BJD

S Y S TE M A T IC R E V IE W British Journal of Dermatology

Evidence-based management of vitiligo: summary of a

Cochrane systematic review
M. Whitton,1 M. Pinart,2,3,4,5 J.M. Batchelor,6 J. Leonardi-Bee,7 U. Gonzalez,8 Z. Jiyad,9 V. Eleftheriadou6 and
K. Ezzedine10,11,12
1
Cochrane Skin Group, University of Nottingham, Nottingham, U.K.
2
Centre for Research in Environmental Epidemiology (CREAL), Barcelona, Spain
3
Hospital del Mar Research Institute (IMIM), Barcelona, Spain
4
CIBER Epidemiolog
a y Salud P
ublica (CIBERESP), Barcelona, Spain
5
Department of Experimental and Health Sciences, University of Pompeu Fabra (UPF), Barcelona, Spain
6
Centre of Evidence Based Dermatology and 7Division of Epidemiology and Public Health, University of Nottingham, Nottingham, U.K.
8
Unit of Dermatology, CL
INICA GO&FER, Barcelona, Spain
9
Department of Dermatology, St Georges Hospital, London, U.K.
10
Department of Dermatology, AP-HP, H^opital Henri Mondor, Cr
eteil, France
11
EA EpiDermE (Epid
emiologie en Dermatologie et Evaluation des Th
erapeutiques), UPEC, Cr
eteil, France
12
Universit
e Paris-Est Cr
eteil, Cr
eteil, France

Summary

Correspondence
Jonathan M. Batchelor.
E-mail: jonathan.batchelor@nottingham.ac.uk
Accepted for publication
1 December 2015
This is a summary of an update of a
Cochrane review published in the
Cochrane Library Issue 2, 2015
(http://www.thecochranelibrary.com).
Funding sources
None.
Conflicts of interest
J.M.B. was an investigator on the HI-Light Pilot
randomized controlled trial (RCT), and is chief
investigator for the main HI-Light Vitiligo Trial.
He has previously attended or lectured at educational
events that were partly or fully funded by sponsorship
from pharmaceutical companies including Astellas,
Dermal, Galderma, LEO Pharma, Pfizer and Stiefel
(a GSK company). V.E. conducted and led the HI-
Light Pilot RCT, as part of her PhD funded by the
National Institute for Health Research. She is also a
coapplicant on the main HI-Light Trial. M.W. is a
coapplicant on the HI-Light Pilot RCT and on the
main HI-Light Trial. The other authors declare no
conflicts of interest.
Vitiligo affects around 1% of the worlds population. Despite it being relatively
common, there is still no effective treatment. The objective of this study was to
update the Cochrane systematic review of randomized clinical trials (RCTs) to eval-
uate the efficacy of treatments for vitiligo. We carried out searches of a range of
databases to October 2013 for RCTs of interventions for vitiligo regardless of lan-
guage or publication status. At least two reviewers independently assessed study eli-
gibility and methodological quality and extracted data using data extraction forms
approved by the Cochrane Skin Group. Our primary outcomes of interest were
quality of life, > 75% repigmentation and adverse effects. We retrieved 96 studies,
of which 39 were new studies, with an overall total of 4512 participants. Repig-
mentation was assessed in all studies, although only five reported on all three of
our primary outcomes. Regarding our two secondary outcomes, six studies mea-
sured cessation of spread but none assessed long-term permanence of repigmenta-
tion at 2 years follow-up. Most of the studies evaluated combination treatments,
which generally showed better repigmentation than monotherapies. Of the new
studies, seven were surgical interventions. The majority of the studies had fewer
than 50 participants. The quality of the studies was poor to moderate at best. Very
few studies specifically included children or participants with segmental vitiligo.
Five years after the last update of this review, there are still important variations in
study design and outcome measures in clinical trials for vitiligo, limiting the evi-
dence for the efficacy of different therapeutic options. The best evidence from indi-
vidual trials showed short-term benefit from topical corticosteroids and various
forms of ultraviolet radiation combined with topical preparations. Long-term fol-
low-up and patient-rated outcomes should be incorporated into study design, and
more studies should assess psychological interventions.

DOI 10.1111/bjd.14356

Whats already known about this topic?

Vitiligo is a skin disease with limited treatment options.
Most of the published vitiligo clinical trials are of poor methodological quality.

