the efficacy of 308-nm excimer laser/light (el) and topical agent combination therapy versus el...

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ORIGINAL ARTICLE

The efficacy of 308-nm excimer laser/light (EL)and topical agent combination therapy versus EL

monotherapy for vitiligo: A systematic review andmeta-analysis of randomized controlled trials (RCTs)

Jung Min Bae, MD, PhD,a Bo Y oung Hong, MD, PhD,b Joo Hee L ee, MD,a

Ji Hae Lee, MD, PhD,a and Gyong Moon Kim, MD, PhDa

Suwon, Korea

Background: Combination therapies of excimer laser/light (EL) and various topical agents are widely usedin the treatment of vitiligo.

Objective: We sought to compare the efficacy of EL and topical agent combination therapy versus ELmonotherapy for vitiligo.

Methods: Manual searches of reference lists and computerized searches of the MEDLINE, EMBASE, andCochrane library (from inception through December 15, 2014) were conducted to identify randomizedcontrolled trials that assessed the efficacy of EL alone or in combination with topical agents for vitiligo. Theprimary outcome was treatment success ($75% repigmentation), and the secondary outcome wastreatment failure (\25% repigmentation); meta-analyses were performed when possible.

Results: We analyzed 8 randomized controlled trials comprising a total of 425 patches/patients. Thecombination of EL and topical calcineurin inhibitors (4 studies: relative risk 1.93, 95% confidence interval1.28-2.91; number needed to treat 4.5, 95% confidence interval 2.9-10) was superior to EL monotherapy for

vitiligo. There was insufficient evidence to support beneficial effects of topical vitamin-D3 analogs(3 studies) and corticosteroids (1 study).

Limitations: These findings are based on small numbers of randomized controlled trials andheterogeneities among included studies are another limitation.

Conclusion: Topical calcineurin inhibitors in conjunction with EL are more effective compared with ELmonotherapy. ( J Am Acad Dermatol http://dx.doi.org/10.1016/j.jaad.2015.11.044.)

Key words: excimer laser; laser; pimecrolimus; tacrolimus; topical calcineurin inhibitor; vitiligo.

V itiligo is one of the major challenging skindiseases in that there is no definitive curativetreatment although a number of interven-

tions have been tried.1 Phototherapy is a mainstay of vitiligo treatment with varying rates of efficacy.

Narrowband (NB)-ultraviolet (UV)B and psoralen

plus UVA have been used for decades, and recently xenon chloride excimer laser/light (EL) therapy was approved by the US Food and Drug Administration for the treatment of vitiligo.2 EL emitsa monochromatic light of 308 nm and induces

photobiological effects similar to those of NB-UVB.

From the Department of Dermatologya and the Department of

Rehabilitation Medicine,b St. Vincent’s Hospital, College of

Medicine, The Catholic University of Korea.

Drs Bae and Hong contributed equally to this work.

Supported by the Basic Science Research Program through the

National Research Foundation of Korea (NRF) funded by the

Ministry of Science, ICT and Future Planning (NRF-2014

R1A1A1036218).

Conflicts of interest: None declared.

Accepted for publication November 9, 2015.

Reprint requests: Jung Min Bae, MD, PhD, Department of

Dermatology, St. Vincent’s Hospital, College of Medicine, The

Catholic University of Korea, 93 Jungbu-daero, Paldal-gu,

Suwon, 442-723 Korea E-mail: [email protected]. Or: Gyong

Moon Kim, MD, PhD, Department of Dermatology, St. Vincent’s

Hospital, College of Medicine, The Catholic University of Korea,

93 Jungbu-daero, Paldal-gu, Suwon, 442-723 Korea E-mail:

[email protected].

Published online January 15, 2016.

