VitiligoFocusonClinicalAspectsImmunopathogenesisandTherapy

Clinic Rev Allerg Immunol (2018) 54:52–67
DOI 10.1007/s12016-017-8622-7
Vitiligo: Focus on Clinical Aspects,
Immunopathogenesis, and Therapy
Katia Boniface 1 & Julien Seneschal 1,2 & Mauro Picardo 3 & Alain Taïeb 1,2,4
Published online: 6 July 2017
# Springer Science+Business Media, LLC 2017
Abstract Vitiligo is an acquired chronic depigmenting disorder
of the skin, with an estimated prevalence of 0.5% of the general
population, characterized by the development of white macules
resulting from a loss of epidermal melanocytes. The nomenclature has been revised after an extensive international work within
the vitiligo global issues consensus conference, and vitiligo (formerly non-segmental vitiligo) is now a consensus umbrella term
for all forms of generalized vitiligo. Two other subsets of vitiligo
are segmental vitiligo and unclassified/undetermined vitiligo,
which corresponds to focal disease and rare variants. A series
of hypopigmented disorders may masquerade as vitiligo, and
some of them need to be ruled out by specific procedures including a skin biopsy. Multiple mechanisms are involved in melanocyte disappearance, namely genetic predisposition, environmental triggers, metabolic abnormalities, impaired renewal, and altered inflammatory and immune responses. The auto-immune/
inflammatory theory is the leading hypothesis because (1) vitiligo is often associated with autoimmune diseases; (2) most vitiligo susceptibility loci identified through genome-wide association studies encode immunomodulatory proteins; and (3)
Katia Boniface and Julien Seneschal equally contributed to this work.
* Alain Taïeb
[email protected]
1
INSERM U1035, ATIP-AVENIR, Université de Bordeaux,
Bordeaux, France
2
Department of Dermatology and Paediatric Dermatology, National
Centre for Rare Skin disorders, Saint-André and Pellegrin Hospital,
Bordeaux, France
3
San Gallicano Institute, Rome, Italy
4
Department of Dermatology and Pediatric Dermatology, St André
Hospital, Bordeaux University Hospitals, 1 Rue Jean Burguet,
33075 Bordeaux, France
prominent immune cell infiltrates are found in the perilesional
margin of actively depigmenting skin. However, other studies
support melanocyte intrinsic abnormalities with poor adaptation
of melanocytes to stressors leading to melanocyte instability in
the basal layer, and release of danger signals important for the
activation of the immune system. Recent progress in the understanding of immune pathomechanisms opens interesting perspectives for innovative treatment strategies. The proof of concept in humans of targeting of the IFNγ /Th1 pathway is much
awaited. The interplay between oxidative stress and altered immune responses suggests that additional strategies aiming at limiting type I interferon activation pathway as background stabilizing therapies could be an interesting approach in vitiligo. This
review covers classification and clinical aspects, pathophysiology with emphasis on immunopathogenesis, and promising therapeutic approaches.
Keywords Vitiligo . Review . Pathophysiology .
Immunopathology . Therapy
Abbreviations
CRT
Calreticulin
CTL
Cytotoxic T cells
ER
Endoplasmic reticulum
HSP
Heat shock protein
IFN
Interferon
IL
Interleukin
NK
Natural killer
pDCs
Plasmacytoid dendritic cells
PRR
Pathogen recognition receptors
ROS
Reactive oxygen species
SV
Segmental vitiligo
TLR
Toll-like receptors
Clinic Rev Allerg Immunol (2018) 54:52–67
TNF
Tregs
UPR
VGICC
VETF
Tumour necrosis factor
Regulatory T cells
Unfolded protein response
Vitiligo Global Issues Consensus Conference
Vitiligo European task force
Introduction
Vitiligo is the most common skin depigmenting disorder
resulting from a selective loss of epidermal melanocytes, and
affects around 0.5% of the world population [1, 2]. Both sexes
are equally affected, and there are no apparent differences in
rates of occurrence according to phototype or race. Twentyfive percent of cases are children with disease onset before the
age of 10, the age of onset in paediatric series varies from 4 to
8 years. Very early onset, as young as 3 months, is acknowledged. The existence of true ‘congenital vitiligo’ remains controversial. In fair-skinned individuals, vitiligo patches are usually detected only after the first exposure of the skin to sunlight, following the first summer of life. The percentage of
segmental vitiligo (SV) is higher in children compared to
adults, whatever the ethnic background, suggesting a mosaic
skin developmental predisposition [1]. The prevalence of SV
in childhood varies from 4.6 to 32.5% in published reports [3].
Vitiligo is a complex disease, associating genetic and environmental factors together with metabolic and immune alterations. Abnormalities leading to impaired melanocyte regeneration and/or proliferation suggest a primary defect of melanocytes [4]. However, a major role of silent inflammation and
autoimmunity is demonstrable, in particular during the progressive phase of the disease [5–10]. Since neither immune
nor non-immune mechanisms in isolation can sufficiently explain all parts of this complex disease, a convergence of combined biochemical, environmental, and immunological factors
in genetically predisposed patients has been proposed as a
unifying background to the pathophysiology of vitiligo [11].
This review summarizes classification, clinical aspects, and
current as well as promising novel therapeutic approaches.
The role of the immune response in vitiligo pathogenesis is
particularly emphasized because of its therapeutic implications in relation to current drug development.
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increasing in size progressively or during flares with time,
corresponding histologically to a substantial loss of functioning epidermal pigment cells and, usually in a second time, of
hair follicle melanocytes. Two other subsets of vitiligo are SV,
and unclassified/undetermined vitiligo, which corresponds to
focal disease and rare variants. A series of hypopigmented
disorders may masquerade as vitiligo, and some of them need
to be ruled out by specific procedures including a skin biopsy
[1, 2].
Clinical Aspects
Vitiligo Subsets
Generalized Common Vitiligo
This most common form of vitiligo (Fig. 1a) is characterized
by milky-white macules involving multiple parts of the body,
most often in a symmetrical pattern. Skin hypopigmentation is
usually asymptomatic, but a minority of patients mention preceding mild pruritus. The disease can start at any site of the
body, but the fingers, hands, and face are frequently the initial
sites. Clinical markers of progression are important to detect
such as pinpoint depigmentation and fuzzy limits of white
macules (Fig. 1b). Obtaining a validated comprehensive list
of validated clinical markers of progression is currently an
international goal, because history-based scores such as
VIDA [13] are considered as grossly inaccurate.
