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Vitiligo: An Update on Pathophysiology and Treatment Options

Reinhart Speeckaert; Nanja van Geel

Am J Clin Dermatol. 2017;18(6):733-744.

Abstract and Introduction

Abstract

The pathophysiology of vitiligo is becoming increasingly clarified. In non-segmental vitiligo, early factors include
activation of innate immunity, inflammasome activation, oxidative stress, and loss of melanocyte adhesion. Nonetheless,
the main mechanism leading to non-segmental vitiligo involves an immune-mediated destruction of melanocytes. Anti-
melanocyte-specific cytotoxic T cells exert a central role in the final effector stage. Genetic research revealed a multi-
genetic inheritance displaying an overlap with other autoimmune disorders. However, some melanocyte-specific genes
were also affected. Segmental vitiligo carries a different pathogenesis with most evidence indicating a mosaic skin
disorder. Current management includes topical corticosteroids and immunomodulators. Narrow-band ultraviolet B can be
used in patients not responding to topical treatment or in patients with extensive disease. Pigment cell transplantation
offers an alternative for the treatment of segmental vitiligo or stable non-segmental lesions. Recent findings have
revealed new targets for treatment that could lead to more efficient therapies. Targeted immunotherapy may halt the
active immune pathways, although combination therapy may still be required to induce satisfying repigmentation. A
recently established core set of outcome measures, new measurement instruments, and biomarker research pave the
way for future standardized clinical trials.

Introduction

Vitiligo is the most frequently occurring depigmentary disorder affecting approximately 0.5–1% of individuals worldwide.
It can develop at any age, although half of the patients have vitiligo before the age of 20 years. No difference in
prevalence exists according to sex, skin type, or race. Nonetheless, some reports indicate that vitiligo develops in
women at an earlier age and marked geographic differences in prevalence rates have been described.[1]

Historically, the cause of vitiligo has been shrouded in mystery. The earliest known reference to vitiligo dates from 2200
BC and vitiligo was also mentioned in the Ebers Papyrus (1550 BC). The development of white spots on the skin has
been described in the Old Testament and Buddhist literature.[2] Vitiligo has carried many misconceptions, especially in
countries where whitening of the skin is associated with infectious diseases such as leprosy. To date, the resulting social
stigmata remain embedded in some cultures, leading to a high psychological burden in patients with vitiligo.[3]

Apart from cultural influences, vitiligo has been shown to exert a detrimental influence on the quality of life. This impact
has long been underestimated because of the lack of vitiligo-specific impact scales. Most dermatology qualityof-life
measures such as the Dermatology Quality of Life Index focus on subjective symptoms such as pruritus or pain.
Moreover, these indices focus on acute disease flares that are not applicable for vitiligo (e.g., Dermatology Quality of
Life Index: assessment of patients' complaints in the previous week). Recently, new impact scales have been developed
for vitiligo such as the Vitiligo Impact Patient Scale, which may better reflect the burden caused by vitiligo.[4] The
psychological impact of vitiligo is clear because of the high rate of depressive symptoms. A recent meta-analysis
showed a pooled odds ratio of 5.05 for depression compared with controls. More than a third of patients with vitiligo had
experienced some type of depressive symptom without necessary fulfilling all criteria for clinical depression.[5]

Types of Vitiligo and Differential Diagnoses

Non-segmental vitiligo (±85 to 90%) is far more common than segmental vitiligo (±10%).[6] Non-segmental vitiligo is
characterized by the development of depigmentations on both sides of the body, whereas segmental vitiligo is typically
limited to one side of the body usually not crossing the midline. In segmental vitiligo, typical distribution patterns in the
face and trunk have been described, which aid in the differential diagnosis.[7,8] Early recognition of the subtype of vitiligo
is essential as the evolution and treatment are markedly different. In most patients, nonsegmental vitiligo has a chronic
course with a continuing chance of progression throughout life. In contrast, segmental vitiligo is characterized by a rapid
disease onset (often in a few days to weeks). The disease usually stabilizes after 1–2 years and other areas of the body
are typically not at risk. However, a form of mixed vitiligo has been described in a small subset of patients.[9] This type
involves a combination of segmental vitiligo and nonsegmental vitiligo in the same patient. Focal vitiligo is a localized
small depigmented area that remains isolated. The diagnosis of focal vitiligo is often only retrospectively possible as it
progresses in half of the cases to non-segmental vitiligo within 2 years after disease onset.[10]

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The main differential diagnoses for vitiligo are other depigmentary and hypopigmentary disorders such as pityriasis
versicolor, pityriasis alba, melasma, halo naevus, naevus hypopigmentosus, naevus anemicus, lichen striatus,
progressive macular hypopigmentation, and hypopigmented mycosis fungoides. A rare but important differential
diagnosis is the spontaneous occurrence of depigmentations in patients with melanoma. In a series of photographs,
vitiligo experts were not able to differentiate melanoma-associated leukoderma clinically from vitiligo.[11] This illustrates
that an increased awareness for suspected pigmented lesions may be warranted in patients with vitiligo, especially in
patients with disease onset at an older age.