0190-9622/$36.00

2015 by the American Academy of Dermatology, Inc.

http://dx.doi.org/10.1016/j.jaad.2015.11.044

1

http://dx.doi.org/10.1016/j.jaad.2015.11.044http://dx.doi.org/10.1016/j.jaad.2015.11.044http://dx.doi.org/10.1016/j.jaad.2015.11.044http://dx.doi.org/10.1016/j.jaad.2015.11.044


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It delivers higher fluence to the depigmentedlesions while sparing uninvolved skin, andclinical studies have shown that EL treatment hadbetter clinical outcomes than NB-UVBphototherapy.3,4 EL treatment also had a faster onsetof repigmentation and required fewer treatmentsessions for a successful response compared withconventional phototherapy,and is currently consideredthe treatment of choice forlocalized vitiligo.5

Topical agents includingcorticosteroids, calcineurininhibitors, and vitamin-D3analogs have also been usedto treat vitiligo with mixedoutcomes.1 However, anincreasing number of

reports suggest that topicalagents may produce syner-gistic effects when combined with phototherapy or EL.6-8

This systematic review of randomized controlled trials(RCTs) compared the efficacy of 308-nm EL alone orin combination with topical agents for vitiligo. Wealso performed meta-analyses of all relevant trialsthat compared EL and topical agent combinationtherapy with EL monotherapy.

METHODSThis systematic review was performed according

to the Preferred Reporting Items f or SystematicReviews and Meta-Analyses statement.9

Search strategy A comprehensive database search was indepen-

dently conducted by 2 reviewers (J. M. B. and Jo. H.L.). The following databases were searchedfrom inception to December 15, 2014: MEDLINE(accessed via PubMed), EMBASE, and theCochrane Central Register of Controlled Trials.

RCTs were identified by a highly sensitive searchstrategy 10 using the following search terms:‘‘vitiligo,’’ ‘‘topical,’’ ‘‘phototherapy,’’ ‘‘excimer,’’‘‘laser,’’ ‘‘ultraviolet,’’ and ‘‘UVB.’’ All publishedarticles limited to human studies with no languagerestriction were included, and the reference lists of all available review articles and RCTs were alsoscanned manually.

Study selection RCTs were selected based on the following inclu-

sion criteria: (1) participants were children or adults

with a diagnosis of vitiligo; (2) at least 1 arm treated

with the combination of EL and any topical agent andat least 1 EL arm; (3) at least 10 subjects or patches ineach treatment arm irrespective of dropout rates; and(4) treatment for more than 12 weeks or 24 sessionsof EL therapy. Exclusion criteria were: (1) duplicatepublication; and (2) control group treated with othermodalities besides EL alone.

All vitiligo subtypes wereincluded in this systematicreview. Laser and light emitidentical 308-nm monochro-matic light and their effectsare known to be similar, thusboth of them were consid-ered as 1 treatment (EL) inthis review.11,12 The use of oral antioxidants in trials wasallowed, because the sole

use of these agents is not aneffective treatment for viti-ligo13,14 and may not impactoutcomes if applied equally to both arms.

Two independent reviewers (J. M. B. and Jo. H. L.) examined the titlesand abstracts of the identified articles. When ab-stracts did not provide sufficient informationregarding inclusion and exclusion criteria, a full-text evaluation was performed to determine eligi-bility. The reviewers compared their results, and

discrepancies were resolved through discussion,and, if necessary, by arbitration of the third reviewer(B. Y. H.).

Assessment of the risk of biasThe quality of the RCTs was determined by

2 reviewers (J. M. B. and B. Y. H.) using theCochrane Collaboration risk-of-bias tool, whichassesses random sequence generation, allocationconcealment, blinding of participants and personnel,blinding of outcome assessment, incompleteoutcome data, selective reporting, and other bias. All parameters were categorized as low, unclear, orhigh risk of bias.15

Outcome measuresThe primary outcome of interest was the

proportion of treatment success, defined as 75% ormore repigmentation of each designated patch or whole lesion in a patient. The results of othermeasurements were excluded. The secondary outcome was the proportion of treatment failure,defined as less then 25% repigmentation of each

designated patch or whole lesion in a patient. The

CAPSULE SUMMARY

d Excimer laser/light (EL) in combination

with topical agents is widely used for the

treatment of vitiligo.

d This systematic review demonstrates

that topical calcineurin inhibitors in

combination with EL are more effective

than EL monotherapy.

d The use of topical calcineurin inhibitorsshould be encouraged to enhance the

response to EL treatment in patients

with vitiligo.