962 British Journal of Dermatology (2016) 174, pp962969 2015 British Association of Dermatologists
 Evidence-based treatments for vitiligo, M. Whitton et al. 963

What does this study add?

There are still important variations in study design and outcome measures in viti-
ligo clinical trials.
Individual trials showed short-term benefit from topical corticosteroids and various
forms of ultraviolet combined with topical preparations.
Long-term follow-up and patient-rated outcomes should be incorporated into study
design, and more studies should assess psychological interventions.

Vitiligo is the most common depigmenting skin disease, with
an estimated prevalence of 1% of the population worldwide.
The disease seems to affect people of all skin types and ethnic
groups equally.1 In the last decade considerable progress has
been made in the understanding of the pathogenesis of viti-
ligo, and the disease is now clearly classified as autoimmune
with a probable genetic background associated with metabolic,
oxidative stress and cell detachment abnormalities.2 Although
vitiligo is still considered by a number of physicians to be a
cosmetic disease, its effects can be psychologically devastating,
often with a considerable burden on daily life.3 Because of the
complex interactions between different factors in vitiligo, a
variety of different treatments are used, although none of
them is fully satisfactory. Possible treatment options include
topical corticosteroids, calcineurin inhibitors, vitamin D
derivatives, phototherapy [ultraviolet (UV)A, narrowband
UVB, photochemotherapy with psoralen plus UVA (PUVA),
psoralen with sunlight], surgical techniques and combinations
of topical therapies and light treatment. Combinations of these
different treatments have also been tested in the last few years.
This review is a summary of the Cochrane systematic review
update including randomized controlled trials (RCTs) to evalu-
ate the efficacy of treatments for vitiligo.4,5
Methods
We conducted an update of a systematic review of RCTs, fol-
lowing on from the original review published in 2006 and a
first update published in 2010. We used a prespecified proto-
col and strategy (Table S1; see Supporting Information). We
included RCTs assessing all types of interventions used in the
management of vitiligo in people of all age groups with any
type of vitiligo (Table S2; see Supporting Information).
Index to Nursing and Allied Health Literature. In addition, a
PubMed alert received by the lead author allowed us to iden-
tify recently published relevant RCTs. We performed a final
prepublication search on 16 October 2014. Although the RCTs
identified in this final search could not be included in the
review, relevant references are listed in Table S3 (see Support-
ing Information); these will be incorporated into the next
review update. Ongoing trials and unpublished literature are
listed in Table S4 (see Supporting Information). We included
studies in languages other than English if they met the inclu-
sion criteria and could be translated.
Selection criteria
Two of the review authors first checked the titles and abstracts
identified in the search and independently assessed the full
text of all potentially relevant studies. At least two authors
checked whether the trials met the inclusion criteria; in case
of any disagreements, consensus was reached after discussion,
involving a third author if necessary. We considered the fol-
lowing three primary outcome measures: quality of life
(QoL), objective measurement of percentage repigmentation
(success rate in terms of > 75% repigmentation) and adverse
effects. We presented the percentage of repigmentation as
> 75% repigmentation on the body surface, as these levels are
regarded as clinically important. We also considered two sec-
ondary outcomes: cessation of spread of vitiligo, and stabiliza-
tion and long-term permanence of repigmentation up to
2 years after treatment. Cessation of spread of vitiligo is
defined as no increase in the size of individual vitiligo patches
measured objectively within a period of (i) < 1 year or (ii)
1 year.

Quality assessment and data extraction

Search strategy
For this update, we reran our existing search strategy for the
Cochrane Skin Groups Specialized Register (Table S1). We
also searched the following databases up to 15 October 2013:
Cochrane Central Register of Controlled Trials (the Cochrane
Library Issue 10, 2013), Medline, Embase, PsycINFO, Allied
and Complementary Medicine, Latin American and Caribbean
Health Science Information database, and the Cumulative
The criteria to assess the methodological quality of the
included studies comprise the following elements of risk of
bias: random sequence generation (selection bias), allocation
concealment, blinding (participant, clinician and assessor) and
incomplete outcome data. Two authors independently
extracted data from potentially eligible RCTs using data extrac-
tion forms approved by the Cochrane Skin Group. Discrepan-
cies were resolved by discussion among the review authors.

