Nonsurgical Repigmentation Therapies in Vitiligo Meta-Analysis of the Literature

STUDY Nonsurgical Repigmentation Therapies in Vitiligo Meta-analysis of the Literature

M. D. Njoo, MD; P. I. Spuls, MD; J. D. Bos, MD, PhD; W. Westerhof, MD, PhD; P. M. M. Bossuyt, MD, PhD

Objective: To assess the effectiveness and safety of non- was significant for topical class 3 corticosteroids (14.32; surgical repigmentation therapies in localized and gen- 95% confidence interval [CI], 2.45-83.72). In the patient eralized vitiligo by means of a meta-analysis. series, topical class 3 and class 4 corticosteroids carried the highest mean success rates (56% [95% CI, 50%- Data Sources: Computerized searches of biblio- 62%] and 55% [95% CI, 49%-61%], respectively). Side graphic databases, a complementary manual literature effects were reported mostly with topical psoralen and search, and contacts with researchers and pharmaceuti- intralesional and class 4 corticosteroids. In the random- cal firms. ized controlled trials on generalized vitiligo, the odds ratio vs placebo was significant for oral methoxsalen Study Selection: Predefined selection criteria were ap- plus sunlight (23.37; 95% CI, 1.33-409.93), oral psor- plied to both randomized and nonrandomized con- alen plus sunlight (19.87; 95% CI, 2.37-166.32), and trolled trials. oral trioxsalen plus sunlight (3.75; 95% CI, 1.24-11.29). In the series, the highest mean success rates were Data Extraction: Two investigators independently as- achieved with narrowband UV-B (63%; 95% CI, 50%- sessed the articles for inclusion. When there was a dis- 76%), broadband UV-B (57%; 95% CI, 29%-82%), and agreement, a third investigator was consulted. oral methoxsalen plus UV-A therapy (51%; 95% CI, 46%-56%). Oral methoxsalen plus UV-A was associated Data Synthesis: Sixty-three studies were found on with the highest rates of side effects. No side effects were therapies for localized vitiligo. Of these, 10 of 11 ran- reported with UV-B therapy. domized controlled trials and 29 of 110 patient series were included. One hundred seventeen studies on thera- Conclusions: Class 3 corticosteroids and UV-B therapy pies for generalized vitiligo were found. Of these, 10 of are the most effective and safest therapies for localized 22 randomized controlled trials and 46 of 231 patient and for generalized vitiligo, respectively. series were included. Among randomized controlled trials on localized vitiligo, the pooled odds ratio vs placebo Arch Dermatol. 1998;134:1532-1540

ITILIGO IS an acquired skin groups of patients, active treatment can disorder characterized by be considered. sharply demarcated depig- Nonsurgical repigmentation thera- mented lesions with vari- pies represent the first-line active treat- able size and shape that ment modality in vitiligo. Currently best Vhave the tendency to expand over time. It studied and therefore most applied are oral is estimated that about 1% of the world and topical psoralen plus UV-A (PUVA), population is affected by the disease, re- phenylalanine plus UV-A, oral and topi- gardless of age, sex, and skin color.1 cal khellin plus UV-A, UV-B narrowband There are several possible ap- and broadband therapy, and corticoste- proaches in the management of vitiligo. roids (oral, topical, and intralesional).3-8 From the Netherlands Institute Some patients can be reassured simply There are many studies reporting on for Pigmentary Disorders by explaining the nature of the skin con- the clinical effectiveness and safety of (Drs Njoo and Westerhof) and dition and by giving advice on the use of the various treatments in vitiligo. Guide- the Departments of camouflage products and sun-protective lines and review articles4-7 have been pub- Dermatology (Drs Spuls, Bos, measures. In others, especially in the and Westerhof) and Clinical Epidemiology and Biostatistics dark-skinned population, vitiligo may (Dr Bossuyt), Academic cause disfigurement that can lead to seri- ous impairment of the quality of life.2 In This article is also available on our Medical Center, University Web site: www.ama-assn.org/derm. of Amsterdam, Amsterdam, certain cultures, patients with vitiligo are the Netherlands. still regarded as social outcasts. For these