J A M A CAD DERMATOLn 2015

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primary authors were contacted for further informa-tion when necessary.

Data extraction Two reviewers (J. M. B. and Jo. H. L.) indepen-

dently read the eligible reports in detail, andabstracted relevant information using a standardextraction sheet that covers the study design,number and description of participants, targeted

subtype and duration of vitiligo, type of topicaltreatments, details of the EL treatment protocols,and primary and secondary outcomes. An intention-to-treat analysis was planned, and dropouts wereincluded in the analysis, if possible.

Data synthesisMeta-analyses were carried out separately for

categories of topical agents as follows: (1) topicalcalcineurin inhibitors, (2) vitamin-D3 analogs, and(3) corticosteroids. A meta-analysis of relative risks(RRs) was performed using the generic inverse

variance method.Heterogeneity across studies was evaluated using

the x 2 test and Higgins I 2 statistic. When substantialheterogeneity was observed ( P \ .1 for the x 2 testand an I 2 value[50%), a random effects model wasapplied. Otherwise, a fixed effects model was used.To aid the interpretation, the number needed to treat was calculated on the basis of the pooled RRs.Funnel plots were used to assess publication biasqualitatively. The meta-analyses were performedusing Review Manager, Version 5.3.5 (NordicCochrane Center, Copenhagen, Denmark).

RESULTSSearch results

A total of 258 records were identified throughsystematic bibliographic retrieval, and 13 articlesremained after the screening of titles andabstracts by the 2 independent reviewers (Fig 1). A total of 13 full-text articles were assessed for eligibility,5 of which were excluded for the followingreasons: (1) published only in abstract form(n = 1)16; (2) no combination therapy (n = 1)17;(3) difference in outcome measures (n = 2)18,19;

and (4) not an RCT (n = 1).

20

Finally, 8 RCTs involving

276 patients met the inclusion criteria and wereincluded in this review.6-8,21-25 A total of 214 patchesor patients were included in the combination therapy group and 211 patches or patients were included inthe EL monotherapy group. The type of topical agent was a calcineurin inhibitorin4 studies,6,7,22,24 vitamin-D3 analog in 3 studies,21,23,25 and corticosteroid in 1study.8

Description of included studies All included studies were RCTs (Table I). The

type of EL intervention was excimer laser in 6studies6-8,21,22,25 and excimer light in 2 studies.23,24

Six were within-patient trials6,7,21-23,25 and theremaining 2 were parallel trials.8,24 Three studiestargeted adults,6,8,21 1 targeted children,22 and theother 4 had no age limits.7,23-25

Risk of bias in included studies All of the included studies were described as

randomized. However, the blinding of participantsand investigators was considered inadequate in allbut 2 studies. The results are summarized in therisk-of-bias graph (Fig 2), which provides anoverview of the reviewers’ judgments of eachitem presented as percentages across all includedstudies. Fig 3 shows the risk-of-bias summary of eachrisk-of-bias item for each included study.

