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Australasian Journal of Dermatology (2014) ,

doi: 10.1111/ajd.12256

REVIEW ARTICLE

Vitiligo treatment update

Benjamin S Daniel1 and Richard Wittal1,2
1

University of New South Wales, and 2Skin and Cancer Foundation, Sydney, New South Wales, Australia

ABSTRACT
Vitiligo is a common depigmenting disease that can
affect the skin and mucosal surfaces. Various treatments have been used over the years with varying
repigmentation rates. This review looks at the evidence of commonly used therapies for vitiligo.

Table 1 Classification of vitiligo according to the Vitiligo Global

Issues Consensus Conference (adapted from Ezzedine and colleagues2)
Vitiligo or non-segmental vitiligo
Acrofacial
Mucosal
Generalised
Universal

Key words: management, treatment, vitiligo.

INTRODUCTION
Vitiligo is a common acquired depigmenting skin disease
affecting about 0.5 to 2% of the population.1 The treatment
of vitiligo varies between countries, depending on the
patients skin type and access to treatments and facilities.
This review looks at the treatments for vitiligo and the
evidence supporting their use. According to the 2012 classification and consensus nomenclature,2 there are three
main types of vitiligo; namely, non-segmental vitiligo (NSV),
segmental vitiligo and undetermined/unclassified vitiligo
(Table 1). The term vitiligo includes the acrofacial,
mucosal, generalised and mixed subtypes. The common
differential diagnoses are listed in Table 2.

Quality of life (QoL)

Vitiligo has a significant impact on QoL, affecting activities
of daily living and personal relationships. Psychological
counselling and support is necessary in the management
of vitiligo, no matter how severe the disease. The effect on
QoL is not directly proportionate to the extent of the
disease and patients often worry that the disease will progress. Depression is common, affecting more than 50% of
patients with vitiligo, especially single patients or women
in the early years of the disease.3 Pre-existing low self-

Mixed
Rare variants
Segmental vitiligo
Uni-segmental, bi-segmental or
pluri-segmental
Undetermined/unclassified vitiligo
Focal
Mucosal

More than one mucosal site

affected
Complete or almost complete
depigmentation of skin/hair
Combination of SV and NSV

Often follows a dermatomal or

blaschkoid pattern
Small localised macules that are
not segmental or NSV
One mucosal site affected

NSV, non-segmental vitiligo; SV, segmental vitiligo.

esteem, impaired self-perception, poor coping methods

and inadequate social support contribute to the psychological impact of the disease.4 Due to time constraints,
however, it may be appropriate for dermatologists to
acknowledge the psychological impact of the disease by
referring patients to a psychologist or counsellor who can
address both the subjective and objective factors of the
condition. Various therapeutic regimens impact on a
patients QoL and should be considered when choosing an
appropriate treatment.5
Patient support groups are an important avenue through
which patients may find information about the disease and
meet others with the same condition. The Vitiligo Association
of Australia (www.vitiligo.org.au)6 is an active support group
set up in 2010 to support patients and families with vitiligo. It
has state branches which meet regularly and is associated
with international vitiligo patient support groups.

Abbreviations:
Correspondence: Dr Richard Wittal, University of New South
Wales, Sydney, NSW, Australia. Email: rwittal@bigpond.com
Benjamin S. Daniel, MBBS. Richard Wittal, FACD.
Conflict of interest: none
Submitted 29 August 2013; accepted 16 August 2014.
2014 The Australasian College of Dermatologists

MBEH
QoL
RCT
TCS
TNF

monobenzyl ether of hydroquinone

quality of life
randomised controlled trial
topical corticosteroids
tumour necrosis factor

2
Table 2

BS Daniel and R Wittal

Differential diagnoses for vitiligo

Pityriasis versicolor
Idiopathic guttate hypomelanosis
Tuberous sclerosis
Piebaldism
Discoid or systemic lupus erythematosus
Sarcoidosis
Scleroderma
Post-inflammatory hypopigmentation/depigmentation: e.g. atopic
dermatitis, psoriasis
Post-traumatic depigmentation (e.g. scars, burns)
Progressive macular hypomelanosis
Cutaneous T-cell lymphoma
Leprosy
Pityriasis alba
Melasma
Naevus anemicus, naevus depigmentosus, halo naevus
Leucoderma of variable causes: for example post-traumatic,
melanoma associated leucoderma
Amelanotic melanoma
Lichen sclerosus et atrophicus
Topical or drug-induced depigmentation

steroids but have a safer side-effect profile.14,15 Patients

with vitiligo have greater amounts of interleukin -10,
interferon- and tumour necrosis factor (TNF)- in their
skin compared to controls. Topical tacrolimus stimulates
melanocyte growth and reduces TNF- levels, resulting in
repigmentation.16 It is particularly effective on the face and
neck and when used in combination with phototherapy or
occlusive dressings. It should be applied twice a day for a
minimum of 6 months.17 The cost of topical tacrolimus
usually limits its use in widespread disease.1820
Unlike in other countries, most of the tacrolimus available in Australia has to be compounded in 0.03% and 0.1%
concentrations. The quality and efficacy of the product is
therefore variable, depending on the compounding
pharmacists.

