segmental form, however lesions of the mixed
type are usually more refractory to treatment. If a lesion
improves after phototherapy, non-segmental vitiligo is
the likely diagnosis. Mixed vitiligo has probably been
under-reported until recently. Furthermore, other rare
or unclassifiable forms of vitiligo exist 3.

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© 2015 Macmillan Publishers Limited. All rights reserved


a b
Figure 4 | Typical presentation of vitiligo.  a | Non-segmental
Nature Reviews Disease Primers
vitiligo is| characterized
by symmetrical bilateral white patches with an acrofacial pattern or involving the entire
body. Lesions show unpredictable evolution over time. b | Segmental vitiligo is
characterized by unilateral distribution of lesions, which often overlap with cutaneous
segments. It shows a sudden onset and rapid stabilization. Mixed vitiligo shows a
segmental pattern early in disease development. With time, it evolves into
non-segmental vitiligo with bilateral lesions.
Wood’s (UV) lamp examination helps to b­etter
detect focal melanocyte loss and the intensity of hypo­
pigmentation, particularly in tanned areas of fair-skinned
individuals (such as the face) or in low-pigmented areas
in darker-skinned individuals (such as the palms).
Furthermore, vitiligous skin has a milky fluorescent aspect
under Wood’s lamp light, which is not observed in other
acquired hypomelanoses. This feature might corres­pond
to the local accumulation of pterins31. A biopsy or other
tests are not necessary except to exclude other disorders138.
Non-segmental vitiligo has to be differentiated from other
diseases of decreased pigmentation (FIG. 5), most impor-
tantly from melanoma, which, as discussed above, can
induce depigmentation. In segmental vitiligo, only one
area is involved in most patients, but occasionally two or
more segments with ipsi- or contralateral distribution are
affected139. Naevus depigmentosus (also known as hypo-
chromic naevus) is a common differential diagnosis of
segmental vitiligo, but naevi usually contain a normal or
subnormal number of melanocytes with reduced melanin
levels. Segmental or hemi­corporeal hypomelanosis of Ito
is rarely mi­sdiagnosed as vitiligo3 (FIG. 5b).
Histopathology
A skin biopsy can be indicated to exclude other dis-
eases (see above). Furthermore, the presence of mild
dermal or epidermal–dermal mononuclear infiltrates
at the m­argin of active vitiligo lesions with ongoing loss
of melanocytes can have important consequences for
management decisions. Such a biopsy finding indicates
active disease and warrants more aggressive therapy
using re­inforced local or systemic agents (see below).
NATURE REVIEWS | DISEASE PRIMERS VOLUME 1 | 2015 | 9
© 2015 Macmillan Publishers Limited. All rights reserved
PRIMER
In addition, inflammatory infiltrates can be mislead-
ing and are sometimes m­isdiagnosed; for example, as
c­utaneous T cell lymphoma.
Screening
No screening methods are available for vitiligo. When
the disease is diagnosed, clinical or laboratory screen-
ing of associated disorders is currently debated. Given
its incidence, autoimmune thyroid disease is frequently
searched for by palpation of the thyroid, thyroid function
tests and measurement of anti-thyroglobulin and anti-
thyroid peroxidase antibodies. Female patients, and
patients with longer duration of disease and greater body
surface involvement, are more likely to have autoimmune
thyroid disease and, therefore, their thyroid function and
anti-thyroid antibodies should be checked regularly 140.
Looking for melanocyte loss in non-skin locations (such
as the inner ear or eye) or its functional consequences
is currently not recommended, as involvement of non-
skin melanocytes has not been established, except in
rare autoimmune conditions such as Vogt–Koyanagi–
Harada syndrome, which sometimes presents with
skin depigmentation5–9,141.
Prevention
There is no primary prevention for vitiligo. Heritability
explains a minor part of disease development, and
environ­mental triggers are not sufficiently known to
w­arrant or enable primary prevention. Secondary pre-
vention, for example through avoidance of skin stress to
limit the Koebner phenomenon133,134,142,143, is frequently
advocated. However, accumulating evidence indicates
that mild inflammation at the border of depigmented
patches is associated with disease progression, and that
the Koebner phenomenon is closely associated with this
inflammatory stage. The Koebner phenomenon either
initiates inflammation133 or reflects enhanced melanocyte
loss caused by mechanical pressure and friction during
the inflammatory progressive or acceleration phase of the
disease133. The effectiveness of limiting mechanical stress
in isolation is difficult to measure because concurrent
interventions are often used, including oral mini-pulses of
corticosteroids, phototherapies or combined approaches,
which are aimed at halting inflammation and disease pro-
gression133. The strength of the Koebner phenomenon can
be quantified with a simple validated score, K‑VSCOR144,
and patients with high scores should be firmly advised to
avoid mechanical stress.
Management
The management of a patient with vitiligo requires time
for a careful initial assessment, which includes evaluating
the patient’s history and risk factors, a clinical examina-
tion and scoring (including photography). The whole skin
should be examined under natural light and UV lamp.
The Vitiligo European Task form12 can be used to record
the personal and familial history of vitiligo and other auto-
immune diseases, and clinical examination items, such as
the skin phototype, disease duration, Koebner phenom-
