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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

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

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PRIMER

Author addresses
of greater social burden19,20. The prevalence increases
with age (0.5% in children <1 year of age; 1% of 1- to
1
Cutaneous Physiopathology, San Gallicano Dermatologic Institute, IFO IRCCS, 5‑year-olds, 2.1% of 5- to 12‑year-olds)20. This finding
via Elio Chianesi 53, 00144 Rome, Italy. was confirmed in a review that reported prevalence
2
Service de Dermatologie et Dermatologie Pédiatrique, Centre de référence pour les rates of 0.06% to 2.3% in the general population and 0%
maladies rares de la peau, INSERM 1035, Université de Bordeaux, Bordeaux, France.
to 2.2% in children21. Vitiligo usually occurs in young
3
Multicultural Dermatology Center, Department of Dermatology, Henry Ford Hospital
Detroit, Michigan, USA.
people between the age of 10 years and 30 years17,18,22,23,
4
Division of Dermatology, Department of Medicine, University of Massachusetts although it can develop at any age (TABLE 1). Almost half
Medical School, Worcester, USA. of all patients present before the age of 20 years, and
5
Department of Dermatology, PGIMER, Chandigarh, India. 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-
of chemically induced depigmentation16,17. Reports ies reported 25%26–28. Segmental vitiligo tends to occur
from Mexico and Japan also indicate high incidences at a younger age25–29, before the age of 30 years in 87% of
of vitiligo17. A study, which included a large Chinese cases and before the age of 10 years in 41.3%.
population 18 and, therefore, possibly bypassed the
selection bias of hospital-based studies, confirms an Mechanisms/pathophysiology
overall prevalence of 0.6%, with lower prevalence of Vitiligo is characterized by the loss of functional melano­
the segmental form (2.5% of the total prevalence) and cytes3,30–32, and multiple mechanisms might contri­bute
higher prevalence of focal vitiligo (36%) than reported to this loss, including metabolic abnormalities, oxida-
in other studies. Differences in disease classification, tive stress, generation of inflammatory mediators, cell
lack of simple laboratory tests, varied populations and detachment and autoimmune responses. The overall
inconsistent reporting by patients could account for this contribution of each of these processes is still under
variability in epidemiological data. Moreover, discrep- debate. Our unified view considers the intrinsic defect in
ancies between prevalence and incidence data might melanocytes as the initial event. In this model, oxidative
be attributable to a higher reporting rate in countries stress in the melanocytes leads to a local inflammatory
in which the social and cultural stigma is considerable response and the activation of innate immune pro-
or the population has darker skin and, therefore, more cesses, which, in subjects with a genetic pre­disposition
prominent lesions19–23. to develop autoimmunity, generates melanocyte-specific
Most cases of non-segmental vitiligo occur sporadi- cytotoxic immune responses (FIG. 2). Several processes
cally. Between 15% and 20% of patients have one or more might be involved in the progressive loss of melanocytes
first-degree relatives with vitiligo24. Adults and children and they either involve immune attack, or cell degener­
of both sexes are equally affected, even if women seek ation and detachment. The pathogenetic mechanisms
treatment more frequently, probably as a consequence 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
Epidermis
inflammatory pathogenesis for segmental and non-
segmental vitiligo. Both are caused by a multistep pro-
Epidermal cess, which includes initial release of proinflammatory
melanocyte
cytokines and neuropetides, triggered by external or
internal injury, with a subsequent vascular dilatation
Sebaceous gland and immune response33.

Oxidative stress
The pathogenetic role of oxidative stress is supported
Bulge
(keratinocyte and
by increased levels of reactive oxygen species (ROS)
Dermis
melanocyte stem cell) in lesional and non-lesional skin both in vitro and
Hair 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
Bulb Bulb melanocyte deactivation of the nicotinamide adenine di­nucleotide
(NADH)-binding site of the enzyme, as catalase
Dermal mRNA expression is unchanged34–38. Other antioxidant
papilla enzymes, including thioredoxin reductase and thio­
redoxin, glutathione peroxidase, glutathione reductase,
Figure 1 | The hair follicle unit.  The anatomical distribution
Nature of differentiated
Reviews and
| Disease Primers
superoxide dismutases, and the repair enzymes methio-
immature melanocytes is shown. The melanocyte stem cells reside in the bulge of the nine sulf­oxide reductases A and B, are also altered in vit-
hair follicle, which is located next to the sebaceous gland, whereas differentiated iligous skin31,39–41, which indicates that ROS generation
melanocytes are located in the papilla and the epidermis. causes widespread alteration of the antioxidant system.