Depigmentation of scars (Fig. 1c) is a common manifestation
of the Koebner’s phenomenon (mechanical induction of the
disease, also by friction or chronic pressure by clothing or
daily activities). Koebner’s phenomenon is usually contemporary of disease flares [14]. Stable lesions are well demarcated
(Fig. 1d).
Mixed vitiligo is a recently described, mostly paediatric
subtype, with segmental involvement preceding typical generalized vitiligo [15], now included as a subset of vitiligo in
the VGICC classification. The presence of leukotrichia and
halo nevi have been noted as predictors of passage to mixed
vitiligo in patients with SV. Mixed vitiligo may exist in adults
but is probably frequently masked by widespread bilateral
lesions.
Classification
Acrofacial Vitiligo
The nomenclature has been revised after an extensive international work within the Vitiligo Global Issues Consensus
Conference (VGICC) [12]. Vitiligo is now a consensus umbrella term for all forms of generalized vitiligo (formerly designated in the international nomenclature as non-segmental
vitiligo) defined as an acquired chronic pigmentation disorder
characterized by white patches, most often symmetrical,
In acrofacial vitiligo, the involved sites are usually limited to
face, head, hands, and feet. A distinctive feature is depigmentation of the distal fingers and facial orifices. It may later
include other body sites, resulting in typical generalized vitiligo. Acrofacial vitiligo was shown to be more frequent in
adult onset cases of vitiligo in a large series studies using latent
class analysis [16].
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Clinic Rev Allerg Immunol (2018) 54:52–67
Fig. 1 Clinical features of vitiligo. a Vitiligo/non-segmental vitiligo. b
Confetti lesions and fuzzy borders in rapidly progressive vitiligo. c
Koebner’s phenomenon on abdominal surgical scars, in a case of progressive vitiligo. d Stable vitiligo with well-demarcated macules. e Extensive
vitiligo progressing towards universal vitiligo. f Segmental vitiligo, large
blaschkolinear pattern. g Segmental vitiligo, checkerboard pattern, with
evidence of follicular repigmentation after phototherapy. h Vitiligo
‘ponctué’/leucoderma punctate. i Hypochromic vitiligo (Courtesy Dr.
Silvia Moretti, Florence). j Follicular vitiligo
Vitiligo Universalis
Segmental Vitiligo
Vitiligo universalis (Fig. 1e) is a rare presentation of vitiligo. It
is the most extensive form of the disease and generally occurs
in adulthood. ‘Universalis’ is generally used when depigmentation is virtually universal (80–90% of body surface), but
some pigmentation may be still present, and hairs partially
spared. Whereas this diagnosis is easy in dark-skinned individuals, it may be more challenging in fair-skinned
individuals.
Mono-segmental vitiligo is the most common form of SV,
referring to the presence of one or more white depigmented
macules distributed on one side of the body, usually respecting
the midline (although some lesions may partly cross the midline), early follicular involvement (leukotrichia), and rapid
development over a few weeks or months, and overall
protracted course, but secondary extension remains possible
in a given segment sometimes years after. The shape of SV
Clinic Rev Allerg Immunol (2018) 54:52–67
lesions may recapitulate some developmental patterns such as
large band Blaschko lines (Fig. 1f). The long held neural theory based on possible dermatomal distribution is challenged
by many exceptions. The aetiology of the SV pattern remains
overall elusive. Rarely, multiple segmental lesions occur simultaneously or not distributed either unilaterally or bilaterally. A clear segmental distribution of the lesions with midline
demarcation, together with the associated features described
in mono-segmental cases (leukotrichia, protracted course),
distinguishes this diagnosis versus vitiligo in bilateral cases.
As in vitiligo, repigmentation may occur, usually under combined therapy (see below), according to a marginal, follicular,
or mixed pattern (Fig. 1g).
Unclassified and Rare Variants
The VGICC classification suggests that focal cutaneous or
mucosal vitiligo (defined as small isolated patch that does
not fit a segmental distribution, and which has not evolved
into vitiligo after a period of at least 2 years) should be until
better consensus on nature and course left within the category
undetermined⁄unclassified vitiligo. Some rare variants are
discussed below.
Vitiligo ponctué/punctata
Lesions present as sharply demarcated depigmented
punctiform 1- to 1.5-mm macules involving any area of the
body (Fig. 1h), and has to be distinguished histopathologically
from guttate hypomelanosis, a common condition with no loss
of melanocytes situated on chronically sun exposed sites such
as the legs and forearms.
Vitiligo Minor/Hypochromic Vitiligo
This disease seems to affect only dark-skinned individuals
(Fig. 1i). ‘Minor’ refers to a partial defect in pigmentation.
The relation to true vitiligo comes from pathology and coexistence with more typical vitiligo macules. Cutaneous T cell
lymphoma needs to be ruled out by repeated biopsies with
molecular studies of clonality, and this diagnosis cannot be
made without a long-term follow-up [17].
Follicular Vitiligo
This designation refers to a form recently described in a young
black patient of generalized vitiligo that primarily involved
the pigment cell follicular reservoir with limited skin involvement, contrasting with marked generalized hair whitening [18]
(Fig. 1j). As noted later in a small series of patients, contrary to
what occurs in common vitiligo, cutaneous depigmentation
follows hair depigmentation which is situated not only in
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vitiliginous areas but also in areas with clinically normalappearing skin [19].