Associated Disorders

Importantly, non-segmental vitiligo is associated with other autoimmune disorders such as thyroid disease, alopecia
areata, psoriasis, diabetes mellitus, rheumatoid arthritis, pernicious anemia, and Addison's disease. Although Addison's
disease is still rare in patients with vitiligo (0.3–0.8%), it is far more frequent compared with the general population
(0.01%).[12] In a systematic review, autoimmune thyroid disease was found in 14.3% of patients with vitiligo, although
prevalence rates vary considerably among studies.[13] A study by our group showed that thyroid disease was most
frequent in women (13.4 vs. 5.4%), and vitiligo patients with thyroid disease almost always had lesions on the hands
(men 94.4%, women 93.9%). The feet and elbows are also predilection areas for thyroid disease. Other autoimmune
disorders were not linked to particular distribution patterns.[14] In patients with segmental vitiligo, no increased rate of
autoimmune disorders is observed.

Heritability and Genes

The genetic origin of vitiligo is evident owing to the familial occurrence of vitiligo. First-grade relatives have a 6–8% risk
of developing vitiligo. The concordance of vitiligo in monozygotic twins is approximately 23%.[15] This reflects the fact
that vitiligo is a multi-genetic disease with a complex pathogenesis. In recent years, several genome-wide association
studies have been conducted in vitiligo. These have identified that the large majority of genes associated with vitiligo
exert an immunodulatory function while a minority of genes have been linked to melanocytes. A remarkable overlap of
affected genes exists with other autoimmune disorders. For many identified susceptibility loci, the functional role in the
pathogenesis of vitiligo is unknown. This underlines our incomplete knowledge of the pathogenesis.[16]

Several genes in the human leukocyte antigen region are associated with vitiligo. Association peaks have been
discovered in the class I and II regions.[17] The human leukocyte antigen complex encodes for the major
histocompatibility complex, which is responsible for the processing and presentation of antigens. The association
between human leukocyte antigen types and autoimmune diseases can be explained by multiple pathways that
ultimately lead to a derailed recognition of self-antigens. This results in the development of autoreactive T cells and/or
failure to raise an efficient regulatory T-cell (Treg) population. Protein misfolding may occur, causing an unfolded protein
stress response or the generation of autoantigens.[18]

A subset of immunoregulatory genes has been linked to vitiligo susceptibility. Genes encoding for factors involved in
T-cell development and priming (e.g., CD44, CD80), T-cell receptor signaling (e.g., SLA, PTPN22, UBASH3A, CLNK),
T-cell activation (e.g., IKZF4, IL2RA, BTNL2, FOXP3), the innate immune response (e.g., IFIH1, TICAM1), and
chemokine or cytokine receptors (e.g., CXCR5, CCR6, SH2B3) have all been found to be associated with vitiligo in
genome-wide association studies.[16,17,19,20]

Melanocytes also carry different genes related to the development of vitiligo. Several of these genes encode for proteins
or enzymes that may serve as autoantigens (e.g., TYR, PMEL, MC1R, OCA2), facilitating the development of an anti-
melanocyte immune response. Others are involved in the regulation of melanocyte development and survival (e.g.,
ZMIZ1), cell death during oxidative stress (e.g., RNASET2), and apoptosis (e.g., FGFR1OP). Other genes regulating
apoptosis (e.g., RERE, CASP7) or immune-induced apoptosis (e.g., GZMB) have also been linked to vitiligo.[16]

Pathophysiology of Non-segmental Vitiligo

An extensive debate has been conducted in the literature regarding the mechanisms leading to vitiligo. Several
hypotheses have been put forward including an autoimmune theory, melanocytorrhagy, oxidative stress, and neural
mechanisms. Although different mechanisms may play a role, the autoimmune hypothesis is currently considered as the
main pathway (Figure 1).

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Figure 1.