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©1998 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/29/2021 METHODS Nonrandomized controlled trials were also analyzed as patient series. Because comparative or placebo- DATA SOURCES controlled trials can contain a description of at least 2 patient series, the total number of patient series could ex- The computerized bibliographic databases MEDLINE (Na- ceed the total number of studies included. tional Library of Medicine, Bethesda, Md) and EMBASE In case of double publications, the most elaborate pub- (Elsevier Science BV, Amsterdam, the Netherlands) were lication was selected. screened for clinical trials from January 1966 to Decem- ber 1997. No language restrictions were applied. As main DATA EXTRACTION key words (including analogs and derivatives), we used “vitiligo,” “phototherapy,” “PUVA therapy,” “ultraviolet Analysis of RCTs therapy,” “phenylalanine,” “khellin,” “glucocorticoste- roids synthetic,” and “anti-inflammatory agents.” Other Treatment was regarded as successful when more than 75% sources were abstract books of symposia and congresses, repigmentation was achieved. The odds ratio (OR) was used theses, textbooks, monographs, reviews, editorials, letters as the effect measure in this meta-analysis because it is regarded to the editor, free or rapid communications, and the ref- as the most satisfactory metric with which to combine across erence lists from all the articles retrieved. Also, 21 leading trials with discrete outcomes.20 The OR describes the odds of authorities in the field of vitiligo and 9 pharmaceutical com- a successful event (ie, Ͼ75% repigmentation) in a patient re- panies were contacted to provide us with any additional ceiving the active therapy relative to a patient receving the pla- published and unpublished references. cebo. As a result, an OR greater than 1 indicates greater effec- The studies were divided into those describing tiveness of the active therapy compared with the placebo. therapies for localized vitiligo and those reporting on To obtain a more precise estimate of the treatment ef- therapies for generalized vitiligo. Localized vitiligo was fect, ORs were combined across similar trials. A random- defined as vitiligo affecting less than 20% of the total effects model according to DerSimonian and Laird21 was body surface.7 used to pool these ORs and to calculate their 95% confidence intervals (CIs). The random-effects model was pre- STUDY SELECTION: INCLUSION ferred over the fixed-effects model because study popula- AND EXCLUSION CRITERIA tions and treatment outcomes in these trials were expected to be statistically heterogeneous, although all RCTs met the Two investigators (M.D.N. and W.W.) independently as- specific selection criteria. Calculations were done with Meta- sessed the articles for inclusion. When there was a dis- Analyst software for MS-DOS (Joseph Lau, Boston, Mass). agreement, a third investigator (P.M.M.B.) was consulted. Included were both randomized controlled trials Analysis Based on Patient Series (RCTs) and nonrandomized controlled trials on oral and topical psoralen plus sunlight or artificial UV-A (both Sample size–weighted averages were calculated for each mo- sources were termed UV-A), including methoxsalen, tri- dality by dividing the total number of patients who achieved oxsalen, bergapten, and unsubstituted psoralen (PS); more than 75% repigmentation by the total number of pa- UV-B broadband and narrowband; phenylalanine plus tients in the included series. The 95% CIs of these aver- sunlight or UV-A; oral and topical khellin plus sunlight or ages were calculated with the computer program Confi- UV-A; and corticosteroids (oral, topical, and intrale- dence Interval Analysis for MS-DOS (British Medical Journal, sional). Topical corticosteroids were divided into class 3 London, England) by means of the exact method. (“potent corticosteroids”), which included the drugs beta- The treatment duration (range and mean values) was also methasone valerate and halometasone, and class 4 (“very determined for each treatment modality. Treatment-specific potent corticosteroids”), which included clobetasol pro- side effects were estimated by dividing the number of patients pionate. With regard to intralesional administration of with side effects by the total number of patients studied. For corticosteroids, studies using triamcinolone acetonide each study, sample size–weighted averages of these frequen- were included. In studies on photoradiation, both natural cies and their 95% CIs were calculated with the same software sunlight and artificial UV-A were used in the same patient as was used for calculation of the success rates. series. These UV sources were regarded as equally effective, provided that sun exposure was performed between DATA SYNTHESIS 11 AM and 2 PM.2 Excluded were double publications, combination therapies, studies that used obsolete drug(s) Fifteen of the 21 leading authorities and 7 of the 9 phar- or dosage schemes, studies that reported on fewer maceutical firms contacted replied and provided us with than 5 patients, and studies with insufficient data on ef- further relevant references. No study required a third re- fectiveness. viewer to resolve disagreements about selection.

lished on how and in which patients these treatments search, it is likely that relevant studies were missed. It should be applied. However, these recommendations has been shown that review articles in journals or in were based on data obtained from only a limited num- textbooks, even if they were recently published, contain ber of references and on personal and institutional pref- unsound, imprecise, and biased information.9-12 erences. No methodological information was given on According to the principles of evidence-based medi- how these guidelines had been developed. Because cine,thebestmedicalcareisprovidedbyintegratingthe“best none of these articles included a systematic literature external evidence, as obtained from clinically relevant re-