Immunopathogenesis of Vitiligo
Intrinsic Abnormalities of Melanocytes and Keratinocytes
Several in vitro and in vivo studies have revealed an altered
redox status, with the presence of oxidative stress in cultured
melanocytes coupled with an increased susceptibility to prooxidant agents [20, 21]. Elevated levels of reactive oxygen
species (ROS) have been observed in lesional and nonlesional skin of vitiligo. The increased ROS production by
melanocytes could result from an external stress, such as ultraviolet (UV) radiation exposure or chemical damage
(monobenzone or other phenols). A wide range of metabolic
pathways leads to the uncontrolled generation of ROS, and
several lines of evidence suggest that mitochondria could be
the main source of ROS in vitiligo [22, 23]. ROS can also
create a pro-inflammatory environment that will contribute
to the activation of the immune system [24]. Moreover, vitiligo melanocytes, probably as a consequence of increased intracellular oxidative stress, present abnormalities of signal
transduction pathways compatible with a condition of stressinduced premature senescence-like phenotype. This is characterized by the production of many proteins among the
senescence-associated secretory phenotypes, including the
production of pro-inflammatory cytokines as interleukin
(IL)-6, matrix metalloproteinase 3 (MMP3), cyclooxygenase-2, insulin-like growth factor-binding protein 3 (IGFB3),
and IGFBP7 [25]. In addition, recent observations showed
that melanocyte exposure to chemical agents (4-TBP—4-tertiary butyl phenol—and MBEH—monobenzyl ether of hydroquinone) known to trigger vitiligo induces the disruption
of the folding machinery of the endoplasmic reticulum (ER),
leading to the accumulation of immature proteins and
resulting in the activation of the unfolded protein response
(UPR) [26]. UPR activation results in transient attenuation
of protein synthesis, increased capacity for protein trafficking
through the ER, protein folding transport, and increased protein degradative pathways, including ER-associated degradation (ERAD) and autophagy. If these adaptive mechanisms
cannot resolve the protein-folding defect, as in vitiligo, cells
enter apoptosis. The UPR comprises three parallel signalling
branches: PRKR-like ER kinase (PERK)-eukaryotic translation initiation factor 2α (eiF2α) pathway, activating transcription factor 6α (ATF6α), and the inositol-requiring enzyme-1
(IRE1)–X-box-binding protein 1 (XBP1). Genome-wide linkage analysis followed by a sequencing study in a Chinese
population with vitiligo identified XBP1 as a candidate gene
for vitiligo predisposition, which was then confirmed in a
vitiligo Caucasian cohort [27–29]. More recently, He et al.
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Clinic Rev Allerg Immunol (2018) 54:52–67
demonstrated that vitiligo melanocytes are more sensitive to
oxidative stress and autophagy, through the impairment of the
nuclear factor E2-related factor 2 (Nrf2) protein, a critical
transcription factor protecting cells from oxidative stress
[30] (Fig. 2). It is also important to note that Nrf2 is involved
in the UPR activation and acts as a direct PERK substrate.
Fig. 2 Immunopathogenesis of vitiligo. In a predisposed patient,
melanocytes present abnormalities that will lead to the release of
DAMPs and inflammatory cytokines that will contribute to activation of
the innate immune response and subsequently to adaptive T cell
responses, through activation of TRM cells that reside in the skin and
recruitment of TEM expressing CXCR3 and/or CCR6. These T cell subsets will produce soluble factors (in particular TNFα and IFNγ) involved
in melanocyte loss and development of white patches
Clinic Rev Allerg Immunol (2018) 54:52–67
Therefore, stress melanocytes can release pro-inflammatory
cytokines but also chemokines important for the recruitment
of immune cells, such as CXCL12 or CCL5 [31].
Intrinsic abnormalities of melanocytes are also associated
with decreased expression of adhesion molecules on melanocytes, such as E-cadherin. We have recently demonstrated that
vitiligo melanocytes in normal-appearing skin of vitiligo patients have impaired expression of E-cadherin, inducing their
detachment from the basal layer of the epidermis under stress
conditions [32].
Nonetheless, several lines of evidence suggest that melanocyte is not the only epidermal cell involved in the induction
of the immune response in vitiligo. Recent studies highlighted
that vitiligo keratinocytes could also be an important actor
through the release of chemokine ligands important for the
recruitment of T cells. Under oxidative stress, UPR activation
in keratinocytes induced the production of CXCL16 by stress
keratinocytes, leading to the recruitment of CXCR6+ CD8 T
cells [33]. CXCL12 and CCL5 are additional chemokines that
are likely involved in T cell homing to the skin in vitiligo [31].
Activation of the Innate Immune Response
Through Damage-Associated Molecular Patterns
(DAMPS) and Other Pro-Inflammatory Signals
Increased oxidative stress, impairment of the UPR activation,
or pathways leading to cell death in both melanocytes and
keratinocytes can induce production of pro-inflammatory cytokines and activation of signals important for the activation of
the immune system in vitiligo. Indeed, activation of the innate
immune system through the activation of pathogen recognition receptors (PRRs) [34] is an important mechanism in host
defence against pathogens but could be impaired under some
circumstances and could induce autoimmunity in a genetically
predisposed patient. These receptors are originally specialized
in the detection of pathogens through pathogen-associated
molecular patterns (PAMPs). Host-derived self-DNA and/or
self-RNA from damaged cells recognized by these nucleic
acid receptors could lead to skin inflammation such as that
found in vitiligo. The view of the machinery of nucleic acid
recognition became more complex with the recent identification of several new nucleic acid receptors [35]. Nucleic acid
receptors are commonly divided in two subgroups based on
their endosomal or cytosolic distribution. In the endosomes,
these receptors include Toll-like receptors (TLR) including
TLR3, TLR7, TLR8, and TLR9. In the cytosol, nucleic acid
receptors embrace the retinoic acid-inducible gene I (RIG-I)like receptors, the cytosolic DNA sensors and receptors are
involved in inflammasome formation. In endosomes, TLR9
senses the presence of CpG-containing DNA whereas TLR7
and TLR8 recognize single-strand (ss) RNA, and TLR3 recognizes double-strand (ds) RNA, leading to the transcription
of pro-inflammatory cytokines like tumour necrosis factor
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(TNF)-α, IL-6, or type I interferon (IFN) α/β [36–38].
Cytosolic receptors like the gamma-IFN-inducible protein
IFI16 and the IFN-inducible protein AIM2 (absent in
melanoma-2) sense dsDNA and recruit the adaptor protein
ASC (apoptosis-associated speck-like protein containing
CARD) to form an inflammasome complex that activates caspase 1, leading to the processing and release of IL-1β and IL18 [39, 40]. Several inflammasomes have been described and
are defined by the NOD-like receptor proteins that they contain: the NLRP1 (NALP1) inflammasome, the LRP3
(NALP3) inflammasome, and the IPAF (NLRC4)
inflammasome [41]. Our group has previously reported an
increased expression of NLRP1 and IL-1β in perilesional skin
of vitiligo that was associated with disease progression [42]
(Fig. 2).