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PRIMER

Box 1 | Vitiligo Global Issues Consensus Conference classification


This imbalance of the pro-oxidants and antioxidant
status in vitiligo has been indicated to cause increased
Vitiligo can be classified into three main types: non-segmental, segmental and mixed sensitivity of melanocytes to external pro-oxidant
vitiligo (see the figure, silhouettes in parts a, b and c, respectively). stimuli37,43,44 and, over time, to induce a pre-senescent
Non-segmental vitiligo can have different patterns; it can occur in mostly acrofacial, status. Stress-dependent melanocyte detachment has
mucosal (at more than two sites) and generalized patterns. Generalized patterns involve
been observed at the borders of lesions48,49. This find-
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
ing possibly explains the Koebner phenomenon (that
non-segmental vitiligo. is, the induction of new lesions by minor skin trauma)
observed in patients with vitiligo49. Unlike keratinocyte–­
a b c keratinocyte adhesion, which depends on desmosomes,
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

NATURE REVIEWS | DISEASE PRIMERS VOLUME 1 | 2015 | 3

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

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PRIMER

◀ Figure 2 | The melanocyte and its environment.  a | In healthy skin, mitochondria melanocytes might be more sensitive to these changes,
produce energy efficiently, and metabolic pathways — including those of biopterin as they have a physiologically low renewal rate and are
metabolism — are modulated according to demand and are well balanced. After external selectively lost owing to stem cell exhaustion and the
stress — for example, ultraviolet (UV) radiation exposure or chemical damage — reactive continuous exposure to toxic insults75–77. In lesions,
oxygen species (ROS) are produced in a tightly regulated manner and serve as useful
apoptotic keratinocytes have been described 76,77.
intracellular messengers. Melanocytes adapt to these stresses without activating immune
Keratinocytes support melanocyte survival and melanin
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, production via growth factors, including bFGF (basic
which unbalance the steady-state equilibrium and make handling additional stressors fibroblast growth factor) and SCF (stem cell f­actor).
difficult. Elevated ROS levels, which are a hallmark of deregulation of energetic pathways, Lesional keratinocytes show apoptotic markers and
damage key enzymes and further compromise important metabolic pathways, for reduced SCF production, which might contribute to
example, in the mitochondrion. Biopterin synthesis and recycling is also affected, leading the melanocyte defects77. The dermal–epidermal net-
to further oxidative stress and cell damage. These changes, in the context of a susceptible work ensures optimal cell proliferation and differenti­
genetic background, activate a signalling cascade that starts with ROS hyperproduction, ation through direct cellular contact and the secretion
activate the unfolded protein response (which identifies and responds to the of soluble factors78–80.
accumulation of unfolded or misfolded proteins) and unmask oxidatively modified
antigens. Membrane debris and damage associated molecular patterns (DAMPs) are
Melanocyte stem cells. Oxidative stress can affect
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 melano­cyte stem cells in the hair follicle and in the der-
(TReg) cells. c | Melanocyte degeneration can also affect autophagic processes and cause mis, which might explain the higher incidence of early
the release of ATP and induce, through p53 overexpression, a senescence associated hair greying in patients with vitiligo and their relatives81.
secretory phenotype (SASP), including interleukin‑6 (IL‑6), matrix metalloproteinase 3 The maturation and function of hair follicle stem cells