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Methox- Khellin Khellin Corticosteroids salen + Trioxsalen + PS + (2%-3%) + (5%) + UV-A UV-A UV-A UV-A UV-A Class 3 Class 4 Intralesional Total No. of studies found 21 3 5 5 4 13 7 5 63 No. found through databases 7 3 2 4 2 7 7 3 35 Hit rate for databases, % 33 100 40 80 50 54 100 60 56 No. of randomized controlled trials 0 0 0 2 2 4 2 1 11

*PS indicates unsubstituted psoralen.

Table 2. Therapies for Localized Vitiligo and Pooled ORs and 95% CIs (Random Effects Model)*

No. of Patients, Active Group, No. of Placebo Group, No. of Therapy Study, y Active + Placebo Responders/Total Responders/Total OR (95% CI)† Koopmans-van Dorp 21 (L-R) 9/21 0/21 32.68 (1.75-610.81) et al,22 1973 Class 3 corticosteroids Kandil,23 1974 17 (L-R) 6/17 0/17 19.78 (1.01-386.03) Bleehen,24 1976 10 (L-R) 1/10 0/10 3.32 (0.12-91.60) Pooled random effects 96 16/48 0/48 14.32 (2.45-83.72) Bleehen,24 1976 10 (L-R) 0/10 0/10 1.00 (0.02-55.27) Class 4 corticosteroids Clayton, 25 1977 23 (L-R) 2/23 2/23 1.00 (0.13-7.78) Pooled random effects 66 2/33 2/33 1.00 (0.16-6.21) Vasistha and Singh,26 25 + 10 17/25 6/10 1.42 (0.31-6.47) Intralesional 1979 corticosteroids Pooled random effects NA NA NA NA Orecchia and Perfetti,27 41 (L-R) 0/41 0/41 1.00 (0.02-51.60) 1992 Topical khellin (2%-3%) Procaccini et al,28 1995 30 (L-R) 8/30 7/30 1.19 (0.37-3.85) Pooled random effects 142 8/71 7/71 1.18 (0.38-3.62) Procaccini et al,29 1993 12 (L-R) 4/12 4/12 1.00 (0.18-5.46) Topical khellin (5%) Procaccini et al,28 1995 29 (L-R) 9/29 9/29 1.00 (0.33-3.04) Pooled random effects 82 13/41 13/41 1.00 (0.39-2.54)

*OR indicates odds ratio; CI, confidence interval; L-R, left-right double-blind placebo-controlled comparative study; and NA, not applicable. †As a standard option, the computer program Meta-Analyst (Joseph Lau, Boston, Mass) corrects a 0 value by 0.5.

search studies into the daily practice.”13,14(p71),15 Combin- 95% CI, 0.16-6.21), intralesional corticosteroids (OR, ing all relevant studies in a meta-analysis can increase the 1.42; 95% CI, 0.31-7.78), topical khellin (2%-3%) plus power and precision of estimates on effectiveness and side UV-A (OR, 1.18; 95% CI, 0.38-3.62), or topical khellin effects profiles.16,17 The development of guidelines for the (5%) plus UV-A (OR, 1.00; 95% CI, 0.39-2.54) and choice of the most effective and safest therapy in vitiligo their respective placebos. Class 3 corticosteroids had a should be based also on the available evidence in the lit- pooled OR of 14.32 (95% CI, 2.45-83.72) vs placebo erature.18,19 We therefore performed a meta-analysis of the (Table 2). available literature on the most widely used forms of non- Patient Series surgical repigmentation therapy, with regard to both effectiveness and safety. Literature Search. A total of 110 patient series could be identified, of which only 29 series could be included, re- RESULTS porting on 993 patients (Table 3). Thirteen series with topical methoxsalen plus UV-A were excluded because THERAPIES FOR LOCALIZED VITILIGO obsolete drug compositions were used (such as methox- Randomized Controlled Trials salen plus 8-isoamyleneoxypsoralen) or because 1% con- centration instead of the currently advised 0.1% concen- Literature Search. With regard to therapies for local- tration of methoxsalen solution was used. Reasons for ized vitiligo, 63 studies were found. Eleven RCTs were exclusion of patient series are listed in Table 3. In cases identified, of which 10 met our eligibility criteria in which several criteria of exclusion were applicable, only (Table 1).22-29 One study on class 3 corticosteroids was the most important one was listed. excluded because it was a double publication (same trial published in 2 languages). The method of randomiza- Effectiveness. Figure 1 shows that class 3 corticoste- tion was not reported in any of the studies found. roids had the highest percentage of patients achieving more than 75% repigmentation (56%; 95% CI, 50%- Effectiveness. Pooled ORs showed nonsignificant dif- 62%), followed by class 4 corticosteroids (55%; 95% CI, ferences between class 4 corticosteroids (OR, 1.00; 49%-61%).