Effect of interventions

Topical calcineurin inhibitors. Four RCTscompared the efficacy of EL and topical calcineurininhibitor combination therapy versus EL monother-apy.6,7,22,24 The type of calcineurin inhibitor used was tacrolimus in 3 studies6,7,24 and pimecrolimus in1 study.22 A total of 104 combination therapy and101 monotherapy cases or patches were included(Table II). Fixed effects pooling of the resultsshowed that combination therapy had a significantsuperior effect on the treatment success of vitiligo(4 studies: RR 1.93, 95% confidence interval [CI]1.28-2.91; number needed to treat 4.5, 95% CI 2.9-10)

(Fig 4). Visual inspection of the forest plot andstatistical testing demonstrated negligible between-study heterogeneity (I2 = 0%, P = .40). Thecombination therapy also significantly reducedtreatment failure in vitiligo (4 studies: RR 0.43, 95%CI 0.24-0.76). The funnel plot did not indicatepublication bias (graph not shown).

Topical vitamin-D3 analogs. Three RCTscompared the efficacy of EL and topical vitamin-D3analog combination therapy versus EL monother-apy.21,23,25 The success rates of both groups were 0 in2 RCTs21,25 and thus quantitative synthesis including

meta-analyses was not possible. Combination

Abbreviations used:

CI: confidence intervalEL: excimer laser/lightNB: narrowbandRCT: randomized controlled trialRR: relative riskUV: ultraviolet

J A M A CAD DERMATOL V OLUME jj, NUMBER j

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therapy showed significantly better effect in 1 RCT(1 study; RR 4.5, 95% CI 1.04-19.47). Regarding thesecondary outcome, the combination therapy had nosignificant effect on reducing the treatment failure

rate (3 studies; RR 0.82, 95% CI 0.59-1.13). Topical corticosteroid. One RCT showed a

significant better effect of topical corticosteroidcombined with EL versus EL alone (1 study; RR 2.57, 95% CI 1.20-5.50), however, the informationabout treatment failure meeting our predeterminedsecondary outcome was not provided.8

DISCUSSIONEL was recently introduced for the accurate,

targeted treatment of vitiligo.2,3 EL also demon-strated superior efficacy and a faster response

compared with NB-UVB for vitiligo,4,26

and its higherirradiance (mW/cm2) was indicated to be crucial tothe induction of immature pigment cell develop-ment.27 However, EL treatment is not effective in allpatients with vitiligo, and the combination treat-ments with topical remedies are widely applied tomake EL treatment more effective in clinical practice.

According to this systematic review, thecombination therapy of EL and topical calcineurininhibitors was more effective than EL monotherapy (RR 1.93, 95% CI 1.28-2.91); this finding is supportedby the highest level of evidence in the hierarchy of

evidence with a low level of heterogeneity (I

2

= 0%,

P = .40). Our results showed that the administrationof topical calcineurin inhibitors to 4.5 subjectsreceiving EL treatment for vitiligo is necessary for 1subject to improve (number needed to treat 4.5, 95%

CI 2.9-10). The addition of topical calcineurininhibitors to EL also reduced the treatment failurerate (\25% repigmentation) (RR 0.43, 95% CI0.24-0.76).

Calcineurin inhibitors selectively inhibit theintracellular protein calcineurin and subsequently suppress tumor necrosis factor-a and interferon-g expression, which is involved in the pathogenesis of vitiligo.28 In addition, tacrolimus increases theproduction of stem cell factor and matrixmetalloproteinases 2 and 9, and directly enhancesnot only the proliferation of both melanocytes and

melanoblasts, but the migration of melanocytes as well.29,30 Although there are concerns on risk of carcinogenic mutations when UV exposure andimmunosuppressant drugs such as calcineurininhibitors are applied simultaneously, tacrolimus was actually shown to be protective againstUV-induced DNA damage and erythema by inhibiting early-phase inflammatory events.24,31

Calcineurin inhibitors have also been suggested toincrease the tolerability to phototherapy through animmunomodulatory mechanism.24

Three RCTs assessed the efficacy of topical

vitamin-D3 analogs combined with EL. However,

Fig 1. Flow diagram of the identification of selected studies.