(MMP3), cyclooxygenase‑2 (COX‑2), and insulin-like growth factor-binding are regulated by dermal cells, including adipocytes,
protein 3 (IGFBP3) and IGFBP7). These SASPs activate dendritc cells. CXCL10, CXC dermal papilla cells and fibroblasts, and it is conceiv-
chemokine-ligand 10; FADH2, flavin adenine dinucleotide; NADH, nicotinamide adenine able that metabolic impairment of dermal cells will
dinucleotide; 6BH4, 6 tetrahydrobiopterin; 7BH4, 7 tetrahydrobiopterin. 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
lost, cardio­lipin pattern and respiratory chain complex skin renewal81,82. A decreased number of dermal stem
expression are altered, and the mitochondrial mass cells has been reported in the dermis of non-lesional
is increased. vitiligous skin, and this seems to be also associated
In other degenerative diseases, mitochondrial dys- with inflammation.
function has been connected to cell damage61–63. A role for
the B cell lymphoma 2 (BCL‑2) protein family as modu- Immune activation
lators of cell survival, metabolism and mitochondrial Stressed melanocytes might initiate immune responses
dynamics is emerging 64–68. Downstream, cytochrome C through several mechanisms83–85. Vitiligo is associ-
participates both in electron transfer and ATP produc- ated with other autoimmune diseases, including auto­
tion, and activates caspases during apoptosis. Sirtuins immune thyroiditis and type 1 diabetes mellitus, which
are another example of the crosstalk between metabo- all involve cellular stress, innate immunity and adaptive
lism and cell fate (they can influence both metabo­lism T cell responses. The role of autoimmunity in vitiligo is
and apoptosis)63,68–71. Damaged mitochondria modulate supported by the presence of antibodies against melano-
the pathway involving SIRT1, phosphoinositide 3‑kinase cytes, the association with polymorphisms at immune
(PI3K), –AKT (protein kinase B), protein kinase A, loci, the presence of prominent T cell perilesional infil-
mammal­ian target of rapamycin (mTOR), and then trates and cytokine expression, and by the association
nuclear PPARγ co-activator 1 (PGC1α), CREB and with other autoimmune diseases86.
FOXO1, restoring normal cellular metabolic status70. As
some of the key steps linking mitochondria to cell fate Activation of innate immunity. In vitiligo, the process
are defective in vitiligo cells, this evaluation of cell is likely to begin with the activation of innate immune
m­etabolism can illuminate our understanding of vitiligo. cells that sense exogenously or endogenously induced
stress signals released from melanocytes and possibly
Keratinocytes and fibroblasts. Some of the alterations keratinocytes31,87 (FIG. 2b). Natural killer cells infiltrate
observed in melanocytes have also been described in normally pigmented skin of patients with vitiligo,
other skin cells, suggesting that vitiligo leads to general­ which suggests that these cells are early responders to
ized degeneration. Keratinocytes and fibroblasts also melanocyte stress87,88. In addition, chemically induced
exhibit oxidative stress, phosphorylation of p38, over- stress causes human melanocytes to secrete exosomes
expression of p53 and a senescent phenotype72–74. These that contain melanocyte-specific antigens and damage-
changes could be the basis for altered secretion of solu- associated molecular pattern molecules (DAMPs). These
ble growth factors supporting melanocyte survival and exosomes activate nearby dendritic cells and induce their
homeostasis. In non-lesional skin from vitiligo patients, maturation into efficient antigen-presenting cells89–91.
p53 overexpression, downstream stress signalling and Vitiligo melanocytes and chemically stressed normal
aberrant expression of p16, which regulates the cell melanocytes release inducible heat shock protein 70
cycle, have been confirmed in both melanocytes and (HSP70) (REF. 92), which alerts infiltrating dendritic
keratinocytes by immunohistochemistry 72,74. However, cells and worsens depigmentation in a mouse model