Pathogenesis of non-segmental vitiligo: after minor injury, damage-associated molecular patterns are released (1) and
oxidative stress is enhanced (2). Melanocytes lose their adhesion (3) and inflammasomes are activated (4). This
proinflammatory signaling leads to antigen processing and dendritic cell presentation in the draining lymph nodes (5).
Specific cytotoxic T cells are generated towards the skin (6). As a result of down-regulated regulatory T-cell activity (7),
lymphocytes produce inflammatory cytokines (8) and autoantibodies (9). Cytokines and oxidative stress exert a
reciprocal stimulation augmenting the immune response (10). A chemokine gradient is generated that preferentially
recruits cytotoxic T cells towards the skin (11). This leads to the immune-based destruction of melanocytes (12). CXCL
chemokine (C-X-C motif) ligand, IFN interferon, IL interleukin, TNF tumor necrosis factor

Innate Immunity

Koebner Phenomenon. Koebner phenomenon is considered as an initial trigger. This is clearly visible in clinical
practice as patients often display depigmentations at sites of chronic friction (e.g., waist region) or after traumata.
Koebner phenomenon may explain some differences in the distribution pattern according to age and sex. In children, the
lower extremities are very frequently affected, while in adults, the upper extremities are more frequently affected.[21] In
men, the beard area is particularly vulnerable, which can be attributed to shaving. The presence of depigmentations
after trauma (friction or injury) is more frequent in patients with active disease.[22]

Danger-Associated Molecular Patterns. Given the importance of Koebner phenomenon, researchers have attempted
to identify factors released during the stress response and damage of vitiligo melanocytes. Danger-associated molecular
patterns (DAMP) are of particular interest as they may trigger the observed inflammatory response in the active stage of
vitiligo. Heat shock proteins, especially heat shock protein (HSP) 70, have been found to be elevated in the skin of
patients with vitiligo and correlated with active disease.[23] Inducible HSP70 is preferentially secreted by stressed
melanocytes and mouse models demonstrated an essential role of HSP70 in the immune response, resulting in vitiligo.
[23,24] HSP70 has been shown to enhance interferon (IFN)-α signaling in plasmacytoid dendritic cells. This may be one
of the mechanisms that bridges innate with adaptive immunity as IFNα induces lymphocyte-attracting chemokines. MxA,

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an IFN-α inducible protein, shows strong expression in active perilesional vitiligo skin, suggesting a contributing effect of
IFN-α in disease progression.[25] S100B is also a DAMP released by damaged melanocytes. S100B levels are
increased in active vitiligo and may stimulate inflammatory responses.[26] High mobility group box 1, another DAMP that
signals through RAGE, is increased in the blood of patients with vitiligo and induces melanocyte apoptosis.[27]

Deficient Melanocyte Adhesion. Another explanation of Koebner phenomenon may be found in intrinsic adhesion
defects of melanocytes. Several research groups provided evidence that vitiligo melanocytes have decreased adhesive
properties.[28] Altered E-cadherin expression levels in melanocytes have been found in vitiligo skin prior to the
development of depigmentations. Deficient E-cadherin expression leads to the loss of epidermal melanocyte adhesion
during oxidative or mechanical stress.[29] Loss of melanocytes from the epidermal layer could be an early phenomenon
in vitiligo.

Oxidative Stress. A large amount of literature shows multiple elevated oxidative stress markers (superoxide dismutase,
malondialdehyde, reactive oxygen species) and a collapse of antioxidative mechanisms (catalase, glutathione) in the
skin and in the blood of patients with vitiligo. This is proposed to be an early factor leading to subsequent immune-
mediated melanocyte destruction. Unfortunately, antioxidants have been used with limited success in vitiligo. Whether
oxidative stress is pathogenic in vitiligo or a side effect of the inflammatory response remains to be elucidated. However,
in-vitro vitiligo melanocytes display an increased sensitivity to oxidative stress, leading to cellular death.[30]

Inflammasomes. To date, the role of inflammasomes has been scarcely investigated in vitiligo. Inflammasomes are a
component of the innate immune system resulting in the release of interleukin (IL)-1β and IL-18. Some interesting
results have been found on NLRP1 with immunohistochemistry showing a significant association of NLRP1 with disease
activity. Interestingly, marked NLRP1 staining was found in keratinocytes throughout the epidermal layer in perilesional
vitiligo skin. NLRP1 staining even outperformed the simple presence of an inflammatory infiltrate to predict further
disease progression.[31] Genetic research showed that NLRP1 haplotypes associated with vitiligo carry an increased
capacity for IL-1β processing.[32]

Adaptive Immunity
Development of a Melanocyte-Specific Response

The resulting inflammation in predisposed skin may lead to antigen presentation of melanocyte peptides by dendritic
cells in the draining lymph nodes. This results in the generation of melanocyte-specific cytotoxic T cells and the
production of melanocyte-specific autoantibodies by lymphocytes. Different subsets of cytotoxic T cells have been found
in patients with vitiligo directed against melanocyte differentiation antigens (e.g., Mart-1, gp100). In-vitro experiments
demonstrate that these cells carry the capacity to eliminate epidermal melanocytes in pigmented vitiligo skin.[33] This
phenomenon is considered the main pathway of melanocyte destruction in vitiligo.