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Khellin Khellin Corticosteroids Methoxsalen + Trioxsalen + PS + (2%-3%) + (5%) + UV-A UV-A UV-A UV-A UV-A Class 3 Class 4 Intralesional Total No. of patient series identified 29 3 8 13 12 25 10 10 110 No. (%) of series Included 4 (14) 2 (67) 2 (25) 3 (23) 3 (25) 6 (24) 7 (70) 2 (20) 29 (26) Excluded 25 (86) 1 (33) 6 (75) 10 (77) 9 (75) 19 (76) 3 (30) 8 (80) 81 (74) Reasons for exclusion of patient series, No. Double publication 0 0 4 0 0 2 0 0 6 Combined with another 6000040616 (experimental) drug Obsolete drug or dosage scheme 13 0 0 0 0 0 0 0 13 Compared or placebo-treated 30088103133 patient series Series of Ͻ5 patients 0 0 0 2 1 0 0 1 4 Inadequate or insufficient 312003009 data on effectiveness

*PS indicates unsubstituted psoralen.

80 THERAPIES FOR GENERALIZED VITILIGO 70 60 Randomized Controlled Trials 50 40 Literature Search. A total of 117 studies on therapies for 30 generalized vitiligo were found. Twenty-two RCTs were 20 identified, of which 10 were included (Table 5).31-38 Eight

>75% Repigmentation 10 % of Patients Achieving 0 studies (from 4 publications) were excluded because they Methox- Triox- PS + Khellin Khellin Cortico- Cortico- Cortico- 31,33,39,40 salen + UV-A salen + UV-A (2%-3%) + (5%) + steroids steroids steroids described combination therapies. Of these 8 stud- (4/176) UV-A (2/50) UV-A UV-A (Class 3) (Class 4) (Intralesional) (2/33) (3/81) (3/64) (6/235) (7/277) (2/77) ies, 4 RCTs were found on oral corticosteroids com- Therapies for Localized Vitiligo bined with oral PUVA. Four other studies (from 2 pub- (No. of Patient Series Included/Total No. of Patients) lications) were excluded because of insufficient data on Figure 1. Effectiveness of therapies for localized vitiligo. Analysis was based outcome measures (“mean achieved percentage repig- on patient series (sample size–weighted averages and 95% confidence mentation” was used as outcome measure).39,40 No RCTs intervals). PS indicates unsubstituted psoralen. were found on oral bergapten plus UV-A, broadband UV-B, or narrowband UV-B. The method of randomiza- tion was not reported in any of the studies found. Side Effects. Of the 29 included series, 28 (97%) reported side effects. Of the topical PUVA group, Effectiveness. The OR vs placebo was significant for oral methoxsalen had the highest proportion of patients methoxsalen plus sunlight (OR, 23.37; 95% CI, 1.33- developing phototoxic reactions (58%; 95% CI, 51%- 409.93), oral PS plus sunlight (pooled OR, 19.87; 95% 65%), followed by trioxsalen (39%; 95% CI, 23%-56%) CI, 2.37-166.32), and oral trioxsalen plus sunlight (pooled and PS (25%; 95% CI, 12%-38%). Atrophy was the OR, 3.75; 95% CI, 1.24-11.29). For therapies that used most common side effect with local corticosteroids, phenylalanine plus UV-A and oral khellin plus sunlight, occurring mostly in patients receiving intralesional no significant differences were found between the ac- corticosteroids (33%; 95% CI, 22%-43%), followed by tive drug and the placebo (Table 6). patients using class 4 corticosteroids (14%; 95% CI, 10%-18%) and class 3 corticosteroids (2%; 95% CI, Patient Series 1%-5%). Other less common reported side effects of corticosteroids were telangiectasia, corticosteroid- Literature Search. A total of 231 patient series were iden- induced acne, and hypertrichosis. Studies on topical tified. Of these, 46 series were included, reporting on 1866 khellin (2%, 3%, and 5%) plus UV-A did not report patients (Table 7). any side effects (Table 4). The exclusion criterion “obsolete drug or dosage The mean treatment duration did not vary much, scheme” was applied for studies that used daily instead of from 5 to 8 months (Table 4). One study reported the the currently advised twice- to thrice-weekly intake of pso- prolonged but intermittent use of class 3 corticosteroids ralen.41 Daily psoralen intake followed by daily UV expo- for a period of 21 months.30 In general, the duration of sure is not recommended because of the risks of cumula- treatment strongly depended on the reponse; when tivephototoxicevents.3,41 Furthermore,studiesonoralPUVA there was no reponse after 2 to 3 months, therapy was performed in the 1950s were excluded because of the use discontinued. of an obsolete drug containing methoxsalen plus 8-isoamy-