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PRIMER

Box 2 | Possible sources of ROS in the epidermis destruction of melanocytes. In a transcriptional profile
of lesional skin from vitiligo patients, the IFNγ‑induced
• Transforming growth factor-β, epidermal growth CXC chemokine-ligand 9 (CXCL9), CXCL10 and
factor and platelet-derived growth factor CXCL11 were the most highly expressed genes, whereas
• X‑rays, ultraviolet A (UVA) and UVB radiation other chemokine pathways were silent 97,99. In addi-
• Orthoquinols and paraquinols tion, the common receptor of these chemokines, CXC
• Phenols receptor type 3 (CXCR3), is expressed on melanocyte-­
• Tumour necrosis factor specific blood CD8+ T cells from patients with viti-
• Nicotinamide adenine dinucleotide phosphate
ligo and on lesion-infiltrating T cells. CXCL10 is also
(NADPH) oxidase elevated in patient serum101–104. Functional studies in
mice confirmed the crucial role of the IFNγ–CXCL10–
• Nitric oxide synthases
CXCR3 axis in both the progression and maintenance
• Monoamine oxidase A
of de­pigmentation in vitiligo97,98. Taken together, these
• Aromatic steroids, oestrogens, progesterone results support investigation of therapies that interrupt
and androgens
this pathway and that target IFNγ, the IFNγ receptor, the
• Xanthine oxidase downstream signalling proteins Janus kinase 1 (JAK1),
• Biopterin photooxidation JAK2 and signal transducer and activator of transcrip-
• Phenylalanine hydroxylase tion 1 (STAT1), and the chemokine CXCL10 and its
• Tyrosine hydroxylase receptor CXCR3 (FIG. 3).
• Electron transport chain The role, if any, that other cytokines have in depig-
mentation is unclear. Some studies have reported
ROS, reactive oxygen species.
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
of vitiligo87,89. Nitrosactive stress-driven alteration of n­umber of circulating T helper 17 (TH17) cells correlates
mitochondrial DNA triggers pro-inflammatory signals with the extent of the disease101,102. The importance of
capable of activating immune responses90. Moreover, regulatory T (TReg) cells in controlling autoimmunity in
stressed melanocytes accumulate unfolded proteins in vitiligo is based on observations made in patients102–108
the endoplasmic reticulum, which activates the unfolded and on functional experiments in mouse models104.
protein response (UPR) through three pathways: s­erine/ TReg cell-mediated suppression of human melanocyte-­
threonine-­protein kinase/endoribonuclease IRE1, specific CD8+ T cells in vitro causes decreased prolifera-
eukaryotic translation initiation factor 2‑alpha kinase 3 tion, cytokine production and T cell receptor affinity,
(EIF2AK3), and cAMP-dependent transcription factor and increased susceptibility to apoptosis, expression of
ATF6α. This homeostatic response mitigates damage cell surface markers CC-chemokine receptor 7 (CCR7)
and promotes cell survival; however, during prolonged and cytotoxic T‑lymphocyte antigen 4 (CTLA4) of the
stress, the cells still die or release immunostimulatory CD8+ T cells105. However, this pheno­type is only induced
signals that disrupt immune tolerance91,92. in melanocyte-specific CD8+ T cells from healthy sub-
jects, but not in those from patients with vitiligo, which
Adaptive immunity. Melanocyte-specific, cytotoxic suggests that TReg cells are indeed important in control-
CD8+ T  cells have been strongly implicated in the ling the development of autoimmunity, and that their
destruction of melanocytes. Patients with vitiligo have function might be abnormal in patients with vitiligo106,107.
higher numbers of cytotoxic CD8+ T cells in the blood Indeed, in vitiligo, TReg cells are decreased or function-
compared with healthy controls; these numbers corre- ally defective, and they show deficient skin homing
late with disease activity, and isolated CD8+ T cells from and low expression of transforming growth factor‑β and
vitiligo patients can identify and kill normal human CC-chemokine ligand 21 (CCL21) (REF. 106). Consensus
melanocytes in vitro92–94. Furthermore, high numbers of on changes and dysfunction of TReg cells in vitiligo has
CD8+ T cells are found in lesions and these cells are both not yet been established108–112.
necessary and sufficient to kill melanocytes94. Infiltrating
T cells isolated from biopsies of vitiligo lesions show an Melanocyte death. The exact mechanism responsible for
enrichment of cells that recognize melanocyte antigens, the death of melanocytes in lesions is controversial113.
and when these cells were reintroduced in non-lesional, Apoptotic mechanisms have been suggested, including
normally pigmented skin from the same patient, they over-expression of ribonuclease T2, which facilitates
migrated to the melanocytes and induced apoptosis95,96. the pro-apototic activity of TNF receptor-associated
CD8‑depleted T  cells were unable to kill melano­ factor 2114, deregulated expression of SIRT1 (REF. 115),
cytes, whereas CD8‑purified populations were even increased release of inducible HSP70116, and apopto-
more potent 96. sis induced by perilesional CD8+ T cells117. However,
CD8 + T  cells from cutaneous lesions produce most of these studies rely on in vitro data — clear evi-
interferon-γ (IFNγ) and tumour necrosis factor (TNF), dence of apoptosis in vivo is still lacking. An alterna-
among other cytokines97–100. IFNγ is also expressed in tive hypothesis is that decreased expression of adhesion
lesions97, which suggests that this cytokine is impor- molecules and oxidative stress lead to melanocytorrhagy
tant in driving autoreactive T cell responses and the (d­etachment and loss of melanocytes)49,50,118,119.