More recently, a major focus of interest has been the stimulator of interferon gene (STING), which is a transmembrane
protein of the endoplasmic reticulum, which upon activation
induces type I IFN production [43]. Several DNA sensors that
include IFI16, the DNA-dependent activator of IFNregulatory factors (DAI), and cyclic GMP-AMP synthase
(cGAS) can activate the STING pathway. Beyond the recognition of dsDNA, dsRNA are also recognized by other cytosolic recognition receptors such as RIG-like receptors (RLRs)
which belong to a superfamily including RIG-I, melanoma
differentiation-associated protein 5 (MDA-5) also called
IFIH1, and laboratory of genetics and physiology 2 (LGP2).
These sensors, upon recognition of RNA, induce activation of
the nuclear factor κB (NF-κB) pathway, leading to the production of pro-inflammatory cytokines [44].
As already suggested, in a genetically predisposed patient,
a self-molecular pattern released during sterile inflammation
in damaged cells can lead to the release of pro-inflammatory
cytokines and induce skin inflammation as shown in vitiligo
[45, 46]. Again, recent genome-wide association studies
(GWAS) have revealed multiple genetic risk factors for vitiligo associated with these PRRs [47]. For example, it has been
reported an association of vitiligo with genes encoding
NLRP1, IFIH1, the Toll-like receptor adaptor molecule 1
(TICAM1), important for TLR signalling, and caspase 7, a
protein activated by the inflammasome complex. Recently,
Spritz’s group has shown that variants of IFIH1 associated
with loss of function could protect against vitiligo [48]. In
addition to nucleic acid recognition, the NLRP3
inflammasome is activated in response to excessive ROS production and mitochondrial stress [34].
Heat shock proteins (HSPs) are protein-folding chaperones
induced in response to cellular stress and UPR activation.
They can activate TLR2, TLR4, and other PRRs [49].
Inducible HSP (HSPi) is induced in chemical-induced stress
in melanocytes and in vitiligo. Interestingly, it was recently
demonstrated that HSP70i induces vitiligo in a mouse model
of the disease, and accelerates disease progression [45, 46].
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Recently, we have found that HSP70i released by epidermal
cells can potentiate the production of IFNα by plasmacytoid
dendritic cells (pDCs) that have been shown to play a crucial
role in the induction of the disease [50]. IFNα can induce the
production of CXCL9 and CXCL10 by epidermal cells, inducing an initial signal for the recruitment of effector T cells
during the initiation of the disease. High-mobility group box 1
(HMGB1) is an important DNA-binding protein that is present in the nucleus of cells, where it regulates DNA accessibility to transcription factors [51, 52]. During stress and cell
death (necrosis), HMGB1 is released into the extracellular
environment, can act as an alarmin, and can interact with
multiple immune sensors and receptors such as advanced
glycation end-products (RAGE) as well as TLR2, TLR4,
and TLR9, leading to activation of NF-κB and production of
IL-6 and TNFα. Moreover, HMGB1 could act directly on
melanocytes leading to their loss in vitiligo [53] but also binds
free DNA and HMGB1-DNA complexes which can induce
type I IFN production by pDCs. Another candidate for sensing
the immune system in vitiligo is calreticulin (CRT), which is a
ubiquitous protein localized predominantly in the endoplasmic reticulum and that plays a central role in intracellular Ca2+
homeostasis [54]. However, in response to stress, CRT can
also localize at the surface of cells such as immune cells,
affecting antigen presentation, complement activation, and
clearance of apoptotic cells. Moreover, CRT can also translocate to the melanocyte surface when these cells undergo
H2O2-mediated oxidative stress, increasing melanocyte immunogenicity and providing a new link between oxidative
stress, cell death, and immune reactions. CRT also induces
the expression of pro-inflammatory cytokines like IL-6 and
TNFα, enhancing the immunogenic potential of melanocytes
[54] (Fig. 2). Surface CRT directs the contact of ROS-stressed
melanocytes to dendritic cells and Langerhans cells, followed
by the activation of downstream adaptive immune responses,
leading to the development of the disease. Lastly, S100B is a
DAMP protein expressed by melanocytes that has been recently found to be upregulated in vitiligo patients and could
be involved in disease development [55].
Local inflammation can also activate natural killer (NK)
cells, found to be increased in vitiligo skin [56]. NK cells
respond to various cellular signals released by cells under
stress, and can be activated through ligands binding to their
receptors NKG2D. Besides their cytotoxic function, NK cells
influence antigen presentation; stimulate function, survival,
and maturation of DCs through the release of proinflammatory cytokines; and drive the adaptive immune
response.
Adaptive Immunity
Several lines of evidence have pointed out the involvement of
T cells and their related cytokines in development of vitiligo.
Clinic Rev Allerg Immunol (2018) 54:52–67
GWAS studies identified an association of both major histocompatibility complex (MHC) class I and II loci with vitiligo
[29, 57, 58], and CD8 and CD4 T cells are consistently found
at the edge of actively depigmenting skin of vitiligo patients
[5, 59]. In addition, suppression of immune tolerance in vitiligo likely involves an altered proportion and/or function of
effector and regulatory T cells (Tregs) [60].
CD4 T Cell Subset Involvement in Vitiligo
The involvement of autoreactive CD4 T cells in melanocyte
loss is still unclear. CD4 T cells play a major role in coordinating the immune response and seem important for the generation of cytotoxic CD8 T cells [61]. Studies using
melanocyte-specific T cell receptor (TCR) transgenic mouse
models suggest that CD4 T cells are involved in depigmentation [62–64] and that melanocyte loss in such models involve
Fas-Fas ligand (FasL)-induced signalling [62]. Dysregulation
of adaptive immune responses with excessive production of
Th1-, Th2-, Th17-, Th22-, and/or Th9-related cytokines is a
common feature of a wide range of inflammatory and autoimmune diseases, including skin inflammatory disorders (e.g.,
psoriasis, atopic dermatitis, alopecia areata). Early reports revealed that both CD4 and CD8 T cells produce mainly IFNγ
and TNFα in vitiligo [65], which is the signature of a Th1/Tc1
cell polarization (this aspect will be further developed in the
‘CD8 T Cell-Mediated Immune Response’ section) (Fig. 2).