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Table I. Characteristics of studies included in this review

Study Country Study design Vitiligo subtype

Participants

(age range, y),

Fitzpatrick

skin type

Mean disease

duration,

y (range) Topical tr ea

1. Topical calcineurin inhibitors

Kawalek et al,6

2004

United States RCT DB WP Symmetric stable vitiligo

vulgaris over 6 mo

8 Adults

(31-51), I-V

ND Topical tacrol

ointment (P

Astellas, ToJapan)

Passeron et al,7

2004

France RCT nonblind

WP

Symmetric vitiligo vulgaris 14 Children and

adults (12-63),

II-IV

18.1 (3-33) Topical tacrol

0.1% ointm

(Protopic, A

Toyama, Ja

Hui-Lan et al,22

2009

China RCT SB WP Symmetric vitiligo vulgaris 49 Children

(6-14), II-IV

1.31 (0.5-3) Topical pimec

1% cream (

Novartis

Pharmaceu

Basel, Switz

Nistico et al,24

2012

Italy RCT nonblind

PT

Acrofacial and segmental

vitiligo

28 Children

and adults

(13-56), II-IV

2.17 (ND) Topical tacrol

0.1% ointm

(Protopic, A

Toyama, Ja

2. Topical vitamin-D3 analogs

Lu-yan et al,23

2006

China RCT SB WP Vitiligo vulgaris and

segmental vitiligo

38 Children

and adults

(6-65), ND

7.7 (0.25-20) Tacalcitol oint

(Bonalfa-hig

Teijin Pharm

Japan)

Goldinger et al,21

2007

Switzerland RCT SB WP Symmetric vitiligo 10 Adults

(24-60), II-IV

ND Calcipotriol cr

(Daivonex,

LEO Pharm

Regensdorf

Switzerland

Oh et al,25 2011 Korea RCT SB WP Nonsegmental vitiligo 20 Children

and adults(15-60), ND

4.1 (0.5-11) Tacalcitol oint

(Bonalfa-higTeijin Pharm

Japan)

3. Topical corticosteroid

Sassi et al,8 2008 Italy RCT nonblind

PT

Focal or generalized vitiligo

(face and/or neck)

84 Adults

(18-75), I-IV

20.1 (ND) Hydrocortison

17-butyrate

cream (ND)

DB, Double-blind; ND , not determined; PT , parallel trial; RCT , randomized controlled trial; SB , single-blind; WP , within-patient trial.


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we did not perform a meta-analysis for the primary outcome because 2 studies showed no treatmentsuccess in either treatment group.21,25 Although 1RCT23 showed significantly better effect of thecombination therapy, it is hard to conclude thatcombination therapy of topical vitamin-D3 analogsand EL is more effective than EL monotherapy.Moreover, the combination of topical vitamin-D3analogs and EL was not shown to be effective inreducing the treatment failure rate compared with ELmonotherapy (3 studies; RR 0.82, 95% CI 0.59-1.13). It was also difficult to determine the beneficial effect of

topical corticosteroids combinedwithEL based on just1studyconductedbySassietal.8 Moreclinical trials areneeded to decide the efficacy of the combinationtherapies with EL and these topical agents.

This review has some limitations. First, there may be therapies that showed no significant difference inefficacy but have meaningful benefits in practice.These benefits may not have been captured becauseof insufficient sample size or the limitations of theavailable outcome measures. Second, the treatmentduration of 12 weeks or 24 sessions was too short toestimate true efficacy in treatment of vitiligo. Third, we included all vitiligo subtypes, races, and agegroups in the quantitative analyses, and a variety of excimer instruments and different treatment pro-tocols. Fourth, the use of oral antioxidants in bothgroups was allowed in this review, and it could beeffective in combination with either EL or EL andspecific topical agents. Lastly, some RCTs included inthis systematic review conducted withoutappropriate blinding of participants or personnel,and might have possible risk of bias. However, weattempted to present the best conclusion with limitednumbers of RCTs as objectively as possible according

Fig 2. Risk-of-bias graph. Our judgments of each risk-of-bias item are presented aspercentages across all included studies.