Regulatory T Cells. Nonetheless, the presence of melanocyte-specific immune cells is not sufficient to develop vitiligo.
It has been shown that anti-melanocyte T cells can be found in healthy individuals. However, these self-reactive T cells
display in healthy persons an anergic phenotype.[34] This indicates that a delicate balance between proinflammatory and
antiinflammatory signaling exists, which becomes deregulated in vitiligo. Regulatory T cells are an important subclass of
T cells responsible for attenuating immunity. The total number of Tregs in patients with vitiligo appears to be decreased
compared with healthy controls and an association with disease activity has been observed. It is generally agreed that
the total suppressive effect of Tregs is abrogated in patients with vitiligo.[35]

Cytokines and Chemokines. CD8 cytotoxic lymphocytes of patients with vitiligo produce predominantly IFN-γ, TNF-α,
and IL-17 upon exposure to melanocyte differentiation peptides.[33] Interferonc appears to be a crucial cytokine in the
final steps leading to melanocyte destruction. Other cytokines such as IL-1β, IL-2, IL-17, IL-22, IL-23, and IL-33 have
also been shown to be elevated in the skin and/or blood of patients with vitiligo or vitiligo mice models.[36–39] Multiple
reports have shown enhanced IL-17 levels, which might play a role in activating the inflammasome.[40,41]

Interferon-γ-related chemokines CXCL9 and CXCL10 were clearly elevated in human vitiligo skin and in a mouse model
of vitiligo. In a vitiligo mouse model, inhibition of CXCL10 by a neutralizing antibody was capable of preventing vitiligo
with signs of repigmentation.[42] Increasing evidence documents that CXCL9 and CXCL10 are linked to disease activity
in vitiligo. Melanocytederived CXCL12 and CCL5 may play a role in the recruitment of antigen-presenting cells and T
cells in vitiligo skin, and serum CXCL12 has been linked to vitiligo activity.[43,44] Additionally, oxidative stress may induce
the secretion of particular chemokines such as CXCL16.[45]

Autoantibodies. Autoantibodies were observed decades ago in vitiligo; however, their pathogenic role has not been
confirmed. Conflicting data exist on the association of the level of autoantibodies and vitiligo activity.[46,47] This resulted
in a decline of research interest in these autoantibodies. However, a small pilot trial with rituximab showed some
promising results, which suggests that the role of B lymphocytes in the pathogenesis of vitiligo might be
underestimated.[48]

Proliferation, Migration, and Differentiation of Melanocytes

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Besides immunological factors explaining the development of vitiligo, the difficulties related to repigmenting vitiligo skin
are still a challenging research topic. The factors influencing successful differentiation, proliferation, and migration of
melanocytes in vitiligo skin are poorly understood. Depletion of the melanocyte reservoir may explain some individual
differences, although other factors are likely to play a role. Recently, a decrease in Wnt pathway signaling induced by
oxidative stress has been found in vitiligo skin. The Wnt pathway is involved in melanocyte differentiation. Activating this
pathway may promote the differentiation of melanoblasts and stimulate repigmentation.[49] Furthermore, UVB-induced
Wnt expression triggers the differentiation of melanocyte stem cells through β-catenin activation. Targeting this pathway
could therefore be a promising approach to induce repigmentation.[50]

Pathophysiology of Segmental Vitiligo

Distribution Pattern Pointing to Somatic Mosaicism

Segmental vitiligo has clear differences compared with its non-segmental counterpart. In segmental vitiligo, only
melanocytes residing in a particular area seem to be susceptible. For many years, the literature has described
segmental vitiligo to follow a dermatomal distribution. This led to the hypothesis that neural mechanisms could play a
role. Several reports pointing to increased neuropeptide release (e.g., neuropeptide Y) have been published.[51]
However, neuropeptides could also be considered as a bystander effect of inflammation. Additionally, the observation
that segmental vitiligo more often does not follow a dermatomal distribution illustrates that neural mechanisms are
probably not the primary cause. Comparison of the distribution pattern of segmental vitiligo with other unilateral skin
disorders revealed that segmental vitiligo has a unique distribution pattern with the most overlap with segmental
lentiginosis.[52] Currently, somatic mosaicism is the most plausible theory, although this hypothesis has not yet been
confirmed on a genetic level.