The precise role of Th17 cells in melanocyte disappearance
in vitiligo remains to be fully determined. Serum IL-17 levels
are positively correlated with the extent of depigmentation
[66]. IL-17 expression is increased both in blood and in
perilesional skin of vitiligo patients, and T cells appear as
the main source of this cytokine [9, 67–69]. In addition, the
upregulation of IL-1β observed in perilesional skin of vitiligo
patients may act as an inducer of Th17 cells [9, 42]. However,
the impact of IL-17 on depigmentation has not been yet extensively studied. Results from the literature suggest that IL17 on its own has little effect on melanogenesis and would
rather act indirectly on pigmentation by enhancing the effects
of TNFα, IL-1β, or IL-6 to inhibit melanocyte function and/or
survival directly or indirectly though upregulation of proinflammatory chemokine production [70, 71]. Hence, if inhibition of the Th17 pathway has already proven efficacy in
autoimmune and inflammatory disorders like psoriasis,
whether targeting this pathway would be relevant in vitiligo
still needs further investigation.
The balance between inflammatory and immunoregulatory
factors is critical to prevent tissue damage during infection and
in the control of detrimental responses to self-antigen. The
VITGEN consortium has identified genetic polymorphisms
of FOXP3, CTLA-4, IL-10, and TGFβ receptor in vitiligo
[29, 47, 60], and several studies reported alterations in Treg
number and/or function in vitiligo patients [60]. The number
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of Tregs expressing transcription factor FOXP3 is significantly reduced in the skin of vitiligo patients [72, 73], contrasting
with the presence of functional Tregs in the circulation of
vitiligo patients [73]. Impairment of Treg function is likely
involved in the loss of tolerance in vitiligo since lower suppressive activities of Tregs towards CD8 T cells together with
an increase in IFNγ and TNFα production have been reported
in patients [74, 75]. Adoptive transfer of Tregs or treatment
with rapamycin (known to promote expansion of Tregs) can
efficiently halt the depigmentation process in disease-prone
mice [76].
CD8 T Cell-Mediated Immune Responses in Vitiligo
Accumulating evidence highlights the major role of CD8 T
cells in melanocyte loss in vitiligo. CD8 T cells in the skin are
more abundant in patients with active disease compared to
patients with stable disease or healthy controls; nonetheless,
such infiltration remains lower than the one observed in cutaneous lupus [10]. These cells produce Tc1-related cytokines
like IFNγ and TNFα. CD8 T cells specific for melanocyte
antigens, such as MelanA/MART-1, gp100, and tyrosinase,
have been detected in the peripheral blood and perilesional
skin of patients with vitiligo, although conflicting results were
reported [65, 77–82]. The progression of the disease could be
directly related to circulating MelanA-specific CD8 T cells
[77, 78], although the functionality of these cells in vitiligo
was raised [81]. The frequency of circulating CD8 T lymphocytes expressing granzyme B, perforin, and IFNγ is higher in
vitiligo patients than in healthy controls [75]. Such activation
of CD8 T cells correlates with impairment of Tregs. In addition, it was reported that Tregs can render self-reactive CD8 T
cells hypoproliferative and cytokine hypoproducing. Anergic
CD8 T cells reactive with MelanA antigen were also identified
in the blood of healthy individuals [83]. Upon self-antigen
stimulation and in the absence of appropriate Treg number
and/or function, as observed in vitiligo, such cells may become activated and may contribute to the development of
abnormal immune responses.
CD8 T cells, also known as cytotoxic T lymphocytes (CTL),
can directly induce cytolysis of target cells through two distinct
pathways: the release of soluble cytotoxic molecules like granzyme B and perforin, and the FasL/Fas interaction, which triggers apoptosis of target cells. The first direct evidence of cytotoxic T cell responses causing skin depigmentation came from
melanoma patients, where the majority of T cells infiltrating
melanoma tumours are reactive to MelanA and gp100 [84,
85]. CD8 T cells from perilesional skin of vitiligo patients recognize melanocyte antigens; express granzyme B and the proinflammatory cytokines IFNγ, TNFα, and IL-17; and can induce autologous melanocyte apoptosis in normally pigmented
skin in vitro [65, 82, 86, 87], suggesting the involvement of a
cytotoxic response to melanocytes. The association of
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autoreactive CTL with depigmentation is also supported
in vivo in disease-prone mouse models of vitiligo [61,
88–90]. Yet, in vivo studies performed in similar mouse models
showed that depigmentation in mice depends on IFNγ, while
cytotoxic mediators like perforin or granzyme were dispensable
[88, 90, 91]. Most of the existing mouse models of vitiligo
focus on depigmentation of the hair rather than the epidermis
and thus may not fully reflect human disease. Those models
also feature sensitization steps which have not been validated in
naturally occurring vitiligo, and may be more relevant to
melanoma-associated depigmentation or vitiligo-like depigmentations associated with immunotherapy used for treating
metastatic melanoma [92]. In addition, we have shown that
despite a higher granzyme B expression in the skin of patients
with active vitiligo compared to patients with stable disease or
healthy controls, its expression remained significantly lower
than in lupus, the archetype of a cytotoxic-mediated disease
[10]. It appears therefore critical to compare the phenotype
and function of skin CD8 T cells populating human vitiligo
skin to other cutaneous inflammatory diseases, which has never
been reported so far. Indeed, studies performed on human vitiligo samples mostly assessed peripheral blood cells, and studies that analysed the skin T cell infiltrate in vitiligo were mainly
performed by immunohistochemistry, which is a hurdle to fully
define the phenotype of infiltrated T cells.
T cells homing to tissues involve chemokine ligandmediated attraction of T cells expressing their cognate receptors. Recently, as suggested above, release of the chemokine
ligands CXCL16 by keratinocytes and CXCL12 and CCL5 by
melanocytes in vitiligo under oxidative stress could be important for the recruitment of T cells [31, 33]. Moreover, accumulating evidence is pointing out the critical role of the CXCR3/
CXCL9-CXCL10 axis in vitiligo pathogenesis. The expression of CXCR3 and its ligands CXCL9 (also known as
monokine induced by IFNγ, MIG) and CXCL10 (also known
as IFNγ-inducible protein-10, IP-10) is increased in the skin
of patients with vitiligo [10, 93]. These chemokines are induced by IFNγ in various cell types, including immune and
epithelial cells. Analysis of the transcriptional profile of
lesional vitiligo skin revealed an IFNγ-specific signature
[93]. IFNγ is produced by both CD8 and CD4 T cells in
vitiligo, although expression by other immune cells and skin
cells is not excluded and has to be assessed. In vivo studies
performed in mouse models of vitiligo also support the critical
role of the IFNγ/CXCR3/CXCL10 pathway [76, 88, 90, 93,
94]. Importantly, accumulation of CD8+ T cells in mouse skin
is dependent on IFNγ and CXCR3.