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PRIMER

CXCR3* treatment develop vitiligo as a consequence57. Vitiligo


JAK1/2* and melanoma share CD8+ T cell antigens, an observa-
IFNγ* IFNγ tion that has contributed to the development of new,
receptor*
STAT1* CXCL9 CD8+ innovative therapies for melanoma58. Finally, allelic vari-
CXCL10* T cell
ants associated with vitiligo directly confer protection
Skin from melanoma, and vice versa124,125. This shows that
cell immune responses in vitiligo and melanoma are simi-
lar and target similar antigens, and suggests that auto­
Figure 3 | Treatment target in interferon signalling.  Interferon-γ (IFNγ) is expressed in
Nature Reviews | Disease Primers immunity in vitiligo develops owing to failed restriction
vitiligous lesions. It drives autoreactive T cell responses and the destruction of
of inherent mechanisms intended to control melanocyte
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 proliferation. The importance of immune mechanisms
confirmed the important role of the IFNγ–CXCL10–CXCR3 (CXC receptor type 3) axis in is further supported by the association of vitiligo with
both the progression and maintenance of depigmentation. These studies open the halo naevus, which is a mole surrounded by a depig-
search for targeted therapies (potential targets indicated by asterisks) that interrupt this mented halo-like area accompanied by a dense immune
pathway, including IFNγ, the IFNγ receptor (IFNγR), IFNγ pathway signalling proteins cell i­nfiltrate in histology 126.
Janus kinase 1 (JAK1) and JAK2 (JAK1/2), signal transducer and activator of transcription 1 Overall, experimental data support intrinsic damage
(STAT1), CXCL10 and CXCR3. and a close link between oxidative stress and immune
responses. For example, histological analysis of develop­
Genetic background ing lesions shows expression of NALP1 (NACHT, LRR
A genetic background for vitiligo development has and PYD domains-containing protein 1), IL‑1 and
been shown in multiple studies (see below); however, catalase127; moreover, the expression levels of haem oxy­
the genetic risk is not absolute. Monozygotic twins, genase 1 in plasma has been linked to the activity phase
for example, only have a 23% concordance of disease; of the disease and to IL‑2 levels128,129. All of these factors
similar percentages have been reported for other auto­ are involved both in stress responses and in triggering
immune diseases such as lupus erythematosus and of innate immunity. In summary, genetic, experimental
type 1 diabetes mellitus, but it is lower than the risk and clinical studies have revealed important pathways
for psori­asis and atopic dermatitis noted in twins120. in the pathogenesis of vitiligo and have identified targets
Additional stochastic or environmental factors influence for the development of new therapies.
vitiligo pathogenesis and influence the penetrance of the
genetic p­redisposition to vitiligo. Diagnosis, screening and prevention
Genetic studies support immune mechanisms as the Risk factors
process underlying vitiligo. Mutations in genes involved There is a clear genetic risk for the development of viti-
in both innate and adaptive immunity increase the risk ligo, either in isolation or in combination with immune-
for vitiligo120 (TABLE 2). However, polymorphisms in non- related inflammatory polyendocrine disorders, which
immune genes have also been identified as risk factors, can present with thyroidal autoimmunity, type 1 dia­betes
including in the melanocyte-specific genes TYR (the mellitus and autoimmune gastric atrophy 130. Familial
gene encoding tyrosinase) and the MC1R (the gene cases occur in a non-Mendelian pattern that suggests
encoding melanocortin 1 receptor)120. Both are T cell complex inheritance131,132. The risk of developing vitiligo
antigens and participate in melanin production; thus, for a patient’s first-degree relatives is increased tenfold
mutations of these genes might contribute cellular stress2. compared to unrelated individuals from the general
Recently, polymorphic expression of MTHFR (the gene popu­lation with the same ethnic background; more-­
encoding methylene tetrahydrofolate reductase, which distant relatives have lower risks120,131. Familial cases
regulates homocysteine levels), has been described in of vitiligo tend to occur at a younger age than sporadic
patients with vitiligo121. This finding is in agreement with cases, which further supports the importance of genetic
the elevated plasma level of homocysteine in patients risks for vitiligo131. Many different risk factors such as
with vitiligo. The high susceptibility of homocysteine ultraviolet (UV) radiation exposure, repeated mechani-
to oxidative stress can contribute to the melanocyte cal or thermal stress133, and exposure to chemicals
d­amage in vitiligo121. XBP1P1 (the gene encoding X‑box (e­specially phenols or catechols)134 have been p­roposed
binding protein 1) is also a disease-associated gene122. for vitiligo, but epidemiologic data remain limited.
It has a central role in mitigating the unfolded protein Some of the gene variants that are associated with
response, and might also drive stress-induced inflamma- an increased vitiligo risk also predispose to other com-
tion in vivo120. Several single-nucleotide polymorphisms mon autoimmune disorders. Many of the vitiligo risk
have been reported in the catalase gene (CAT), which genes120 (TABLE 2) govern immune and inflammatory
might impair the enzyme function34,38,123. pathways, and a few correspond to pigment cell anti-
gens (see above). Among associated immune-related
Summary inflammatory disorders, thyroid pathologies predomi-
Interestingly, the risk for vitiligo is inversely correlated nate (Graves disease and Hashimoto thyroiditis), but
with the risk for melanoma — patients with vitiligo are alopecia areata, type 1 diabetes mellitus, psoriasis and
relatively protected from developing melanoma57,58,123, atopic dermatitis are also commonly encountered135,136
and a subset of patients with melanoma who experi- in the vitiligo clinic. Other conditions such as pernicious
ence spontaneous remission or successful response to anaemia, lupus erythematosus, or Addison disease are