Topical vitamin D3 analogues

Calcipotriol is effective when used in combination with
TCS, especially in difficult-to-treat areas such as the
eyelids.21,22 It is unknown if there is any significant advantage of using calcipotriol with phototherapy.2325

Camouflage

Antioxidants

Cosmetic and tanning products conceal the patchiness of

depigmented skin and improve the patients self-confidence
and QoL. Camouflage does not treat the underlying disease
and will not induce repigmentation. It is offered as conservative therapy for patients who do not wish to have
treatment.7

Oxidative stress and free radicals are thought to play a role

in the pathogenesis of vitiligo, with elevated levels of hydrogen peroxide in the epidermis of vitiliginous skin. Current
studies are evaluating the evidence and safety of these antioxidants, including the naturally occurring glutathione.
(Table 3) The evidence supporting the combination of
some antioxidants with phototherapy is poor. An Australian
randomised controlled trial (RCT) and other trials have
failed to show any benefit in adding pseudocatalase to
NBUVB.26,27 There is no additional benefit in applying topical
superoxide dismutase to phototherapy alone.28 Topical steroids in the form of 0.05% betamethasone may be just as
effective as topical catalase or dismutase superoxide in vitiligo.29 The combination of Polypodium leucotomos with
NBUVB resulted in a higher rate of repigmentation than a
placebo in the head and neck, especially in light-skinned
individuals.30
An Italian RCT treated 35 patients with non-segmental
vitiligo with NBUVB plus either oral antioxidants (two
tablets which contained -lipoic acid, vitamin C, vitamin E,
polyunsaturated fatty acids and cysteine monohydrate) or
placebo.31 A similar formulation is not currently available in
Australia. After 2 months the treatment group had a statistically significant increased rate of catalase activity and
reactive oxygen species production than the placebo group.
At 6 months significant repigmentation was evident in 47%
of those with antioxidants compared to 18% in the placebo
group.
Recent evidence suggests minocycline has antioxidant
effects and may be potentially beneficial in vitiligo.35,36

MEDICAL THERAPIES
Topical and oral corticosteroids
Topical corticosteroids (TCS) are used as first-line therapy
as monotherapy (e.g. in localised vitiligo), or in combination with phototherapy or other topical agents (e.g. in generalised vitiligo).8 Commonly prescribed TCS include
betamethasone dipropionate, clobetasol dipropionate and
mometasone furoate. Because of adverse effects and
tachyphylaxis, TCS should not be used for longer than 3
months and steroid holidays should be encouraged.9,10 Sideeffects are generally not noticed with short bursts of TCS.
Systemic corticosteroids halt disease progression and
induce repigmentation when used at the onset or early
stages of disease, in some cases resulting in complete
repigmentation.11,12 Short pulses of systemic corticosteroids
are used in international centres without long-term sideeffects. To stabilise rapidly expanding lesions within 14
months, an oral mini-pulse with dexamethasone 510 mg
for 2 days per week (the equivalent of prednisolone
2535 mg on Saturday and Sunday) can be used. This can be
combined with NBUVB.13

Calcineurin inhibitors

Immunosuppressive agents

Tacrolimus and pimecrolimus, as monotherapy or in combination with phototherapy, are just as effective as topical

Despite its autoimmune nature, immunosuppressive therapies have not been shown to be significantly beneficial.