2015 British Association of Dermatologists British Journal of Dermatology (2016) 174, pp962969
964 Evidence-based treatments for vitiligo, M. Whitton et al.
Statistical analysis
For the primary outcomes, we have expressed the results as
risk ratios (RRs) with 95% confidence intervals (CIs) for
dichotomous outcomes, and differences in means with 95%
CIs for continuous outcomes. For within-participant study
designs reporting dichotomous outcomes, we expressed the
results as conditional odds ratios with 95% CIs. Dichoto-
mous outcomes are presented as > 75% repigmentation on
the body surface. Where data are presented as other
dichotomous categories (i.e. not as 75%), we calculated RRs
but did not present the data in the figures. For dichoto-
mous outcomes, where small numbers of events were seen
in the intervention groups, P-values were reported using
Fishers exact test. Where possible, we conducted analyses
based on intention to treat.
For studies with a similar type of active intervention, we
performed a meta-analysis to calculate a weighted treatment
effect across trials, using a random-effects model. We assessed
statistical heterogeneity using the I2 statistic. Where it was not
possible to perform a meta-analysis, we summarized the data
for each trial and have presented forest plots only for primary
outcome measures. We considered a P-value < 0
05 as statisti-
cally significant.
Records identified through the Cochrane
Skin Group Specialised Register, CENTRAL in
Identification
the Cochrane Library, Medline, Embase,
AMED, PsycINFO, CINAHL and LILACS
databases (n = 430)
Records screened
Screening
(n = 430)
Full-text articles assessed
for eligibility
Eligibility
(n = 52)
Studies included in the
updated search
(n = 39)
Included
Total studies included in the
updated review
(n = 96; includes 57 studies
from previous update)
British Journal of Dermatology (2016) 174, pp962969
Results
In this update, we assessed 96 trials, including 39 new trials
and 57 from the previous 2010 update, with a total of 4512
participants (Fig. 1; Table S2). Most of the RCTs, which cov-
ered a wide range of interventions, had fewer than 50 partici-
pants. Most of the studies included participants with
nonsegmental vitiligo. One study included participants with
segmental vitiligo only. Two studies specified the type of viti-
ligo included as localized or generalized. One study included
only participants with localized vitiligo. Sixteen studies
assessed any type of vitiligo, including segmental vitiligo. The
remaining studies did not specify the type of vitiligo. Only
seven trials were conducted on children. All of the studies
assessed repigmentation, five measured cessation of spread,
and nine investigated the effect of treatment on QoL. Most of
the studies [65 of the total 96 (68%) and 33 of 39 new trials
(85%)] assessed adverse events.
The trials evaluated a wide range of interventions including
topical treatments, light therapies, oral treatments, surgical
methods and psychological therapies. Fifty-four percent of the
new studies (21 of 39) assessed new interventions and 33% (13
of 39) assessed single interventions, whereas the rest assessed
combination interventions, mainly with some form of light
Records excluded
(n = 378)
Full-text articles excluded (n = 13)
Nonrandomized studies (n = 9)
Inadequate method of
randomization (n = 4)
Fig 1. PRISMA flowchart for the literature
search.
2015 British Association of Dermatologists