Role of Immunity

In 2010, a patient with segmental vitiligo with a recent onset vitiligo was investigated. Perilesional biopsies showed an
inflammatory infiltrate and perilesional lymphocyte isolation confirmed the presence of anti-Mart-1- and gp100-specific
cytotoxic T cells.[53] More recently, the presence of inflammatory cells was observed in 39/50 (78%) of recently evolving
segmental vitiligo lesions, suggesting that immune-mediated mechanisms may indeed play a role.[54]

Although no definitive statements are currently possible, segmental vitiligo could represent a somatic mosaicism of
melanocytes, leading to a localized and self-limiting inflammatory response.[55] This subsequently results in the loss of
melanocytes in a localized area. This mechanism would be similar to other presumably mosaic skin diseases such as
lichen striatus.

Therapeutic Options in Vitiligo

Because of its complex pathogenesis, the management of vitiligo remains challenging. The conclusions of the most
recent updated Cochrane systematic review were hampered by the heterogeneity of the performed clinical trials.[56]

Because of the wide range of interventions, limited number of participants, and different study designs, firm
management recommendations could not be proposed. Therefore, the management of vitiligo is currently based on the
most recent consensus guidelines.[57,58] The management of vitiligo involves a personalized approach and several
factors influence the therapeutic choice (disease duration, impact, skin type, extent, sex, age, involved areas, social life,
and cultural influences). Dermatologists should be aware of the patients' expectations and explain thoroughly the
expected results ().

Table 1. Medical management of vitiligo

  Treatment Expected results Comments

Non-segmental vitiligo      
First-line option Topical potent Disease stabilization Discontinuous scheme
corticosteroids Some chance of preferred (e.g., 2/4
repigmentation (face > rest weeks)
of body > acral areas) Long-term treatment (at
least 6 months)
Topical Disease stabilization Some More expensive
immunomodulators chance of repigmentation compared with topical
(tacrolimus, (face > rest of body > acral corticosteroids
pimecrolimus) areas) Twice daily more efficient
than once daily

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First-line option in extensive
disease or second-line option
in the case of lack of
repigmentation using topical
treatment
Stable disease
Very active disease with high
impact
Very extensive disease with
high impact
Segmental vitiligo
Active disease (in most
patients up to 6 months to 2
years after onset)
Stable disease
 
NB-UVB/excimer laser Repigmentation in the
majority of patients,
although complete
repigmentation is rare
Pigment cell Inferior success rates in
transplantation non-segmental vitiligo
compared with segmental
vitiligo
Oral corticosteroids Most patients achieve
disease stabilization,
although limited
repigmentation in
monotherapy
Depigmentation therapy Removal of remaining
(laser therapy, pigmented areas
cryotherapy, MBEH)
Topical potent Disease stabilization
corticosteroids
Topical Disease stabilization
immunomodulators
(tacrolimus,
pimecrolimus)
Pigment cell Very high success rates
transplantation
   
Effective treatment often
requires 7–12 months of
phototherapy
Number of safe
treatments is limited
because of possible
increased risk of skin
cancer
Often relapse after
discontinuation if
untreated
Results are dependent
on disease stability and
location
Only reserved for a
limited area
Important possible side
effects (weight gain,
hypertension)
Only for a limited
duration (3–6 months)
Recurrence of pigment
possible (importance of
sun protection)
Discontinuous scheme
preferred (e.g., 2/4
weeks)
More expensive
compared with topical
corticosteroids
Results are dependent
on disease stability
Only reserved for a
limited area

MBEH monobenzyl ether of hydroquinone, NB-UVB narrow-band ultraviolet B

General Measures

Avoiding Koebnerizing factors (friction, trauma) can help to limit the triggering factors that develop new depigmentations.
A good sun protection with sunscreens or clothing prevents sunburn on depigmented areas. Moreover, sun protection
can help to diminish the bothersome enhanced contrast between depigmented and tanned pigmented skin, which
occurs during summer. However, both spontaneous and treatment-induced repigmentation are mostly observed during
summer periods on ultraviolet (UV)-exposed areas. This indicates that a moderate UV exposure could be a useful
strategy to induce repigmentation in vitiligo.[59]