Hence, in vitiligo skin, the increased expression of IFNγ
and TNFα will induce CXCL9 and CXCL10 secretion together with the initial role played by IFNα, leading to the recruitment of T cells bearing CXCR3 in the skin, therefore amplifying inflammation (Fig. 2). These inflammatory cytokines
also directly impact melanocyte function. IFNγ can inhibit
60
melanogenesis and induce melanocyte apoptosis and senescence [95, 96], although high concentrations of IFNγ have to
be used to obtain a significant effect. IFNγ also seems important for maintaining epidermal pigmentation homeostasis
[97]. An increased expression of TNFα in vitiligo patients’
skin has been consistently observed [98], and both CD8 and
CD4 T cells have been identified as potent producers [65, 82];
yet, keratinocytes, fibroblasts, and even melanocytes could be
other sources of this cytokine under inflammatory conditions.
In vitro studies revealed direct inhibitory effects of TNFα on
melanogenesis and melanocyte function [99, 100]. TNFα,
together with IL-17, upregulates production of melanoma mitogens CXCL1 and IL-8 in melanocytes while suppressing
genes of the pigmentation pathway [71].
Skin Resident T Cells
Human skin contains 20 billion T cells, representing twice more
than in the entire blood volume, and most of them are resident T
cells [101]. Human skin is populated by distinct populations of
both recirculating and resident T cells that protect our organism
against invading pathogens [102, 103]. Resident memory cells
rapidly respond to pathogen or foreign antigens that attempt to
breach skin epithelium, independently of T cell recruitment
from the circulation. These skin-resident T cells are nonrecirculating T cells that display an effector memory phenotype
and express high levels of skin-homing receptors such as cutaneous lymphocyte antigen (CLA) and the chemokine receptor
CCR4, and they are characterized by expression of CD69 (also
known to be a T cell activation marker) and CD103 (also
known as αE integrin). Inadvertent activation of these skin
TRM must be tightly controlled, and we have shown in a different context that a skin resident population of Tregs can locally
proliferate and dampen skin effector memory T cell responses
[104]. In a predisposed patient, dysregulation of TRM could be
very damaging in the context of inflammatory disorders, such
as vitiligo. To date, whether TRM cells are involved in melanocyte loss in vitiligo remains unknown. Very recently, Cheuk
et al. reported that CD49a defines a specialized subset of
tissue-resident CD8 T with cytotoxic potential that could be
involved in vitiligo [105]. In addition, vitiligo often recurs on
the same anatomic sites, in favour of a local memory immune
response. Therefore, investigating the possible contribution of
autoreactive skin TRM cell subsets in vitiligo would add a better
understanding of the specific immune memory response in this
disease and is important to determine the optimal treatment
strategy for the patient.
Management and Therapy Overview
Several issues are important for managing appropriately a patient with vitiligo. Many patients are concerned by
Clinic Rev Allerg Immunol (2018) 54:52–67
disfigurement and difficulties in social interaction. The treatment plan should take into consideration the patient’s priorities in this respect. The risk of transmission of vitiligo and its
association with other diseases are also questioned by parents
and patients. Concerning the transmission of vitiligo, the fear
of the disease explains the referral of young children in vitiligo
families for minor lesions such as pityriasis alba or nevus
depigmentosus, and reassurance is needed. Data on the heritability of vitiligo among most races studies indicate a risk of
vitiligo in first-degree relatives of 4–6%, a marked increase
over the 0.5% assumed prevalence of vitiligo [106]. Common
genetic variants associated with the disease have been identified, and provide insights into biological pathways and reveal
possible novel drug targets [107]. Some rare family trees show
an impressive aggregation of cases of vitiligo and autoimmune disorders, and may justify a more comprehensive
autoimmune screen. Consanguinity is clearly a risk factor, as
shown in Middle East studies [108]. In general, thyroid autoimmunity and function are prescribed as a baseline test. The
need to reiterate tests on a regular basis has been advocated in
female patients and patients with longer duration of disease
and greater body surface involvement which are more likely to
present with autoimmune thyroid disease [109]. An atopic
diathesis is common in childhood onset vitiligo, but generally
the sites of involvement are distinct and Koebnerization due to
atopic dermatitis lesions is not an important issue [110]. Most
patients receive a strong warning against sun exposure to prevent skin cancer, and recommending phototherapy for treatment may be difficult. Recent studies analysing the risk of
skin cancer have been reassuring, suggesting that vitiligo provides a better surveillance against skin cancer, not only melanoma [111]. Overall, there is no evidence indicating that vitiligo per se changes one individual’s longevity.
Vitiligo treatments have so far been analysed using the
proportion of treated patients who achieve a specified degree
of repigmentation, usually starting at >50% for a ‘good’ response. ‘Good’ for this level of skin repigmentation is indeed
debatable in a patient-oriented view because satisfaction
needs, in addition to stopping disease progression, complete
restoration of pigmentation, especially in visible areas. This
point has been recently examined in depth by the VGICC
[112]. The VETF has proposed a simple method of assessment
which combines analysis of extent, grading of depigmentation, and progression [113]. Clinical photographs and, if possible, UV light photographs are needed for accurate monitoring of repigmentation.
For stopping progression, besides UV therapies, systemic
steroids have been evaluated mostly in open studies and seem
to arrest disease progression. Commonly used repigmentation
therapies for vitiligo that are supported by data from randomized controlled trials (RCT) include UV light (whole body
irradiation or UV targeted to lesions) and topical agents (corticosteroids, calcineurin inhibitors, calcipotriol).
Clinic Rev Allerg Immunol (2018) 54:52–67
Camouflaging and depigmenting (in widespread disease) are
the other current options. Table 1 outlines a stepwise treatment
approach according to type of vitiligo and extent, which needs
to be modulated by visibility, age, and coping. A ‘zero’ line is
always possible, meaning no treatment if the disease is not
bothering the patient. Intermittent tacrolimus applications
twice weekly on facial lesions prevent recurrence of lesions
and can be recommended as a maintenance treatment [114].
