DY Nonsurgical Repigmentation Therapies in Vitiligo Meta-analysis of the Literature M.D. Njoo, MD; P. 1. Spuls, Objectives To assess the effectiveness and safety of non- surgical repigmentation therapies in localized and gen- eralized vitiligo by means of a meta-analysis. Data Sources: Computerized searches of biblio- ‘graphic databases, a complementary manual literature search, and contacts with researchers and pharmaceut- cal firms. ‘Study Selection: Predefined selection criteria were ap- plied to both randomized and nonrandomized con- trolled tials, Data Extraction: Two investigators independently as- sessed the articles for inclusion. When there was a dis- agreement, a third investigator was consulted Data Synthesis: Sixty-three studies were found on therapies for localized vitiligo. OF these, 10 of 11 ran- domized controlled trials and 29 of 110 patient series were included. One hundred seventeen studies on thers- pies for generalized vitiligo were found. Of these, 10 of 22 randomized controlled trials and 46 of 231 patient series were included, Among randomized controlled tri- als on localized vitiligo, the pooled odds ratio vs placebo MD; J. D. Bos, MD, PRD; W. Westerhof, MD, PRD; P. M. M, Bossuyt, MD, PhD \vas significant for topical class 3 corticosteroids (14.32; 95% confidence interval [Cl], 245-83.72). In the patient series, topical class 3 and class 4 corticosteroids carried the highest mean success rates (56% [95% Cl, 50%- 69296] and 55% [95% Cl, 4994-019], respectively). Side elfects were reported mostly with topical psoralen and {ntralesional and class 4 corticosteroids, In the random- ized controlled trials on generalized vitiligo, the odds ralio vs placebo was significant for oral methoxsalen plus sunlight (23.37; 95% C1, 1.33-409.03), oral psor- alen plus sunlight (19.87; 95% Cl, 2.37-166.32), and oral tioxsalen plus sunlight (3.75; 05% C1, 1.24-11.29). In the series, the highest mean success rates were achieved with narrowband UV-B (63%; 95% Cl, 50%- 76%), broadband UV-B (57% 05% Cl, 20%-82%), and oral methoxsalen plus UV-A therapy (51%: 05% Cl +46%6-56%). Oral methoxsalen plus UV-A was associated with the highest rates of side elfects. No side effects were reported with UV-B therapy Conelustons: Class 3 corticosteroids and UV-B therapy are the most effective and safest therapies for localized and for generalized vitiligo, respectively Arch Dermatol, 1998;134:1532-1540 ITILIGO ISan acquired skin disorder characterized by sharply demarcated depig- ‘mented lestons with vari- groups of patients, active treatment can be considered, Nonsurgical repigmentation thers- ples represent the first-line active treal- From the Netherlands Institute {for Pigmentary Disorders (Drs Njoo and Westerhof) and the Departments of Dermatology (Drs Spal, Bos, and Westerhof) and Clinical Epidemiology and Biostatistics (Br Bossuyd), Academie Medical Cener, University ‘of Amsterdam, Amsterdam, the Netherlands Downloaded From: on 08/28/2018 able size and shape that have the tendency to expand over time. It fs estimated that about 1% of the world population is alfected by the disease, re- gardless of age, sex, and skin color." There are several possible ap- proaches in the management of vitiligo. Some patients can be reassured simply by explaining the nature of the skin con- dition and by giving advice on the use of camoullage products and suun-protective measures. In others, especially in the dark-skinned population, vitiligo may cause disfigurement that can lead to seri fous impairment of the quality of life? In certain cultures, patients with vitiligo are slill regarded as social outcasts, For these (©1908 American Med ‘ment modality in vitiligo. Currently best studied and therefore most applied are oral and topical psoralen plus UV-A (PUVA), phenylalanine plus UV-A, oral and top cal khellin plus UV-A, UV-B narrowband and broadband therapy, and corticoste- roids (oral, topical, and intralesional).