Topical Treatment

Topical Corticosteroids. Topical corticosteroids are still the first-line option for the treatment of vitiligo. The anti-
inflammatory effects might decrease disease progression, although the cessation of spread has been rarely used as an
outcome measure.[60] Most repigmentation can be observed in the face and neck while the trunk, extremities, and
especially the hands display usually only limited repigmentation.[61] Recent lesions have a higher tendency for
repigmentation. The efficacy between potent and ultra-potent corticosteroids seems to be similar. Side effects include
skin atrophy, telangiectasia, and striae, which are rare if a discontinuous treatment scheme is used (e.g., 15 days of
application per month). In the case of the occurrence of acneiform eruptions (especially in the face), a switch to topical
immunomodulators may be advisable. Treatment with potent topical corticosteroids is often continued for at least 6

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months to monitor its efficacy.[58] In our experience, this treatment is sufficient for the majority of patients with vitiligo.
However, it should be clearly explained to the patient that the primary aim of topical treatment is to achieve disease
stability. Repigmentation can be observed especially in the summer period on the face, while in other areas, the
absence of progression should be considered as a successful treatment result.

Topical Immunomodulators. Topical tacrolimus and pimecrolimus are calcineurin inhibitors attenuating T-cell activity
and decreasing the production of proinflammatory cytokines. In-vitro experiments document that they enhance
melanocyte migration and pigmentation.[62,63] Similar to corticosteroids, topical immunomodulators show the most
repigmentation in the face, while the results are moderate at other sites of the body. Overall, the results of topical
immunomodulators are comparable to corticosteroids.[64] Twice-daily application of tacrolimus has been shown to be
more effective compared with once-daily application.[65] The responses of tacrolimus seem slightly higher compared
with pimecrolimus.[66] The higher potency of tacrolimus compared with pimecrolimus has also been demonstrated in an
invivo Koebner induction model.[67] The most frequent side effect of topical immunomodulators is a burning sensation
during the first 10–14 days of application, which is usually transient. Flushing after alcohol intake is also often observed
and can be bothersome for some patients. Topical immunomodulators can be used in the case of side effects owing to
topical corticosteroids (e.g., acneiform eruptions) or to attempt repigmentation in the face when treatment with topical
corticosteroidids shows no signs of recovery.

Topical Antioxidants. Although still relatively frequently prescribed, the efficacy of topical antioxidants has only been
observed in a limited number of trials.[68,69] Currently, consensus guidelines do not recommend the use of topical
antioxidants.

Phototherapy

Phototherapy has long been recognized as an efficient treatment to induce repigmentation. Nonetheless, the patient
should be informed about the expected results, side effects, and the expected duration of the treatment. Narrow-band
UVB is the phototherapy of choice and is usually carried out two to three times weekly. Signs of repigmentation are
observed in the majority of patients. Nonetheless, complete repigmentation is only found in a small minority of
patients.[70] Njoo et al. found only 6% complete repigmentation after 12 months of NB-UVB monotherapy in children.[71]
Complete clearance was slightly higher (16.5%) in another study including patients with vitiligo of all ages.[70]
Additionally, the patient should be informed about the risk of relapse after discontinuation of the therapy. Approximately
half of patients will develop vitiligo lesions in repigmented skin within the first year if untreated.[72,73] According to Caron-
Schreinemachers et al., the minimal erythemal dose of vitiligo is 35% lower compared with normal skin, which requires
an adaptation of the UVB dose.[74] This treatment is continued provided the repigmentation continues for a maximum of
1–2 years. An evaluation of the evolution based on follow-up photographs can be recommended every 3 months. After
stopping phototherapy, continuation of a topical treatment may be advisable to prevent recurrence. Twice-daily
application of tacrolimus has been shown to decrease the rate of recurrent lesions.[75]

Photochemotherapy shows less repigmentation compared with NB-UVB and is associated with increased side
effects.[76] The 308-nm excimer laser may show faster repigmentation compared with NB-UVB, although no studies
found significant differences for ≥50% repigmentation between an excimer laser or NB-UVB.[77]

Side effects include a dose-dependent burning of the skin and hyperpigmentation of the skin. Targeted phototherapy
devices have been developed, which can be useful especially on visible areas such as the face and the hands. The risk
of skin cancer development is correlated with an increased number of phototherapy sessions.[78] While this association
is clear for photochemotherapy, the carcinogenic risk of NB-UVB treatment is less evident. No consensus exists on the
maximum number of NB-UVB treatments considered to be safe in vitiligo. Despite being one of the most effective
treatments to induce repigmentation, the limitations of phototherapy should be clearly explained to the patient. Complete
repigmentation is rarely observed and recurrences after phototherapy are frequent, especially without a (topical)
maintenance treatment.[75] Ultraviolet-induced tanning results in an increased contrast between pigmented and
depigmented areas, which can be bothersome and a reason to stop phototherapy.