Systemic regimens to maintain disease stabilization such as
methotrexate for psoriasis or low-dose corticosteroids for lupus have been tried on a small-scale in vitiligo, and more work
is needed to recommend their routine use [115]. Overall, the
level of evidence for recommendations in vitiligo is low because of the variability of assessment methods and scarcity of
good randomized controlled studies. The need to combine
phototherapy with other agents to trigger repigmentation explains also the difficulty to design good studies [116].
UV Treatments
The currently preferred treatment in adults and compliant children with NSV is narrow-band UVB (NB-UVB), which delivers peak emission at 311 nm. The colour match of
repigmented skin is excellent, but the response rate remains
low based on patients’ expectations. With twice weekly NB
UVB treatments for 1 year, a majority of patients with NSV
repigment 75% of the affected areas. At least 3 months and
preferably 4 months of treatment is warranted before identifying a patient as a non-responder, and approximately 9–
12 months of treatment is usually required to achieve the maximal repigmentation. Unfortunately, access to this treatment is
frequently limited in some areas due to low availability or long
Table 1 General outline of
management for vitiligo in adults
61
distances to treatment centres. Home phototherapy devices are
thus more convenient and suitable for small-extent disease
[117]. The optimal dose may differ at different sites, and an
option is shielding the area with the lower MED after reaching
its optimal dose, while continuing to expose higher MED
areas until optimal dosing. There is no apparent relationship
between the degree of initial depigmentation and the response
to NB UVB treatment, but the duration of the disease is inversely correlated with the degree of treatment-induced
repigmentation. The best results are achieved on the face,
followed by the trunk and limbs. The poorest outcomes have
been noted for hand and feet lesions that at best show a moderate response. Relapses are common at all sites; around 60–
70% of patients resume depigmentation in areas repigmented
by treatment within 1 year whatever the regimen PUVA or
NB-UVB, justifying more research on maintenance and stabilizing therapies.
Responses of segmental vitiligo to narrow-band UVB are
at best limited when the same NB-UVB therapy is applied for
6 months, but combined treatment with oral minipulses of
corticosteroids seems promising [118]. Overall, earlier and
more aggressive treatment schemes are thus advisable. The
use of targeted high-fluency UVB (excimer laser or monochromatic excimer lamp, both at 308 nm) which may reach
deeper targets such as amelanotic melanocytes of the hair
follicle, and also avoid irradiation of uninvolved skin, may
improve outcomes, as well as combined approaches. Results
are also promising in cases of vitiligo involving limited areas.
The safety of UV treatments is overall good because of the
generalized use of narrow-band UVB treatments and targeted
high-fluency therapies. The risk of sunburn needs to be
prevented by a phototype-adapted regimen. PUVA therapy,
Type of vitiligo
Usual management
Segmental and limited vitiligo <2–3%
body surface involvement
First line: Avoidance of triggering factors, local therapies
(corticosteroids, calcineurin inhibitors) combined with localized
NB-UVB therapy, especially excimer monochromatic lamp or
laser, or home NBUVB phototherapy.
Vitiligo >3% BSA
Second line: Consider surgical techniques if repigmentation
cosmetically unsatisfactory on visible areas.
First line: Usual initial combination total body NBUVB with
systemic/topical therapies, including reinforcement with localized
UVB therapy (see text)
Second line: Consider surgical techniques in non-responding areas
especially with high cosmetic impact.
Third line: Consider depigmentation techniques in non-responding
widespread (>50%) or highly visible recalcitrant facial/hands vitiligo
A no-treatment option (zero line) can be considered in patients with a fair complexion after discussion. For
children, phototherapy is limited by feasibility in the younger age group and surgical techniques rarely proposed
before prepubertal age. There is no current recommendation validated to the case of rapidly progressive vitiligo,
not stabilized by UV or combined therapy. Camouflage, psychological support, and maintenance treatment are
indicated in all cases. UV ultraviolet, NB-UVB narrowband UVB phototherapy
62
which led to more concerns for skin cancer risk after longterm treatment for psoriasis, has been abandoned in most
European departments, but is still in use in countries with a
majority of darker phototypes [119].
Clinic Rev Allerg Immunol (2018) 54:52–67
UV results in repigmentation of at least 70% of the treated
area.
Camouflage and Depigmentation
Topical Therapies and Combined Therapies
Topical therapies are not suitable for widespread NSV, but
may be effective in cases with more localized disease (including SV). Combined treatments are frequently considered
when phototherapy alone does not show efficacy after 3–
4 months, or in an attempt to accelerate response and reduce
cumulative UV exposure. As compared with PUVA, which
determines a predominant perifollicular pattern of
repigmentation, topical corticosteroids (and topical calcineurin inhibitors—TCI—such as tacrolimus and pimecrolimus)
exhibit a diffuse repigmentation type, which is faster but less
stable. Class 3 (potent) topical corticosteroids achieve more
than 75% repigmentation in more than 50% of patients. TCI
are preferred for face and neck lesions, because they do not
cause skin atrophy. The efficacy of TCI is enhanced by exposure to UV radiation delivered by high-fluency UVB devices
but not so clearly by conventional NB-UVB. The concerns
about the risk of cutaneous or even extracutaneous cancer
provoked by topical calcineurin inhibitors have been disproportionate [120]. Calcineurin inhibitors can promote
repigmentation without immunosuppression [120]. The combined use of UV and calcineurin inhibitors is not yet fully
approved, but recommended by the VETF/EDF/EADV/
UEMS guidelines [119]. Topical corticosteroids can also increase the efficacy of UVB [121].
Surgery
Surgical methods such as minigrafting, which consists in
transplanting punch grafts from an autologous donor site—
currently less used when other options are possible—or cellular transplantation using autologous epidermal cell suspensions containing melanocytes or ultrathin epidermal grafts or
a combination of cellular transplantation and ultrathin
grafting, are used in cases of focal/segmental vitiligo if medical approaches fail. Several variants have been recently developed. UV irradiation is frequently associated. Patients with
vitiligo are considered good candidates for surgical techniques
depending on availability and cost, if their disease is stable
(over the preceding year) [12] and has a limited extent (2–3%
of body surface area). Contrary to SV, in which the grafted
cells come from apparently disease-free areas, the survival of
living but potentially abnormal transplanted melanocytes is
less predictable in vitiligo. Koebnerization limits efficacy
(hands in particular). In case of strict preoperative selection
for disease stability in vitiligo, cellular transplantation plus
Topical camouflaging products mask aesthetic skin disfigurement on a transient, semi-permanent, or permanent basis (tattoos). Benefits can be obtained by the skilled use of corrective
cosmetics. For dihydroxyacetone (DHA), the most used selftanner, the higher the concentration, the better the response
observed particularly in darker phototypes. Chemical or laser
depigmentation can definitely be a choice in a small subset of
carefully selected patients, but results are variable both in efficacy and duration.