Fig 3. Risk-of-bias summary. Our judgments of eachrisk-of-bias item for each included study.


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Table II. Interventions and clinical outcomes in the studies included in this review

Study Country

Enrolled

patients/

patches

Excimer laser/light protocol

Intervention

Completed

patients/patc Type Frequency Duration

1. Topical calcineurin inhibitors

Kawalek et al,6

2004

United States T: 12 Patches Laser Three times

weekly

24 sessions

or 10 wk

T: Excimer laser 1 topical

tacrolimus 0.1%

T: 10 Patche

C: 12 Patches C: Excimer laser 1 placebo

(Aquaphor, Beiersdorf Inc,

West Chester, OH)

C: 10 Patche

Passeron et al,7

2004

France T: 23 Patches Laser Twice

weekly

24 sessions T: Excimer laser 1 topical

tacrolimus 0.1%

T: 23 Patche

C: 20 Patches C: Excimer laser C: 20 Patche

Hui-Lan et al,22

2009

China T: 49 Patches Laser Twice

weekly

30 sessions T: Excimer laser 1 topical

pimecrolimus 1%

T: 48 Patche

C: 49 Patches C: Excimer laser C: 48 Patche

Nistico et al,24

2012

Italy T: 20 Patients Light Twice

weekly

12 wk T: Excimer light 1 topical

tacrolimus

0.1% 1 oral vitamin E

T: 20 Patien

C: 20 Patients C: Excimer light 1 oralvitamin E

C: 20 Patien

T’: 13 Patients T’: Oral vitamin E T: 12 Patien

2. Topical vitamin-D3 analogs

Lu-yan et al,23

2006

China T: 38 Patches Light Once

weekly

12 wk T: Excimer light 1 tacalcitol T: 35 Patche

C: 38 Patches C: Excimer laser 1 vehicle C: 35 Patche

Goldinger

et al,21 2007

Switzerland T: 10 Patches Laser Three times

weekly

24 sessions T: Excimer laser 1 calcipotriol T: 9 Patches

C: 10 Patches C: Excimer laser 1 placebo C: 9 Patches

Oh et al,25

2011

Korea T: 20 Patches Laser Twice

weekly

16 wk T: Excimer laser 1 tacalcitol

C: Excimer laser

T: 16 Patche

C: 16 PatcheC: 20 Patches

T’: 13 Patches T’: Tacalcitol T’: 13 Tacalc

3. Topical

corticosteroid

Sassi et al,8

2008Italy T: 42 Patients Laser Twice

weekly12 wk T: Excimer laser 1

hydrocortisone

17-butyrate hydrophilic

cream

T: 40 Patien

C: 42 Patients C: Excimer laser C: 36 Patien

C, Control; ITT, intention to treat; NA, not available; PP, per protocol; T, treatment; T 9 , other treatment.


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to predetermined inclusion and exclusion criteria,and our results have several implications ontreatment strategies in patients with vitiligo.

In summary, this systematic review revealed that

adding topical calcineurin inhibitors on EL

yields significantly superior outcomes than EL mono-therapy. Addition of topical vitamin-D3 analogs ortopical corticosteroids on EL showed insufficientevidence to support their use in combination thera-

pies. Considering the difficulties in complete

Fig 4. The efficacy of 308-nm excimer laser/light alone or in combination with topicaltreatments for vitiligo. Topical calcineurin inhibitors ( A and B), vitamin-D3 analogs (C and D),and corticosteroid (E). CI , Confidence interval.


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recovery of vitiligo, the combination therapiesenhancing the treatment response are promising.However, more clinical trials are needed to deter-mine the efficacy of diverse combinations with EL.

We wish to thank Dr Sang Ho Oh for providing

important data from his randomized controlled trial of combination treatment for nonsegmental vitiligo using a308-nm excimer laser and topical tacalcitol.

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