enon, and extent and activity of lesions. The first assess-
ment will serve as a basis for treatment decisions and for
PRIMER
a b c Once the patient has been assessed, a personalized
d e
Figure 5 | Differential diagnosis of vitiligo.  a | Tuberous sclerosis
Nature is characterized
Reviews by
| Disease Primers
concomitant occurrence of skin abnormalities, seizures, developmental delay, and
lung and kidney diseases. b | Ito hypomelanosis is characterized by hypopigmentation
along Blaschko lines (lines that represent the growth patterns of normal skin
development). c | Pytiriasis alba is characterized by hypomelanotic, not amelanotic,
desquamated patches with feathered edges. d | Pytiriasis versicolor is caused by
Malassezia spp. infection and characterized by irregular hypopigmented patches in
dark-skinned subjects. It involves mainly chest, arms, face and neck, and is sometimes
associated with itching. e | Piebaldism is present at birth but, in individuals with low
phototypes, becomes visible only after sun exposure. It is characterized by a white
forelock and ventral depigmentation.
follow‑up care after treatment initiation. Identification of
the type of disease guides management. Patients with any
type of vitiligo should be offered psychological support
and counselling 145 because of the impact of the disease on
the quality of life.
Non-segmental vitiligo
In non-segmental vitiligo, after a period of stability, an
acceleration phase with rapid disease progression over a
few weeks can occur. This requires urgent intervention
with systemic oral mini-pulse steroids145, a treatment
that consists of corticosteroid administration only twice
a week. Mini-pulse steroid therapy is easy to administer
compared to traditional steroid therapy or other immuno­
suppressive treatment, owing to the ‘pulse’ modality. As
patients have to take tablets only twice a week, adher-
ence is high and adverse effects are low. In this context,
the Koebner phenomenon should be avoided as much as
possible. Other than the need for frequent thyroid checks
(discussed above), the possible association of vitiligo with
other immune-mediated inflammatory diseases is u­sually
of limited practical consequence, but the existence of
speci­fic organ symptoms or a family history of other auto-
immune disorders should prompt adequate i­nvestigations
and specialist advice139,146.
10 | 2015 | VOLUME 1 www.nature.com/nrdp
© 2015 Macmillan Publishers Limited. All rights reserved
therapeutic algorithm is constructed based on the stabil­
ity of the disease, the affected body surface area, the
site of the lesion and hair follicle reservoir involvement.
Patients should always be consulted, as most of the treat-
ment options are time consuming and require long-term
follow‑up care. The aim of the treatment can be to halt
disease progression, to repigment the skin or to depig-
ment it. In addition, a cosmetician or a s­pecialized nurse
can help with cosmetic camouflage.
In 2008, the British Association of Dermatologists
reported clinical guidelines for the diagnosis and manage­
ment of vitiligo145, which were based on the first Cochrane
review and expert consensus on vitiligo147. In 2010 and
2015, the updates of the Cochrane review highlighted
the lack of a cure for vitiligo and the inability of current
treatment options to halt disease progression in a lasting
way 148,149. Reviewed treatment options included topical
therapies (such as corticosteroids, immunomodulators,
placenta-derived melagenine and vitamin D), photothera-
pies (such as narrowband ultraviolet B (UVB) or UVA
light therapy, psoralen combined with UVA (PUVA), and
excimer lamp and laser), oral treatments (such as cortico­
steroids and antioxidants), surgical treatments and other
interventions (combined treatments). Most randomized
controlled trials included in the review had a limited
n­umber of participants and no definite clinical recom-
mendations for the treatment of vitiligo could be made149.
The Vitiligo subcommittee of the European Dermatology
Forum has reported a new guideline for the management
and treatment of vitiligo in which treatments, includ-
ing both medical and surgical therapies, were graded
from first- to fourth-line options150. These guidelines
discussed the efficacy and tolerability of the follow­ing
therapies: topical treatments (corticosteroids and calci­
neurin inhibitors), phototherapies (narrowband UVB
light, excimer lamp and laser, and photochemo­therapies),
combination treatments, and oral systemic steroids and
other immunosuppressive agents. Patients with dark skin
frequently prefer PUVA, because it is particularly effec-
tive in these patients. The high effectiveness might be
due to the higher UVA dose that can be administered to
these patients compared with light-skinned individuals151.
A detailed algorithm that summarizes the therapeutic
modalities and suggests a stepwise approach is shown in
FIG. 6. Recently, afamelanotide, a potent α‑melanocyte
stimulating hormone (α‑MSH) analogue, has been shown
to be synergistic with narrowband UVB in promoting
repigmentation152,153. This opens new treatment perspec-
tives that not only focus immune-modulating drugs but
also target melanocyte differentiation and proliferation.
Previously, topical immune modulators (TIMs), and UVB
light and excimer laser were shown to act on melanocyte
precursors in hair follicles and the dermis in vitro153.
Segmental vitiligo
The risk of other autoimmune disease, including auto­
immune thyroditis, is not increased in patients with
segmental vitiligo154. Segmental vitiligo usually shows
early involvement of the follicular reservoir of melano-
cyte precursors and hair whitening. The treatment of
 PRIMER