** There are many studies reporting on the clinical effectiveness and safety of the various treatments in vitiligo. Guid lines and review articles*” have been pub- This article is also available on our Web site: www.ama-assn.org/derm. Association, All rights reserved.METHODS DATA SOURCES ‘The computerized bibliographic databases MEDLINE (Na- tional Library of Medicine, Bethesda, Md) and EMBASE (Elsevier Science BV, Amsterdam, the Netherlands) were screened for clinical tials from January 1966 to Decem- ber 1997. No language restrictions were applied. As main key words (including analogs and derivatives), we used “vi ligo,” “phototherapy.” "PUVA therapy,” “ultraviolet therapy,” “phenylalanine,” *khellin,” "glucocorticoste- roids synthetic,” and ~anti-inflammatory agents.” Other sources were abstract books of symposia and congresses, theses, textbooks, monographs, reviews, editorials, letters to the editor, fee of rapid communications, and the rel- rence lists from all the aticles retrieved. Also, 21 leading suthortiesin the field of vitiligo and 9 pharmaceutical com= panies were contacted to provide us with any additional published and unpublished references ‘The studies were divided into those describing therapies for localized vitiligo and those reporting on therapies for generalized vitiligo. Localized vitiligo was defined as viiligo affecting less than 20% of the total body surface.” STUDY SELECTION: INCLUSION AND EXCLUSION CRITERIA ‘Two investigators (M.D.N. and W.W.) independently as. sessed the articles for inclusion, When there was a dis agreement, a third investigator (P.MLM.B.) was consulted. Included were both randomized controlled trials (RCTS) and nonrandomized controlled trials on oral and topical psoralen plus sunlight or artificial UV-A (both sources were termed UV-A), including methoxsalen, ti oxsalen, bergapten, and unsubstituted psoralen (PS); UV-B broadband and narrowband; phenylalanine plus sunlight or UV-A; oral and topical khellin plus sunlight oF UV-A; and corticosteroids (oral, topical, and intrale- sional). Topical corticosteroids were divided into class 3 (potent corticosteroids"), which included the drugs bet rmethasone valerate and halometasone, and clas # ("very potent corticosteroids"), which included clobetasol pro- plonate. With regard (o intralesionsl administration of corticosteroids, studies using triamcinolone acetonide ‘were included. In studies on photoradiation, both navural sunlight and arificial UV-A were used in the same patient series. These UV sources were regarded as equally ellec- tive, provided that sun exposure was performed between. IL AMtand 2 px? Excluded were double publications, combination therapies, studies that used obsolete drug(s) fr dosage schemes, studies that reported on fewer than 5 patients, and Studies with insufficient data on ef fectiveness Nonrandomized controlled trials were also analyzed as patient series, Because comparative or placebo- ‘ontolled tals can contain a description of at least 2 pa tient series, the total number of patient series could ex ceed the total number of studies included, Incase of double publications, the most elaborate pub- lication was selected DATA EXTRACTION Analysis of RCTS “Treatment was regarded as successul when more than 75% repigmentation was achieved. The odds ratio (OR) was used sstheelfect messurein thismeta-anaysisbecauseit regarded ‘sthe most satisfactory metric with which to combine across trials with discrete outcomes. The OR describes the adds of successful event (ie, >75% repigmentation) ina patient re- ‘ving the active therapy relative toa patient receving the pla cebo.Asaresult,an OR greater than 1 indicates greater eflec- tiveness of the ative therapy compared with the placho. “To obtain a more precise estimate ofthe treatment el- fect, ORs were combinted across similar tials. A random- effects model according to DerSimonian and Laird" was ‘used to pool these ORS and to calculate their 95% conf dence intervals (Cis). The random-effects model was pre~ ferred over the fixed-elfects model because study poptla- tions and treatment outcomes in these tials were expected. tobe statistically heterogencous, although all RCTs met the speciicselection criteria, Calculations were done with Meta Analyst soltware for MS-DOS (Joseph Lau, Boston, Mass). Analysis Based on Patient Series Sample size-sveighted averages were calculated foreach mo- dalty by dividing the total numberof patients who achieved ‘more than 75% repigmentation by the total numberof pa- tients in the included series. The 95% Cls ofthese aver- ages were calculated with the computer program Cont dence interval Analysis for MS-DOS (British Medical Journal London, England) by means ofthe exact method. “The