Systemic Agents

Oral Corticosteroids. Oral corticosteroid mini-pulse therapy involves the use of moderate doses of corticosteroids (e.g.,
2.5–10 mg dexamethasone 2 consecutive days in a week) to arrest disease progression. Oral corticosteroid mini-pulse
(10 mg dexamethasone two times/weekly) therapy has been shown to stop disease progression in 88% of patients after
18.2 weeks of treatment.[79] However, repigmentation is only rarely observed. Side effects include weight gain, acne,
sleep disturbances, agitation, hypertrichosis, and menstrual abnormalities, which limits long-term use.[79] Combination
with NB-UVB is effective to stop progression and induce rapid repigmentation, although caution is warranted for long-
term side effects when combining UVB with systemic immunosuppressants.[80]

Antioxidants. A very heterogeneous collection of clinical trials has been published on the use of oral antioxidants. Most
studies are hampered by a limited patient size and confirmatory results are mostly lacking. As some studies document
that the combination of oral antioxidants (e.g., polypodium leucotomos, vitamin E, vitamin C) and NBUVB leads to
increased repigmentation rates, oral antioxidants can be considered in patients undergoing phototherapy.[81,82]

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Surgery

Pigment cell transplantation may offer a valuable alternative in a selected group of patients with vitiligo. Different
pigment cell transplantation techniques have been developed including cellular graft transplantation and tissue grafting
(e.g., punch grafting, split-thickness grafting, epidermal blister grafting). Regardless of the used technique, the stability
of the lesions is a major criterion linked to the outcome of the procedure. Pigment cell transplantation is most effective in
patients with stable segmental vitiligo.[83] In patients with non-segmental vitiligo, pigment cell transplantation has a
higher chance of an acceptable repigmentation if the disease is stable for at least 1–2 years and no Koebner
phenomenon is present.[58,83]

Combination Treatments

It should be noted that most treatments have an anti-inflammatory/immunosuppressive capacity that halts the immune
attack in vitiligo but has no direct effect on melanocyte differentiation, migration, and proliferation. Most patients with
vitiligo seem to retain melanocyte stem cells in the hair follicle bulge, which needs to be activated to induce
repigmentation.[84] Because of its complex pathogenesis, it makes sense to combine different treatments for vitiligo.[85]
Currently, NB-UVB is only rarely been used as monotherapy. The combination of NB-UVB with topical corticosteroids
and topical immunomodulators has been shown to increase repigmentation rates.[86] Some concerns have been raised
about the combined use of two immunosuppressants on the risk of skin cancer. In particular, the combination of NB-UVB
and topical immunomdulators has been a topic of debate.[87] No clear safety risks have currently been demonstrated,
although long-term follow-up data are not yet available.

Depigmentation

In patients with very extensive vitiligo (body surface area >50 to 60%) or disfiguring refractory vitiligo on the face or the
hands, depigmentation of the remaining pigmented areas can be considered. Different methods of depigmentation exist
such as bleaching creams (e.g., monobenzone ethyl ester), laser treatment, or cryotherapy. Monobenzone ethyl ester
requires a relatively long duration of treatment and a 5- to 12-month period can be necessary to achieve satisfactory
depigmentation. For laser and cryotherapy, multiple sessions are required. Repigmentation of previously depigmented
areas can occur regardless of the used method. Therefore, strict sun protection during and after depigmentation
procedures is advised to limit the chance of repigmentation.[88]

Cosmetic: Camouflage

Camouflage may be a valuable option.[89] A wide range of cosmetic products (including cover creams, self-tanners) is
available. Owing to individual differences in skin type, affected body locations, and personal preferences, patients often
need to be referred for specialized advice for camouflaging their vitiligo, which could reduce the daily impact of the
disease and social stress related to vitiligo. Caution is advised for permanent camouflage and tattoos as vitiligo can
progress over time. This could lead to unsatisfying results.