Vitiligo or non-segmental vitiligo

Avoidance of triggering factors

Stable Not stable

Limited BSA (<20%) Extensive BSA (>20% and <60%) Widespread BSA (>60%)

Topical treatment Combination Combination Oral mini-pulse

(corticosteroid or TIM)
Targeted UVB
Combination (topical
treatment and targeted UVB)
Surgical treatment
• Topical treatment
(corticosteroid or TIM)
• Phototherapy NB-UVB
or PUVA (for dark skins)
Immunosuppressive agents?
• Topical treatment corticosteroid
(corticosteroid or TIM) (3–6 months)
• Phototherapy NB-UVB
or PUVA (for dark skins)
Depigmenting therapies

No or poor response No or poor response

Active Stable

NB-UVB Surgical
Topical treatment (corticosteroid or TIM) treatment
Systemic therapies (oral mini-pulse corticosteroid) for visible Camouflage, make-up
Immunosuppressive agents? areas Depigmenting therapies

Figure 6 | Management algorithm for the treatment of vitiligo.  Vitiligo is treated according
Natureto the phase
Reviews (activePrimers
| Disease or
stable) of the disease and the involved body surface area. The most commonly used depigmenting agents belong to the
phenol and catechol classes. BSA, body surface area; NB‑UVB, narrowband ultraviolet B light therapy; PUVA, psoralen
and ultraviolet A light therapy; TIM, topical immune modulator; UVB, ultraviolet B light.