2014 The Australasian College of Dermatologists

Therapies for vitiligo

Table 3

Evidence of antioxidants in vitiligo

Pseudocatalase

Superoxide dismutase and

topical catalase or
dismutase superoxide
Polypodium leucotomos

Antioxidants (containing
lipoic acid, vitamin C,
vitamin E,
polyunsaturated fatty
acids and cysteine
monohydrate)

Khellin

Phenylalanine

There are conflicting reports of the

beneficial use of pseudocatalase,
though RCTs, including an
Australian study, have shown no
additional benefit of
pseudocatalase compared to
NBUVB alone26,27
No proven benefit28,29

A RCT comparing Polypodium

leucotomos with NBUVB to
placebo found greater
repigmentation in the head and
neck area in light-skinned
patients than in those exposed to
the antioxidant30
RCT compared the NBUVB plus
either oral antioxidants or
placebo. After 2 months, the
treatment group had a statistically
significant increased rate of
catalase activity and reactive
oxygen species production than
the placebo group. At 6 months,
significant repigmentation was
evident in 47% of those with
antioxidants compared to 18% in
the placebo group31
Used in systemic or topical forms in
combination with UVA. It has
comparable repigmentation rates
as that of psoralens but with less
phototoxicity32,33
Induces some repigmentation when
used with UVA, though there are
safety concerns over excess
phenylalanine34

RCT, randomised controlled trial.

There are individual case reports of improvement with

methotrexate37 and i.v. immunoglobulin,38 though a pilot
study of methotrexate 25 mg/week for 6 months in six
patients with generalised vitiligo failed to show any clinical
improvement.39
Low-dose azathioprine is beneficial,40 with greater
repigmentation after 4 months with azathioprine (0.6
0.75 mg/kg/day) + PUVA than in PUVA alone (58 vs 25%,
P < 0.001).
RCT assessing cyclosporine and cyclophosphamide are
lacking.41 One report indicated one of six patients treated
with cyclosporine 6 mg/kg42 had a minimal to moderate
response, while another case report reported some
repigmentation on the face and forearms of a patient with
pemphigus vulgaris treated with combination dexamethasone and cyclophosphamide pulse therapy.43
Vitiligo seems to have a protective benefit against melanoma and non-melanoma skin cancers. A large cohort
study found the risk of melanoma and non-melanoma skin
cancer was less than one-third that of patients without
vitiligo.44

Figure 1 Previously depigmented area now shows follicular

repigmentation with NBUVB.

Phototherapy
Phototherapy is typically administered thrice per week and
is more effective if commenced early on in the disease.
It is used as first-line therapy in extensive disease. It can be
used in combination with topical therapies such as
corticosteroids, tacrolimus or calcipotriol.45
NBUVB is as effective as systemic PUVA but with fewer
side effects.46,47 It produces a better colour match and often
superior repigmentation with less erythema.48,49 About 56%
of patients get 50% improvement in body surface area with
NBUVB compared to 36% with PUVA.50
Using NBUVB with topical tacrolimus produces more than
50% repigmentation in the face, trunk and limbs.51 Acral
regions and the genitals, however, do not respond as well.
In a recent observational study, four patients with generalised vitiligo were treated with NBUVB and 4 monthly s.c.
implants of 16 mg afamelanotide. Repigmentation occurred
240 days after the afamelanotide implant with only mild
adverse effects reported.52
Though UVA alone can induce repigmentation, efficacy is
enhanced when administered with psoralen, with reports of
100% repigmentation on the head and neck.5355 In addition
to its numerous adverse effects, oral PUVA is associated with
hyperpigmentation and a noticeable difference between
affected and unaffected skin (Fig. 1).50,56
Time is the major limitation with phototherapy,57 with
some patients finding it difficult to attend centres with
phototherapy facilities. Alternatively, patients have acquired
their own UV machines or hand-held devices, which can be
dangerous given the absence of supervision and monitoring. Unsupervised exposure to UV machines can increase
the risk of all types of skin cancer and may not be beneficial
in the long term. The advent of in-built safety mechanisms
is important, but further studies are still required to assess
the safety of these home UV machines.
Targeted treatment with an excimer laser induces T-cell
apoptosis and stimulates melanocyte development and progression along the hair follicle.58 The excimer laser and
light sources are concentrated sources of NBUVB light that
2014 The Australasian College of Dermatologists

BS Daniel and R Wittal

is useful for safely treating small localised areas of vitiligo.

Two treatments are given weekly for about 6 weeks. The
cost is set by the operator and there is no Medicare rebate.
Repigmentation rates with an excimer laser are more rapid
than NBUVB and are enhanced when used in combination
with topical tacrolimus or steroids rather than as
monotherapy.59 The excimer lamp is just as effective
as excimer laser60 and can treat a larger area and is less
expensive.
Though the evidence is lacking, it is recommended that
phototherapy should continue for at least 3 months to halt
the disease and induce repigmentation. If the vitiligo
responds, then treatment can continue for up to 1 year.
Phototherapy should be ceased when there is no further
response. There is no evidence supporting maintenance
phototherapy.10

Measuring clinical response

Clinical response can be monitored with objective methods
such as clinical photographs and vitiligo area scoring index
scores. Technological advances with computer imaging
analysis software and accurate imaging techniques will
better assess the efficacy of treatments with skin changes.