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

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PRIMER

a b 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–
Figure 4 | Typical presentation of vitiligo.  a | Non-segmental
Nature Reviews Disease Primers
vitiligo is| characterized Harada syndrome, which sometimes presents with
by symmetrical bilateral white patches with an acrofacial pattern or involving the entire skin depigmentation5–9,141.
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
Prevention
segmental pattern early in disease development. With time, it evolves into There is no primary prevention for vitiligo. Heritability
non-segmental vitiligo with bilateral lesions. explains a minor part of disease development, and
environ­mental triggers are not sufficiently known to
w­arrant or enable primary prevention. Secondary pre-
Wood’s (UV) lamp examination helps to b­etter vention, for example through avoidance of skin stress to
detect focal melanocyte loss and the intensity of hypo­ limit the Koebner phenomenon133,134,142,143, is frequently
pigmentation, particularly in tanned areas of fair-skinned advocated. However, accumulating evidence indicates
individuals (such as the face) or in low-pigmented areas that mild inflammation at the border of depigmented
in darker-skinned individuals (such as the palms). patches is associated with disease progression, and that
Furthermore, vitiligous skin has a milky fluorescent aspect the Koebner phenomenon is closely associated with this
under Wood’s lamp light, which is not observed in other inflammatory stage. The Koebner phenomenon either
acquired hypomelanoses. This feature might corres­pond initiates inflammation133 or reflects enhanced melanocyte
to the local accumulation of pterins31. A biopsy or other loss caused by mechanical pressure and friction during
tests are not necessary except to exclude other disorders138. the inflammatory progressive or acceleration phase of the
Non-segmental vitiligo has to be differentiated from other disease133. The effectiveness of limiting mechanical stress
diseases of decreased pigmentation (FIG. 5), most impor- in isolation is difficult to measure because concurrent
tantly from melanoma, which, as discussed above, can interventions are often used, including oral mini-pulses of
induce depigmentation. In segmental vitiligo, only one corticosteroids, phototherapies or combined approaches,
area is involved in most patients, but occasionally two or which are aimed at halting inflammation and disease pro-
more segments with ipsi- or contralateral distribution are gression133. The strength of the Koebner phenomenon can
affected139. Naevus depigmentosus (also known as hypo- be quantified with a simple validated score, K‑VSCOR144,
chromic naevus) is a common differential diagnosis of and patients with high scores should be firmly advised to
segmental vitiligo, but naevi usually contain a normal or avoid mechanical stress.
subnormal number of melanocytes with reduced melanin
levels. Segmental or hemi­corporeal hypomelanosis of Ito Management
is rarely mi­sdiagnosed as vitiligo3 (FIG. 5b). The management of a patient with vitiligo requires time
for a careful initial assessment, which includes evaluating
Histopathology the patient’s history and risk factors, a clinical examina-
A skin biopsy can be indicated to exclude other dis- tion and scoring (including photography). The whole skin
eases (see above). Furthermore, the presence of mild should be examined under natural light and UV lamp.
dermal or epidermal–dermal mononuclear infiltrates The Vitiligo European Task form12 can be used to record
at the m­argin of active vitiligo lesions with ongoing loss the personal and familial history of vitiligo and other auto-
of melanocytes can have important consequences for immune diseases, and clinical examination items, such as
management decisions. Such a biopsy finding indicates the skin phototype, disease duration, Koebner phenom-
active disease and warrants more aggressive therapy enon, and extent and activity of lesions. The first assess-
using re­inforced local or systemic agents (see below). ment will serve as a basis for treatment decisions and for