therapy. Combination interventions generally gave better results.
Only five studies reported on all of our three primary outcomes,
namely QoL, > 75% repigmentation and adverse effects.
We analysed the data from 25 of the 55 parallel-group
studies that met at least one of our main outcome criteria.
Ten analyses from studies comparing various interventions
showed a statistically significant difference between the num-
ber of participants achieving > 75% repigmentation. Most of
these were from studies that assessed combination interven-
tions, which generally included some form of light treatment.
Topical preparations, in particular corticosteroids, caused the
most adverse effects, although in the combination studies it
was difficult to ascertain which treatment caused these effects.
None of the studies was able to demonstrate long-term bene-
fits. We found only one study of psychological interventions,
published in 2004, and none evaluating micropigmentation,
depigmentation or cosmetic camouflage. There are 32 studies
awaiting classification. We did not include these studies in the
review either, because they were published after the date of
our final search or because we have insufficient evidence of
randomization (Table S3).
Primary outcomes
Quality of life
Although vitiligo has a major negative psychosocial impact,
only nine studies (out of 96) assessed our primary outcome
of QoL (Table S2).
Both Skindex-296,7 and the Dermatology Life Quality
Index814 were used in studies to assess QoL. Other instru-
ments such as the Childrens Dermatology Life Quality Index
were also used.8,11 Only one study reported QoL as the pri-
mary outcome measure.11 There was only one study12 where
the investigators found a statistically significant result for this
outcome, which showed a result in favour of a melanocyte
suspension suspended in the patients own serum, compared
with suspension in normal saline (P = 0
005). However, there
were insufficient data to enable us to perform an analysis.
Repigmentation > 75%
Fifty-three of the 96 studies included in this update (55%)
assessed this primary outcome, 25 of which were published
since the last update in 2010 (Table S2). However, not all
of the studies used objective methods of assessing repig-
mentation, and so we were often unable to analyse the
data. The studies also used a wide range of methods to
measure successful repigmentation. In this update we
found only eight studies reporting statistically significant
repigmentation, as we were more specific about the defini-
tion of > 75% repigmentation, and included only studies
that reported this outcome as follows: > 75%, 75%, 75
90%/100% or 7690%/100%. We were able to carry out
only one meta-analysis of three studies for this outcome, in
which 60% more participants achieved > 75% repigmenta-
2015 British Association of Dermatologists
Evidence-based treatments for vitiligo, M. Whitton et al. 965
tion with narrowband (NB)-UVB compared with PUVA.
However, this was not statistically significant (RR 1
60,
95% CI 0
743
45; I2 = 0%) (Fig. 2a).
Adverse effects
Sixty-five of the 96 studies (68%) assessed adverse effects
(Table S2). This percentage increased in the update, as 33 of
39 (85%) of the new studies assessed this outcome. Most
studies examining topical corticosteroids reported adverse
effects common to this class of drug, including folliculitis,
atrophy, telangiectasia and acneiform lesions. However, one
study15 reported no adverse effects in participants treated with
mometasone furoate 0
1%, and another16 reported no adverse
effects with hydrocortisone butyrate 0
1%. Most studies that
examined the use of topical calcineurin inhibitors used tacroli-
mus 0
1% ointment, and the main adverse effects reported
were a burning sensation, pruritus, erythema, atrophy and
facial flushing after alcohol intake.
In terms of light therapy, new PUVA studies reported
adverse effects similar to those reported previously, such as
erythema, pruritus, nausea, dizziness and thickening of the
skin. One study17 reported that adverse effects were more
common with PUVA than with NB-UVB, and two participants
in this study discontinued oral PUVA therapy due to severe
dizziness. Similar adverse effects were reported with broad-
band (BB)-UVA, particularly with low-dose BB-UVA, which
caused itching, burning, erythema and thickening of the skin.
With regard to NB-UVB, phototoxic reaction and Koebneriza-
tion were reported, as well as transient itching and dryness of
the skin in several older studies. One study18 assessed oral
psoralen with NB-UVB vs. NB-UVB alone. Nausea was
reported in the former group, and a phototoxic reaction,
depigmentation and hyperpigmentation in both groups.
Curiously, a meta-analysis of adverse events in three studies
showed a significantly greater risk of nausea for NB-UVB than
for PUVA (RR 0
13, 95% CI 0
020
69; I2 = 0%; three studies,
n = 156) (Fig. 2b). This is unusual, as psoralen is expected to
cause nausea in some people but NB-UVB does not characteristi-
cally cause nausea. Surgical interventions such as punch grafts or
minigrafts sometimes led to adverse effects, for example cobble-
stoning, scarring, graft depigmentation and graft displacement.
Suction blister grafts or split-skin grafts led mainly to the Koeb-
ner phenomenon, which is of major clinical importance. It can
also cause hypopigmentation or, to a lesser extent, hyperpig-
mentation, scarring and infection at both donor and recipient
sites. All participants undergoing fractional carbon dioxide laser
reported pain and burning sensation during laser treatment, and
erythema or oedema after laser treatment.
Secondary outcomes
Cessation of spread of vitiligo
Six studies assessed the secondary outcome of cessation of
spread of vitiligo or stabilization of the disease. There was
British Journal of Dermatology (2016) 174, pp962969
966 Evidence-based treatments for vitiligo, M. Whitton et al.