Microtattooing/tattooing
Tattooing is useful for sites with a poor rate of
repigmentation such as the lips, nipples and distal fingers.
The tattoo colour often does not match the normal surrounding skin perfectly and may fade with time.

SURGICAL THERAPIES
Surgical therapies are reserved for patients with stable
disease who have failed medical treatments.61 They are typically used for difficult-to-treat areas such as the hands, feet,
lips and nipples,62 and better results have been demonstrated in segmental rather than generalised vitiligo. The
Koebner phenomenon should be explained to all patients
before they embark on surgical therapies for vitiligo.63
Tissue grafting and cellular suspensions are the two main
melanocyte transplantation techniques currently available
for stable vitiligo. Stable vitiligo is defined as an absence of
new areas of depigmentation or enlargement of existing
areas for at least 6 months. Success rates with surgical
therapies are dependent on patient selection, the stability of
disease and the absence of the Koebner phenomenon.
Tissue-grafting techniques include full thickness punch
grafts, epidermal blister grafts and split-thickness grafts.
Cellular grafting consists of cultured or non-cultured epidermal suspensions.
Mini-grafting (punch grafting) is performed by transplanting 12 mm full thickness punch biopsies of normally
pigmented skin into areas affected with vitiligo.62 It is time
consuming and has potential adverse effects, including
cobble-stoning and scarring, especially at the donor site
(Fig. 2).64
2014 The Australasian College of Dermatologists

Figure 2

Punch grafting.

Epidermal blister or suction blister grafting is performed

by inducing a blister in the depigmented recipient site with
either liquid nitrogen or topical PUVA and removing the
epithelium.62 Dermabrasion or similar blister formation by
negative pressure suction is used at the donor site to
remove the normally pigmented epithelium. Tissue grafting
techniques are time-consuming, need training and often
require special equipment such as vacuum equipment for
blister formation.
Split thickness grafts involve mechanical or chemical dermabrasion of the depigmented recipient skin to remove the
superficial epithelium followed by a split-thickness biopsy
of normally pigmented donor skin. The melanocytes from
this biopsy are prepared using either cultured or noncultured means and transplanted to the dermabraded skin.62
A review of surgical autologous transplantation techniques looking at 63 studies found the highest mean success
rates with split-thickness skin grafting (87%; 95% CI
8291%) and epidermal blister grafting (87%; 95% CI
8390%). The success rates of the other treatments varied
between 13 to 53%.62
ReCell (Avita Medical Europe, Royston, UK), a harvesting
kit used to prepare a non-cultured epidermal suspension
from a split-thickness skin biopsy65 is effective in obtaining
a good colour match66 but does not seem to be as effective
compared to standard cellular grafting techniques (Fig. 3).
Cultured melanocyte grafting is limited by expense,
timing of procedure and results. Non cultured grafting can
be performed faster with equivalent or better results
without the use of a research laboratory.67 Cultured suspension also has potential risk of transmission of viral infections and the development of malignancy.

DEPIGMENTATION TECHNIQUES
Depigmentation is reserved for patients with extensive or
recalcitrant disease. Though there is no consensus as to the
stage of disease that depigmentation should be initiated,68 it
is usually offered if greater than 60% body surface area is

Therapies for vitiligo

Patchy depigmentation, repigmentation upon cessation,

the need for ongoing sun avoidance, exposure to social
stigmas and cultural ramifications are the major issues
associated with depigmentation therapies. Systemic absorption of topical depigmentation agents can be toxic to
melanocytes in other parts of the body such as the eyes.73

Treatment with biologics

Figure 3 Application of melanocyte cell suspension following

dermabrasion.