segmental vitiligo depends on the timing of the inter-
vention. At an early stage, best within the first 6 months,
treatment with potent topical corticosteroids or TIMs
combined with light therapy, such as narrowband UVB
light or targeted excimer lamp or laser, can be proposed.
If the lesion is still in the active phase, oral steroid mini-
pulse therapy is also possible. By contrast, at a later stage
of the disease or when previous therapies fail, surgery can
be considered (see below).
Surgical management of vitiligo
Surgical methods, including tissue grafts and cellular
transplants, are emerging as an important solution for
stable vitiligo that is refractory to conventional treat-
ment 154–157. The outcome of surgical therapy depends
on patient selection, mainly regarding disease stability.
Ideally, patients should not have new lesions or growth
of the existing lesions for 1 year. However, overall stability
can be difficult to assess and sometimes it is helpful only
to consider the stability of the actual lesion, for which
surgical intervention is planned. Non-segmental vitiligo
in particular is a dynamic process and some patients have
active and stable lesions at the same time. Thus, a surgi-
cal approach can be applied to selected stable areas in
patients with generalized involvement. A test graft can
be carried out to assess stability, but this is not a reliable
method. Each patient should be assessed individually,
including a careful analysis of compliance and expecta-
tions. Different surgical approaches should be considered
from tissue grafts to the more-recent c­ellular transplants.
Tissue grafts. Tissue grafts use unprocessed pigmented
epidermis and dermis, which are transplanted to depig-
mented areas. Only limited areas and selected body
regions can be treated owing to the limited amount of
healthy tissue that can be taken. The recipient area does
not need extensive preparation. Donor tissue is collected
as thin or ultra-thin split-thickness grafts (in contrast
to full-thickness grafts that use the whole skin), from
epidermal suction blisters and as hair follicle or mini
punch grafts156–160.
Cellular transplants. In contrast to tissue grafts, cel-
lular transplants involve more-complex processing of
the grafts before surgery; sometimes the isolated cells
are also cultured. Either epidermal mixed cells or pure
melano­cytes are used. Isolated epidermal cells can be
used with or without in vitro expansion161,162. The pro-
duction of cultured melanocytes requires extensive
manipulation and adequate laboratory equipment and
expertise. Moreover, it is a time-consuming procedure
with two surgical sessions per patient and cannot be
used for large areas owing to the low in vitro replica-
tion rate of melanocytes161. Non-cultured epidermal cell
suspensions might be preferred to pure m­elanocytes,
because they include undifferentiated melano-
cytes, which are able to continue the differenti­ation, as
well as keratinocytes that produce specific melano­cyte
growth f­actors79,82. Furthermore, non-cultured epi­
dermal cell transplants can be used for large areas and
p­rovide a good colour match.