(a)
Study or subgroup NB-UVB PUVA Risk Ratio Weight Risk Ratio
M-H,Random, M-H,Random,
n/N n/N 95% CI 95% CI
Sapam 201217 4/25 2/25 228% 200 [040, 995]

Yones 200714 0/28 0/28 Not estimable

Bhatnagar 200730 9/25 6/25 772% 150 [063, 359]

Total (95%CI) 78 78 1000% 160 [074, 345]

Total events: 13 (NB-UVB), 8 (PUVA)
Heterogeneity: Tau2 = 00; Chi 2 = 010, df = 1 (P = 076); I 2 = 00%
Test for overall effect: Z = 121 (P = 023)
Test for subgroup differences: Not applicable

01 02 05 1 2 5 10
Favours PUVA Favours NB-UVB

(b)
Study or subgroup NB-UVB PUVA Risk Ratio Weight Risk Ratio
n/N n/N M-H, Random, 95% CI M-H, Random, 95% CI

1 Nausea
Sapam 201217 0/25 2/25 319% 020 [001, 397]

Yones 200714 0/28 2/28 318% 020 [001, 399]

Bhatnagar 200730 0/25 8/25 363% 006 [000, 097]

Subtotal (95% CI) 78 78 1000% 013 [002, 069]

Total events: 0 (NB-UVB), 12 (PUVA)
Heterogeneity: Tau2 = 00; Chi2 = 050, df = 2 (P = 078); I 2 =00%
Test for overall effect: Z = 239 (P = 0017)
2 Itching
Bhatnagar 200730 3/25 4/25 555% 075 [019, 301]

Sapam 201217 2/28 5/28 445% 040 [008, 189]

Subtotal (95% CI) 53 53 1000% 057 [020, 160]

Total events: 5 (NB-UVB), 9 (PUVA)
Heterogeneity: Tau2 = 00; Chi 2 = 035, df = 1 (P = 055); I 2 =00%
Test for overall effect: Z = 107 (P = 028)
3 Erythema
Sapam 201217 0/28 2/28 09% 020 [001, 399]

Yones 200714 17/25 23/25 991% 074 [055, 099]

Subtotal (95% CI) 53 53 1000% 073 [055, 098]

Total events: 17 (NB-UVB), 25 (PUVA)
Heterogeneity: Tau2 = 00; Chi 2 = 090, df = 1 (P = 034); I 2 = 00%
Test for overall effect: Z = 212 (P = 0034)

001 01 1 10 100
Favours NB-UVB Favours PUVA

Fig 2. (a) Meta-analysis of studies assessing narrowband ultraviolet B (NB-UVB) vs. psoralen + UVA (PUVA). (b) Meta-analysis of adverse effects
in the included studies. CI, confidence interval.

only one study19 that showed the superiority of the active

Long-term repigmentation
intervention over placebo, in which participants receiving oral
Ginkgo biloba were more than twice as likely to achieve cessation None of the studies assessed long-term repigmentation (at
of spread than those receiving placebo (RR 2
20, 95% CI 2 years follow-up).
1
223
95).

British Journal of Dermatology (2016) 174, pp962969 2015 British Association of Dermatologists