involved or if visible areas such as the face and hands are

affected.68 Repigmentation, especially after cessation of the
depigmenting agent, can occur.69
Depigmenting therapies include monobenzyl ether of
hydroquinone (MBEH), monomethyl ether of hydroquinone,
88% phenol, laser and cryotherapy.
Though the exact mechanism of action of MBEH, also
known as monobenzone or p-(benzyloxy)phenol, remains
unknown, hypopigmentation is noticed after 3 months of
application with complete depigmentation within 12
months.70 A retrospective study found complete depigmentation in up to 44% of patients treated with 20% MBEH, with
hypopigmentation in a further 33%. No hypopigmentation
occurred in 22% and one patient ceased treatment due to
contact dermatitis. The strength of MBEH is determined by
the response and reported adverse effects. 20% MBEH
should be the initial strength, which can be decreased to 5%
if contact dermatitis occurs. If no response is noticed after 3
months, then the strength can be gradually increased from
20 to 40%.71
In Australia, MBEH has to be compounded at a pharmacy.
The quality and effectiveness of the product may vary, given
it is non-standardised. Adverse effects include burning and
itching, erythema, dryness, contact dermatitis and oedema,
irregular patchy depigmentation with unpredictable
hypopigmentation and hyperpigmentation and nail discolouration. Burning and itching may be alleviated by combining MBEH with emollients.70
Depigmentation with topical 4-methoxyphenol, also
known as monomethyl ether of hydroquinone, mequinol or
p-Hydroxyanisole occurs after 4 months,68 with slower
response rates than with MBEH. Adverse effects include
mild burning, itching, leucoderma and repigmentation after
sun exposure.72
Lasers such as Q-switched alexandrite and ruby laser
selectively destroy melanocytes inducing depigmentation.73
Eight patients who did not respond to 4-methoxyphenol
received one treatment of Q-switched ruby laser (694 nm).
Four (50%) reported pain and three had depigmentation.

Because of the higher levels of TNF- in lesional and perilesional skin, it is thought that blocking TNF- may reduce
melanocyte destruction and promote melanocyte stem cell
differentiation.74 This is supported by a case report in which
a patient with ankylosing spondylitis had amelioration of his
vitiligo when treated with infliximab.75 Despite this,
infliximab, adalimumab and etanercept were not effective
in a recent small case series.76 In fact, there is concern that
biological agents and TNF-inhibitors worsen and trigger
vitiligo.77,78 New onset vitiligo just 6 weeks after commencing infliximab for ulcerative colitis79 as well as worsening of
existing vitiligo have been reported. Similarly, adalimumab
has been implicated as a possible trigger for vitiligo.80,81
Clinical improvement with rituximab needs to be confirmed with larger studies. Further studies are required to
determine whether a causal relationship between vitiligo
and biologics exists and if there is a therapeutic role for TNF
inhibitors.

Future therapies
Gene therapy is a potential treatment in the future, with
research into the pathophysiology of vitiligo and the
methods and effectiveness of gene therapy and stem cell
treatments.82
Ongoing studies are assessing the evidence and safety of
combining phototherapy with various antioxidants such as
piperidine, capsaicin, L-carnosine and curcumin.83 Other
potential agents currently under investigation include
statins, basic fibroblast growth factors, prostaglandin E2
analogues and COX-2 inhibitors. A trial assessing the effect
of afamelanotide in 60 patients is underway. Promising
results have been demonstrated in small or pilot studies
with topical bimatoprost (0.03% twice/day), a prostaglandin
F2-alpha analogue ophthalmic solution and topical
photocil.84,85
CO2 laser, micrografting, microphototherapy, the utilisation of melanocytes from the outer root sheath of hair follicles and dressings post-vitiligo surgery are also being
investigated.10,83
In the future, treatments or vaccines targeting specific
components of the immune system such as heat shock proteins may be effective in preventing or halting disease.86
There is evidence that inducible heat shock proteins may
prevent depigmentation.87 The chemokine CXCL 10 is
elevated in the skin and serum of patients with vitiligo. The
inhibition of CXCL 10 in mouse models results in
repigmentation, suggesting a possible therapeutic target
(Fig. 4).88
2014 The Australasian College of Dermatologists

BS Daniel and R Wittal

1st Line
Conservave therapy

Counselling, psychological assistance, paent support groups

No treatment

Topical
Corcosteroids
Vitamin D analogues(e.g. calcipotriol)
Calcineurin inhibitors(e.g. tacrolimus, pimecrolimus)

Limited
disease

Camouage and
sunscreens
2nd Line
Extensive
disease

3rd Line

Phototherapy +/- topicals, anoxidants,

khellin, phenylalanine

Surgical therapies(e.g. punch graing, autologous

melanocyte transplantaon, split thickness gra,
blister gra) or laser

Systemic immunosuppressive agents

In adults with extensive diseasere calcitrant to

other therapies, consider depigmentaon

Figure 4

Treatment options for Vitiligo.

CONCLUSION
Despite progress in recent years, treating vitiligo still
remains challenging, requiring a systematic approach
which addresses a patients needs, QoL and expectations.
Future studies will advance our knowledge about the
disease, its pathophysiology and genetics, and therapeutic
options available to treat it.

7.

8.

9.

10.

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