NATURE REVIEWS | DISEASE PRIMERS VOLUME 1 | 2015 | 11

© 2015 Macmillan Publishers Limited. All rights reserved

PRIMER

a Quality of life
Quality of life refers to physical functioning, psycho-
logical state and social interactions with others, and it
encompasses subjective factors, usually from the patient’s
perspective165. Vitiligo has a major impact on the qual-
ity of life — many patients feel stressed and stigmatized
by their condition. The skin has a central role for many
aspects of life; it is looked after, painted, decor­ated and
covered (FIG. 7a). Skin integrity is relevant in cultural,
religious and economic contexts. Any colour or aspect
modification of the skin impacts the quality of life of
the individual166–179. For example, in some religions, skin
colour affects expectations for the fate of the soul after
death. Patients with vitiligo can experience unpredict­
able worsening of their condition, leading others to be
suspicious or worried about the patients’ appearance.
Vitiligo frequently leads to low self-esteem and avoid-
ance behaviours due to fear and negative evaluations
by others171. Moreover, discrepancies prevail between
b Features of vitiligo therapy efficacy, physician evaluation and expectations
of the patient, which cause frustration for the patient and
Deviation from Unpredictable Sense of their family (FIG. 7b).
group norm evolution of disease imperfection
Several factors affect impact of vitiligo, including age
at onset, extent, distribution, stigma, sexual dysfunc-
Quality of life tion, self-esteem and self-concept, effectiveness of the
treatment and of the overall management. Onset of viti-
ligo in adolescence is a risk factor for impaired quality
Identification Control Social Attention Importance of life172,173. Childhood vitiligo can have a long lasting
with group over body success to body care of body integrity impact on the child’s self-esteem and can be associ-
ated with substantial psychological trauma173. Children
Factors influenced by social and religious backgrounds and obligations with vitiligo have been observed to restrict athletic
activities to avoid wearing clothes that expose depig-
Figure 7 | Determinants of quality of life in vitiligo.  aNature Reviews
| The skin | Disease
has a central Primers
role in mented patches and miss more school days than their
social and religious customs of many cultures. b | Often there is a mismatch between healthy counterparts173. As children grow older, vitiligo
social, cultural and religious obligations, and the perception of perturbed body integrity
causes more embarrassment and self-consciousness —
in patients with vitiligo. The current social duties that patients may experience are to
achieve professional success, to take care of the body, to conform to group standards,
95% of teenagers (15 to 17 years old) were bothered
and to maintain total control over their body. Answering these obligations is difficult by their v­itiligo compared with 50% of children (6 to
when physical appearance is compromised, as is the case in vitiligo. Consequently, 14 years old)173.
patients with vitiligo experience judgment by others and negative self-esteem, which is The extent of lesions involving face, arms, legs and
worsened by the unpredictable evolution of the disease. Patients experience a sense of hands correlates with a lower dermatology life quality
imperfection and inadequacy in terms of ability to follow the high and sometimes index (DLQI)172. DLQI is calculated by adding the score
impossible social standards. of each question. The higher the score, the more the
quality of life is impaired. Stigmatization was shown
to be the most influential factor in patient well-being
Over the years, cellular transplant procedures have and perceived quality of life, more so than age of onset
been modified and simplified to make them cost-­ or duration of disease172. The degree of stigmatization
effective159 and new options are emerging from the stud- varies between different cultures, which explains some
ies on hair follicle, dermal and mesenchymal stem cells; of the variations in DLQI seen between countries.
for example, multilineage-differentiating stress endur- For example, vitiligo is associated with a DLQI of 6 in
ing (muse) cells162–164. These cells have been identified as Malaysia and a DLQI of 1 in Italy (REF. 170). Compared
pluripotent stem cells in mesenchymal tissues, including with patients with other skin diseases, such as atopic
the dermis and adipose tissue163,164. These cells are able dermatitis, patients with vitiligo had significantly lower
to differentiate to all three lineages, migrate to targeted anxiety trait, interaction anxiousness and depression,
sites and have no tumorigenic activity. Furthermore, and the disease had a lower overall impact on quality
muse cells are easily accessible, and harvesting them of life172. The presence of visible lesions did not affect
bypasses the ethical aspects associated with the use of the global pattern, which links impaired quality of life
fertilized eggs or fetal tissue. muse cells can spontane- more to the activity of the disease than to involvement
ously proliferate and differentiate and they contribute of exposed areas. This can be explained by patients
to tissue recovery in damaged or stressed tissue164. Thus, experiencing discomfort owing to the uncontrolled
muse cells might be an interesting therapeutic option progression of the disease rather than noting lesions in
for vitiligo. visible areas174.