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PRIMER

a b c Once the patient has been assessed, a personalized


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
d e 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
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 controlled trials included in the review had a limited
lung and kidney diseases. b | Ito hypomelanosis is characterized by hypopigmentation n­umber of participants and no definite clinical recom-
along Blaschko lines (lines that represent the growth patterns of normal skin mendations for the treatment of vitiligo could be made149.
development). c | Pytiriasis alba is characterized by hypomelanotic, not amelanotic, The Vitiligo subcommittee of the European Dermatology
desquamated patches with feathered edges. d | Pytiriasis versicolor is caused by Forum has reported a new guideline for the management
Malassezia spp. infection and characterized by irregular hypopigmented patches in and treatment of vitiligo in which treatments, includ-
dark-skinned subjects. It involves mainly chest, arms, face and neck, and is sometimes ing both medical and surgical therapies, were graded
associated with itching. e | Piebaldism is present at birth but, in individuals with low from first- to fourth-line options150. These guidelines
phototypes, becomes visible only after sun exposure. It is characterized by a white
discussed the efficacy and tolerability of the follow­ing
forelock and ventral depigmentation.
therapies: topical treatments (corticosteroids and calci­
neurin inhibitors), phototherapies (narrowband UVB
follow‑up care after treatment initiation. Identification of light, excimer lamp and laser, and photochemo­therapies),
the type of disease guides management. Patients with any combination treatments, and oral systemic steroids and
type of vitiligo should be offered psychological support other immunosuppressive agents. Patients with dark skin
and counselling 145 because of the impact of the disease on frequently prefer PUVA, because it is particularly effec-
the quality of life. tive in these patients. The high effectiveness might be
due to the higher UVA dose that can be administered to
Non-segmental vitiligo these patients compared with light-skinned individuals151.
In non-segmental vitiligo, after a period of stability, an A detailed algorithm that summarizes the therapeutic
acceleration phase with rapid disease progression over a modalities and suggests a stepwise approach is shown in
few weeks can occur. This requires urgent intervention FIG. 6. Recently, afamelanotide, a potent α‑melanocyte
with systemic oral mini-pulse steroids145, a treatment stimulating hormone (α‑MSH) analogue, has been shown
that consists of corticosteroid administration only twice to be synergistic with narrowband UVB in promoting
a week. Mini-pulse steroid therapy is easy to administer repigmentation152,153. This opens new treatment perspec-
compared to traditional steroid therapy or other immuno­ tives that not only focus immune-modulating drugs but
suppressive treatment, owing to the ‘pulse’ modality. As also target melanocyte differentiation and proliferation.
patients have to take tablets only twice a week, adher- Previously, topical immune modulators (TIMs), and UVB
ence is high and adverse effects are low. In this context, light and excimer laser were shown to act on melanocyte
the Koebner phenomenon should be avoided as much as precursors in hair follicles and the dermis in vitro153.
possible. Other than the need for frequent thyroid checks
(discussed above), the possible association of vitiligo with Segmental vitiligo
other immune-mediated inflammatory diseases is u­sually The risk of other autoimmune disease, including auto­
of limited practical consequence, but the existence of immune thyroditis, is not increased in patients with
speci­fic organ symptoms or a family history of other auto- segmental vitiligo154. Segmental vitiligo usually shows
immune disorders should prompt adequate i­nvestigations early involvement of the follicular reservoir of melano-
and specialist advice139,146. cyte precursors and hair whitening. The treatment of