Fig 3. Summary of risk-of-bias assessment.
Quality assessment
Table S5 (see Supporting Information) shows the criteria used
to assess the methodological quality of the included studies,
and Figure 3 summarizes our findings. The methodological
quality of the studies was poor to moderate at best. The
method for generating the randomization sequence was
reported clearly in about two-thirds of the studies, although
concealment was not reported clearly in the majority of these.
In all other assessments of methodological quality, more than
half of the studies had a high risk of bias.
Discussion
Since the last update of this Cochrane systematic review pub-
lished in 2010, the number of published vitiligo trials has
increased considerably. We identified 96 studies, of which 39
were added in this current update (Table S6; see Supporting
Information). More than half of the 39 new studies assessed
new interventions, most of which were new combination
therapies. Light therapy remains the most common interven-
tion assessed in this update, either as monotherapy or in com-
bination with other treatments. Sixty-five studies of various
types of light therapies were assessed in total. Twenty-seven
were new studies and 38 were from the previous two versions
of the review. In this update there was also a notable increase
in the number of studies assessing surgical interventions for
stable vitiligo (Table S7; see Supporting Information), as well
as topical calcineurin inhibitors (tacrolimus and pime-
crolimus), reflecting a tendency to use these agents instead of
topical corticosteroids, which may produce more adverse
effects. However, we found no studies on camouflage, depig-
mentation or psychotherapy in the updated search. The only
study using psychological interventions was from the original
review.
There has also been a small but noticeable improvement in
the quality of the design of some of the more recent studies,
but overall the methodological quality of studies remains
highly variable, and is often very poor. There is increased
awareness of the importance of good reporting of trials, such
as that proposed in the CONSORT statement,20 and this is
reflected in the greater quality of reporting in a few, but by
no means all, of the studies in this update.
We were unable to establish contact with several principal
investigators and coinvestigators of the studies for clarification
2015 British Association of Dermatologists
Evidence-based treatments for vitiligo, M. Whitton et al. 967
or retrieval of missing study details. We were unable to assess
studies for publication bias due to the small number of studies
assessing similar interventions. Similarly, funding sources for
each individual study were not reported in this review, which
may have led to potential inaccuracies in assessment of the
risk of bias of the included studies.
Most of the studies in this review update have small num-
bers of participants, due mainly to the large numbers of intra-
participant studies (40 of 96, 42%). Caution should be
exercised when drawing conclusions from underpowered
studies such as these. The majority of studies included partici-
pants with symmetrical vitiligo, so segmental vitiligo was
under-represented. Very few studies were carried out specifi-
cally on children, despite the fact that the onset of vitiligo is
often before the age of 20 years. We included studies with
heterogeneous design, thus hindering firm recommendations
for clinical practice.
In conclusion, vitiligo remains something of an orphan
disease. Although many treatments are currently used for its
management, none is licensed specifically for vitiligo and
none is fully effective.1 Previously published reviews and
studies5,21,22 are broadly in agreement with our findings,
particularly regarding the need for better study design and
reporting, and the use of validated patient-rated outcome
measures.23
It is important to stress that there is currently neither a cure
for vitiligo nor an effective method of limiting the spread of
the disease. The small numbers of participants and heterogene-
ity of design of the studies in this review make it difficult to
make firm recommendations for clinical practice. In general,
combination interventions were superior to monotherapies;
the majority of analyses giving significant results were from
studies assessing various combination treatments. Most of
these studies used light therapies (UVA, PUVA or UVB, partic-
ularly NB-UVB) and laser light therapies.
Although there is empirical evidence in the literature to
support the use of cosmetic camouflage to improve the QoL
of people with vitiligo,2426 there were no trials of this inter-
vention. Vitiligo does not have major physical symptoms but
there is increasing evidence that it can have a significant
impact on QoL and self-esteem.27,28 Therefore, there may be
some people with vitiligo who require more in-depth psycho-
logical support than the use of cosmetic camouflage. The
2010 update retrieved only one study comparing cognitive
behavioural therapy and person-centred approaches. No new
British Journal of Dermatology (2016) 174, pp962969
968 Evidence-based treatments for vitiligo, M. Whitton et al.
studies assessing psychological therapies were found for this
update.
Despite the recommendations of the 2010 update of this
Cochrane review, there is still no consensus on which out-
come measures should be used for vitiligo trials. Standardiza-
tion of outcomes is also crucial. The agreed outcomes used in
trials for vitiligo treatments should be reliable, clinically rele-
vant and important to both clinicians and patients. Recently, a
core outcomes set for future vitiligo trials was agreed upon
by a large international group of patients, clinicians and
representatives of regulatory authorities. This project was
coordinated by the International Federation of Pigment Cell
Societies,29 and work is ongoing, with the aims of defining
unified scales to measure the core outcomes set and develop-
ing patient-rated outcomes. Implementation of unified scales
and outcomes will facilitate meta-analysis of future vitiligo tri-
als and produce robust clinical recommendations.
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2015 British Association of Dermatologists
 Evidence-based treatments for vitiligo, M. Whitton et al. 969

Table S4. Characteristics of ongoing studies.

Supporting Information Table S5. Methodology used for each of the risk-of-bias
Additional Supporting Information may be found in the online domains.
version of this article at the publishers website: Table S6. Summary of new studies included in this update
Table S1. Search terms and equations used for this review of the review.
update. Table S7. Surgical treatments.
Table S2. Characteristics of the included studies.
Table S3. Characteristics of the studies awaiting classifica-
tion.

2015 British Association of Dermatologists British Journal of Dermatology (2016) 174, pp962969