12 | 2015 | VOLUME 1 www.nature.com/nrdp

© 2015 Macmillan Publishers Limited. All rights reserved

 PRIMER

to melanocyte disappearance. Cellular, molecular and

Degenerative processes Immune activation
Vitiligo
pathogenesis
Common origin of Easy access Epigenetic
Comorbidities
melanocytes and neurons to skin factors
Model for autoimmune and neurodegenerative diseases
Figure 8 | Vitiligo as a model for autoimmune and degenerative diseases.  Vitiligo
Nature Reviews
represents a practical model for autoimmune and/or degenerative | Disease
diseases becausePrimers
of
its features (indicated by yellow boxes): vitiligo affects the skin (easy access), it involves
mainly melanocytes (cells that share a common origin with neurons), it exhibits a
multifactorial pathogenesis (involving degenerative and autoimmune events), and it is
influenced by epigenetic factors.
However, the DLQI is not specific to vitiligo and does
not address the cultural context of the patient. Recently,
vitiligo-specific scales have been reported: VitQoL, vitiligo
life quality 175 and vitiligo impact scale176,177. These scales
need to be validated in larger studies and different parts
of the world, with examination of variations relating to
cultural groups and stigma.
The considerable psychosocial stress and potential
psychiatric comorbidity related to vitiligo has important
implications for management and disease development, as
stress can be a precipitating factor. Social anxiety caused
by vitiligo can be improved by self-help cognitive behav-
ioural therapy 178. Treatment of vitiligo only according to
clinical disease severity might not adequately address a
patient’s suffering. Increasing awareness of quality of
life impairments will help to assure that vitiligo is not
under‑appreciated, under-treated and under-funded.
Outlook
Studies on human evolution indicate that skin pigmenta-
tion was an adaptive response to the environment after
the hair coat was lost. Pigmentation is important for
body homeostasis — it provides photoprotection and
participates in skin barrier function and anti-microbial
defences of the skin. Furthermore, it conditions social
and sexual behaviour. Vitiligo affects 0.5 to 2% of the
world population and affects patients’ lives both bio-
logically and psychologically. It is caused by complex
degenerative and autoimmune processes, which lead
genetic studies have improved our knowledge on patho-
genesis and have opened possibilities for new targeted
therapies. However, several aspects need to be further
explored, including the occurrence of co‑morbidities,
the integrity of the skin barrier, and the presence of skin
ageing markers. Understanding whether the skin stem
cell compartment is defective, how clock genes — which
regulate cell regener­ation in hair follicles — function, and
how melano­cytes interact with their surroundings, could
answer the relevant, often underestimated question of the
lack of m­elanocyte regeneration in vitiligo.
Vitiligo represents an excellent disease model (FIG. 8)
to understand how autoimmunity is initiated and how
organ-specific autoimmune disease progresses. The abil-
ity to perform translational research in autoimmunity
directly using patient tissues is somewhat unique. Skin is
very accessible and easy to sample. This enables the c­ulture
of melanocytes and other skin cells, and identification of
autoantigens and autoreactive T cell clones that execute
cell death. One of the major topics that need to be clarified
is the link between biochemical defects, oxidative stress
and induction of autoimmunity. Immunotherapies, such
as cyclosporine or TNFα antagonists, are often ineffect­
ive in treating vitiligo179, probably because these drugs act
only on a specific final mechanism without inter­fering
with early deregulated processes. Topical s­teroids and
calcineurin inhibitors modify the local inflammatory
milieu and immune response; furthermore, they affect
signal transduction pathways and calcium flux. Thus,
these drugs have multiple effects on cell biology, i­ncluding
cell differentiation180.
Melanocytes and neurons share the same ontogenic
origin181. Recently, it was reported that vitiligo melanocytes
express markers that are also detected in cells from neuro­
degenerative diseases, such as Alzheimer disease54. This
finding suggests that vitiligo represents a model for degen-
erative diseases in general — knowledge about vitiligo
pathogenesis could be important for more than the skin.
In the next 10 years, we need to focus on the molecu-
lar mechanisms that lead to metabolic defects and, there-
fore, to melanocyte degeneration54,182 and autoimmunity.
Profiling the biological mediators of such processes might
identify new therapeutic targets and drugs that can stop
disease progression. Another goal is to develop drugs
that promote dermal or hair follicle stem cell differen-
tiation, and stimulate repopulation and repigmenation
of depigmented areas. More reliable ways to treat vitiligo
would greatly increase the compliance and satisfaction
of patients.

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Author contributions
Introduction (M.P.); Epidemiology (K.E., I.H., D.P.);
Mechanisms/pathophysiology (M.L.D., M.P., J.E.H.);
Diagnosis, screening and prevention (K.E., I.H., D.P., A.T.);
Management (K.E., A.T.); Quality of life (I.H., D.P., M.P.);
Outlook (M.P.); overview of Primer (M.P.).
Competing interests statement
M.P. received research grants from Giuliani, Cantabria,
Stealth Peptides, Fidia, and he was speaker for Pierre Fabre.
J.E.H. received research grants from AbbVie, Sanofi/
Genzyme, Combe, Gliknik; he was consultant for Pfizer and
B i o m e d i c a l S ys t e m ; h e wa s a s p e a ke r fo r A l ke m
Pharmauceticals. I.H. was an investigator for Clinuvel, Estee
Lauder, and Ferndale Laboratories and he received
equipment from Canfield. A.T. received research grants from
Galderma and Astellas. M.L.D. and D.P. declare no
competing interests.