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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) • Topical treatment • Topical treatment corticosteroid
Targeted UVB (corticosteroid or TIM) (corticosteroid or TIM) (3–6 months)
Combination (topical • Phototherapy NB-UVB • Phototherapy NB-UVB
treatment and targeted UVB) or PUVA (for dark skins) or PUVA (for dark skins)
Surgical treatment Immunosuppressive agents? 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- Tissue grafts. Tissue grafts use unprocessed pigmented
vention. At an early stage, best within the first 6 months, epidermis and dermis, which are transplanted to depig-
treatment with potent topical corticosteroids or TIMs mented areas. Only limited areas and selected body
combined with light therapy, such as narrowband UVB regions can be treated owing to the limited amount of
light or targeted excimer lamp or laser, can be proposed. healthy tissue that can be taken. The recipient area does
If the lesion is still in the active phase, oral steroid mini- not need extensive preparation. Donor tissue is collected
pulse therapy is also possible. By contrast, at a later stage as thin or ultra-thin split-thickness grafts (in contrast
of the disease or when previous therapies fail, surgery can to full-thickness grafts that use the whole skin), from
be considered (see below). epidermal suction blisters and as hair follicle or mini
punch grafts156–160.
Surgical management of vitiligo
Surgical methods, including tissue grafts and cellular Cellular transplants. In contrast to tissue grafts, cel-
transplants, are emerging as an important solution for lular transplants involve more-complex processing of
stable vitiligo that is refractory to conventional treat- the grafts before surgery; sometimes the isolated cells
ment 154–157. The outcome of surgical therapy depends are also cultured. Either epidermal mixed cells or pure
on patient selection, mainly regarding disease stability. melano­cytes are used. Isolated epidermal cells can be
Ideally, patients should not have new lesions or growth used with or without in vitro expansion161,162. The pro-
of the existing lesions for 1 year. However, overall stability duction of cultured melanocytes requires extensive
can be difficult to assess and sometimes it is helpful only manipulation and adequate laboratory equipment and
to consider the stability of the actual lesion, for which expertise. Moreover, it is a time-consuming procedure
surgical intervention is planned. Non-segmental vitiligo with two surgical sessions per patient and cannot be
in particular is a dynamic process and some patients have used for large areas owing to the low in vitro replica-
active and stable lesions at the same time. Thus, a surgi- tion rate of melanocytes161. Non-cultured epidermal cell
cal approach can be applied to selected stable areas in suspensions might be preferred to pure m­elanocytes,
patients with generalized involvement. A test graft can because they include undifferentiated melano-
be carried out to assess stability, but this is not a reliable cytes, which are able to continue the differenti­ation, as
method. Each patient should be assessed individually, well as keratinocytes that produce specific melano­cyte
including a careful analysis of compliance and expecta- growth f­actors79,82. Furthermore, non-cultured epi­
tions. Different surgical approaches should be considered dermal cell transplants can be used for large areas and
from tissue grafts to the more-recent c­ellular transplants. p­rovide a good colour match.

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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.

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PRIMER

to melanocyte disappearance. Cellular, molecular and


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

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PRIMER

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