Psychosocial Aspects and Counselling
A low self-esteem and high levels of perceived stigma seem to
be important factors for quality-of-life impairment in vitiligo
patients. A simple visual analogue scale from 0 to 10 with the
notice ‘How much does your skin disease bother you currently?’ helps to measure coarsely how patients feel about their
disease independently of medical findings. Patients with high
perceived severity are the best targets of psychological interventions. Cognitive-behavioural therapy might help improve
the quality of life, self-esteem, and perceived body-image
[122].
Sunscreens are needed in case of real risk of sunburn on
non-photoprotected skin, but not on a routine basis, because
moderate sun exposure (heliotherapy) is a good substitute to
UV therapies. Photoadaptation exists in depigmented vitiligo
skin. Repeated frictions for applying sunblockers without real
sunburn risk may be more detrimental than beneficial. It is
important to make time available to discuss photoprotection
issues vs therapy by UV light in the vitiligo clinic, because this
is an important source of confusion for the patients.
Evidence-Based Guidelines
General guidelines for adults and children have been elaborated by the British Association of Dermatologists [123] and
guidelines for surgery by the Indian Association of
Dermatologists, Venereologists and Leprologists (IADVL)
Dermatosurgery Task Force [124]. A treatment algorithm
has been also proposed based on evidence-based medicine
principles [125]. In addition to the Indian and Japanese guidelines, the European VETF/EDF guidelines have been published in 2013 [119] and are currently undergoing revision.
Beyond guidelines, personalized/stratified strategies have
been proposed [126].
Clinic Rev Allerg Immunol (2018) 54:52–67
Emerging Targeted Therapies in Vitiligo
Therapeutic options for patients with vitiligo have overall limited efficacy, and it remains critical to identify new therapeutic
strategies that would reduce direct and indirect costs of this
disease and potentially benefit other autoimmune conditions
associated with vitiligo. Blocking the initiation of the disease
by inhibiting the impact of DAMPs on the activation of the
disease, such as HSP70i, could be a promising therapy to
prevent relapse of the disease. Moreover, targeting IFNα or
inhibiting the activation of pDCs, as it was suggested in other
chronic inflammatory diseases like lupus or psoriasis, could
be another option to dampen the inflammatory response important for disease initiation.
Regarding the adaptive immune response, the CXCR3/
CXCL9-10/IFNγ pathway is the most extensively studied in
vitiligo and appears to be important in the development of
vitiligo. Therapies targeting this pathway through inhibition
of CXCR3, its ligand, or downstream-induced signalling
could thus represent an attractive strategy in this disease.
Two case reports revealed that the use of the JAK inhibitors tofacitinib (a JAK1/3 inhibitor) or ruxolitinib (a JAK1/
2 inhibitor) might be effective in inducing repigmentation
in vitiligo [127, 128]. In addition, a proof-of-concept clinical trial just showed that topical application of ruxolitinib
provided significant improvement in facial vitiligo in a
small cohort of patients [129]. A phase II pilot interventional study assessing the efficacy of topical application of
ruxolitinib in vitiligo is ongoing (clinical trial Gov identifier: NCT02809976). Biological effects of a number of
soluble inflammatory mediators, like IFNγ, IFNα, IL-2,
or IL-15, rely on activation of the JAK-STAT pathway.
Therefore, we can foresee that JAK inhibition would halt
the inflammatory and immune signals that are important
for T cell survival and depigmentation, and may represent
a promising strategy in vitiligo.
Anti-TNF therapies are commonly used in a number of
autoimmune and inflammatory disorders, in particular in the
field of dermatology, rheumatology, and gastroenterology.
However, despite the apparent major role of TNFα in vitiligo,
the limited number of studies that assessed efficacy of antiTNFα in vitiligo suggests that blocking this cytokine is effective at best in halting disease progression but does not induce
significant repigmentation [91, 130].
Inhibition of the immune response in vitiligo appears as a
promising strategy. However, repigmentation of vitiligo
lesional skin needs repopulation of the epidermis with differentiated melanocytes. The WNT signalling, which has been
shown to be repressed in depigmented skin of vitiligo patients,
is an important pathway for melanocyte differentiation. Ex
vivo treatment of vitiligo skin explants with WNT agonists
or GSK3β inhibitors triggered the differentiation of melanoblasts [131]. Therefore, the use of pharmacological agents that
63
would activate the WNT signalling could be an interesting
approach in vitiligo.
The safety and cost of emerging targeted therapies is currently questioned for their use in a non life-threatening disease. However, the development of therapies in dermatology
has been hampered by this kind of argument, and physicians
know that vitiligo can be a devastating disorder. The example
of psoriasis and the recent development of biologics in atopic
dermatitis will fortunately pave the way for the specific development of targeted therapies in vitiligo. The specific risk of
increased skin cancer risk for all therapies modulating immune pathways will however remain a strong concern for
vitiligo [111].
Conclusion
Vitiligo, despite its prevalence, remains a disease with limited
therapeutic options for patients. However, recent progress in
the understanding of immune pathomechanisms opens interesting perspectives for innovative treatment strategies. The
proof of concept in humans of targeting of the IFNγ/Th1
pathway is much awaited. The interplay between oxidative
stress and altered immune responses suggests that additional
strategies aiming at limiting the type I interferon activation
pathway as background stabilizing therapies could be an interesting approach in vitiligo. Hopefully, the status of vitiligo
is currently changing from a neglected non-medical problem
to a big challenge at the high end of modern translational
medicine with real perspectives for cure via specific drug
development.
Compliance with Ethical Standards
Conflicts of Interest The authors declare that they have no conflict of
interest.
Funding None.
Ethical Approval and Informed Consent Not necessary.
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