Future Perspectives

Currently, firm guidelines for the management of vitiligo are difficult because of the heterogeneity in vitiligo trials.
Important efforts have been undertaken for increased standardization. Using e-Delphi procedures, repigmentation, side
effects, and maintenance of pigmentation have been identified as the core outcome domains.[90] New outcome measure
instruments such as the Vitiligo Extent Score have also been developed to measure the extent of vitiligo.[91] This
progress could help to improve the comparability of future vitiligo trials and drawing of accurate conclusions for the daily
management of patients with vitiligo.

Biomarkers are being investigated that may help to identify patients with active disease and follow vitiligo activity during
treatment. In this way, the response of therapy may be monitored more efficiently. Further research is necessary to
confirm if these biomarkers could be used to follow individual patients over time to evolve towards a more personalized
treatment approach.

Based on recent research, several new treatment targets have been identified. The identification of a central role of the
IFN-γ-STAT1-CXCL10 pathway offers opportunities for targeted drug development.[92] Two case reports using Janus
kinase inhibitors (tofacitinib citrate and ruxolitinib) were published, demonstrating signs of repigmentation.[93,94] Topical
Janus kinase inhibitors are currently in the pipeline with clinical trials underway in pharmaceutical companies. Recently,
the topical Janus kinase 1/2 inhibitor ruxolitinib showed significant repigmentation in facial vitiligo.[95] Consistent
elevation of cytokines (especially IL-17, but also IL-2, IL-22, IL-23, and IL-33) has been documented in patients with
active vitiligo and these cytokines can also be considered as treatment targets.[36–39]

To date, vitiligo can be considered as a chronic progressive disorder that is only partially reversible in most patients. In
light of our expanding knowledge of the pathogenesis, stopping progression can be considered as an immunological
issue while stimulation of repigmentation involves the differentiation and migration of melanocytes. Both outcomes are

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therefore likely to require a different treatment approach. Currently, most trials are focusing on repigmentation, which is
contradictory as the majority of treatments are anti-inflammatory and do not necessarily induce repigmentation. Owing to
its complex pathogenesis, vitiligo may benefit most from combination treatments. Indeed, to date, the best results have
been obtained by combination treatments that work on both aspects.[85,96] Other molecules also need to be explored.
The use of topical prostaglandins is promising. A recent trial found that topical prostaglandin F2α analogs were at least
as effective as tacrolimus to induce repigmentation in combination with NB-UVB.[97]

Other methods to initiate melanocyte differentiation and proliferation need to be explored. The afamelanotide trial
combining NB-UVB with an alpha-melanocyte-stimulating hormone analog showed more repigmentation compared with
monotherapy with NB-UVB.[98] The best results were obtained in dark-skinned patients. The tanning-inducing capacity
of afamelanotide increases the contrast between lesional and healthy skin, which may however exert negative effects on
the quality of life.[99]

A better investigation into the working mechanisms of NB-UVB may lead to synergistic combination treatments. Wnt/β
catenin regulates melanocyte stem cell differentiation and Kit signaling induces migration of differentiated melanoblasts
in UVB-irradiated skin.[50] As the Wnt pathway can induce melanocyte differentiation and migration but is deregulated in
vitiligo skin, the development of Wnt agonists could be a new treatment for repigmentation.[49]

Conclusions

Non-segmental vitiligo is a multifactorial skin disorder with an immune-mediated melanocyte destruction as the main
underlying mechanism. The involvement of immunity is confirmed by genome-wide association studies pointing to an
elaborate interplay between immunoregulatory genes and melanocyte-specific genes. In contrast, segmental vitiligo is
most likely a mosaic genetic skin disorder and is less frequently associated with other autoimmune disorders. Treatment
includes topical corticosteroids and topical immunodulators and the first-line treatment for repigmentation remains NB-
UVB. Recent progression in the establishment of the core outcome measures for vitiligo, new measurement instruments,
and biomarkers pave the way for a new generation of targeted treatments, which will likely be tested in the coming
years. Nonetheless, combination treatments still offer the highest chance for successful repigmentation.

Sidebar
Key Points

Recent research and genetic profiling have provided new insights into the pathogenesis of both nonsegmental vitiligo
and segmental vitiligo.

New promising treatment targets have been discovered that offer hope for this challenging disorder. Current treatments
are effective but have limitations.

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Compliance with Ethical Standards

Funding This research was supported by a postdoctoral research grant to Reinhart Speeckaert from the Ghent
University Special Research Fund (BOF; Grant No. 01P12914) and a research grant to Nanja van Geel from the
Scientific Research Foundation-Flanders (FWO Senior Clinical Investigator; Grant No. FWO11/FKM/001).

Am J Clin Dermatol. 2017;18(6):733-744. © 2017 Adis Springer International Publishing AG

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