weatment duration (range and mean values) wasalso determined foreach treatment modality. Treatment-specific Side ellecte wereestimatedby dividing the numberof patients with side effects bythe total numberof paticnts studied. For cach study, sample size-sweighted averages ofthese requen- cesand their 95% Cla were calculated with the same software fs was used for calculation ofthe succes aes, DATA SYNTHESIS Fifieen of the 21 leading authorities and 7 of the 9 pha ‘maceutical firms contacted replied and provided us wit further relevant references. No study required a third r= viewer to resolve disagreements about selection, lished on how and in which patients these treatments should be applied. However, these recommendations ‘were based on data obtained From only a limited num- ber of references and on personal and institutional prel- erences, No methodological information was given on how these guidelines had been developed. Because none of these articles included a systematic literature search, hhas been shown that review articles in journals or in textbooks, even if they were recently published, contain unsound, imprecise, and biased information”! According to the principles of evidence-based medi- cine, the best medical care is provided by integrating the "best external evidence, a obtained from clinically relevant re- is likely that relevant studies were missed. IL (©1908 American Med Downloaded From: on 08/28/2018 Association, All rights reserved.‘Table 1. Therapy for Localized Vitlig: Results ofthe Literature Search” ‘oan Wan conten ova “un” We Gane mee ie orate ond 8 7 8 7 Ne foutd ugh dase > 4 2 0G "rat or daitce, 6 mo so ss im tt andonzed conto tis 0 2 2 ke PS indeaes unsubstituted psorae, ‘Table 2. Therapies for Localized Vitiligo and Pooled ORs and 95% Cis (Random Etfects Model)" Toit) [peceenals es aca) 22 ton(ox0909) OR nates oda; Cl, confidence terval, {sa Stndard option, te computer program Met-Ana (sep Lu, Boston, search studies into the daily practice." Combin- ingall relevant studies in a meta-analysis ean increase the power and preciston of estimates om effectiveness and side effects profiles.” The development of guidelines for the choice of the most effective and safest therapy in vitiligo sshoulld be based also on the available evidence in the lit. erature." We therefore performed a meta-analysis of the available literature on the most widely used forms of non- ‘surgical repigmentation therapy, with regard to both ef- fectiveness and sale (as THERAPIES FOR LOCALIZED VITILIGO Randomized Controlled Trials Literature Search, With regard to therapies for local- ized vitiligo, 63 studies were found. Eleven RCTs were identified, of which 10 met our eligibility eri (able 1)" One study on class 3 corticosteroids was ‘excluded because it was a double publication (same trial published in 2 languages). The method of randomiza- tion was not reported in any of the studies found. Effectiveness. Pooled ORs showed nonsignificant dif- ferences between class 4 corticosteroids (OR, 1.00; (©1908 American Med Downloaded From: on 08/28/2018 gh doable Bing pace conte comparative study, nd WA not apokab is) eorectsa dae by 08, ralestonal corticosteroids (OR, 1.42; 05% Cl, 0.31-7.78), topical khellin 2%-3%) plus UV-A (OR, 1.18; 95% Cl, 0.38-3.62), or topical khellin (GX) plus UV-A (OR, 1.00; 95% Cl, 0.39-2.54) and their respective placebos. Class 3 corticosteroids had a pooled OR of 14.32 (05% Cl, 2.45-83.72) vs placebo (Table 2), Patient Series Literature Search. A total of 110 patient series could be identified, of which only 29 series could be included, re- porting on 993 patients (Fable 3). Thi topical methoxsalen plus UV-A were excluded because obsolete drug compositions were used (such as methox- salen plus 8-isoamylencoxypsoralen) or because 19% con- centration instead of the currently advised 0.1% concen- tration of methoxsalen solution was used. Reasons for exclusion of patient series are listed in Table 3. In cases in which several criteria of exclusion were applicable, only the most important one was listed. en series with Effectiveness, Figure ¥ shows that class 3 corticost roids had the highest percentage of patients achieving more than 75% repigmentation (56%: 95% Cl, 50%- 62%), followed by class 4 corticosteroids (35%; 95% Cl, 499-619) Association, All rights reserved.