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Khellin Khellin Corticosteroids Methox-salen + Trioxsalen + PS + (2%-3%) + (5%) + UV-A UV-A UV-A UV-A UV-A Class 3 Class 4 Intralesional No. of included series 4 2 2 3 3 6 7 2 Treatment duration, 4-6 (5) 1-6 (5) 6-7 (7) 3-9 (5) 6-9 (8) 2-21 (8) 2-12 (6) 4-12 (8) range (mean), mo No. of series with side 421 33672 effects reported Total No. of patients 176 33 40 81 64 235 277 77 Patients with local side effects† Atrophy 0 0 0 0 0 5 (2) [1-5] 39 (14) [10-18] 26 (33) [22-43] Telangiectasia 0 0 0 0 0 0 8 (3) [1-5] 2 (3) [0-9] Corticosteroid acne 0 0 0 0 0 16 (7) [4-10] 25 (9) [6-12] 0 Hypertrichosis 0 0 0 0 0 2 (1) [0-3] 1 (1) [0-2] 0 Phototoxic reactions 102 (58) [51-65] 13 (39) [23-56] 10 (25) [12-38] 0 0 0 0 0 (erythema and blistering)

*PS indicates unsubstituted psoralen. †Data are reported as number of patients with sample size−weighted average percentages in parentheses and 95% confidence intervals in brackets.

Table 5. Therapy for Generalized Vitiligo: Results of the Literature Search*

Methox- Triox- Phenyl- UV-B Oral salen + salen + Bergapten + PS + alanine + Khellin + Cortico- UV-A UV-A UV-A UV-A UV-A UV-A Broadband Narrowband steroids Total No. of studies found 35 23 5 6 20 9 2 3 14 117 No. found through databases 17 17 2 5 13 5 2 1 8 70 Hit rate for databases, % 49 74 40 83 65 56 100 33 57 60 No. of randomized 63 0 34 2 0 0 422 controlled trials

*PS indicates unsubstituted psoralen.

leneoxypsoralen. Other reasons for exclusion are listed in ten and trioxsalen (1%; 95% CI, 0%-2%; and 2%; 95% Table 7. In cases in which several criteria of exclusion were CI, 0%-3%, respectively). Phototoxic reactions were seen applicable, only the most important one was listed. mostly in patients who ingested methoxsalen (25%; 95% For the effectiveness and safety analysis, studies on CI, 20%-30%), followed by bergapten (6%; 95% CI, 4%- oral corticosteroids were further divided into studies that 8%). In patients using trioxsalen and PS plus UV-A, pho- described daily intake of corticosteroids and studies on totoxic reactions rarely occurred (1%; 95% CI, 0%-3%; oral minipulse therapy. and 0%, respectively). Abnormal results of liver function tests were observed mostly in patients using khel- Effectiveness. Figure 2 shows that phototherapy with lin (17%; 95% CI, 8%-26%). Miscellaneous systemic re- narrowband UV-B had the highest percentage of pa- actions (headache, dizziness) were reported mostly in tients who achieved more than 75% repigmentation (63%; patients taking oral PS (24%; 95% CI, 14%-33%). Pru- 95% CI, 50%-76%), followed by broadband UV-B (57%; ritus, as one of the miscellaneous cutaneous effects, was 95% CI, 29%-82%). Only 1 study of each was included. most frequently seen with the use of methoxsalen (31%; Oral methoxsalen plus UV-A and oral bergapten plus 95% CI, 26%-37%). An increased contrast between nor- UV-A had success rates of 51% (95% CI, 46%-56%) and mal and depigmented skin was also reported mostly with 43% (95% CI, 38%-48%), respectively. The differences the use of methoxsalen (10%; 95% CI, 6%-13%). Stud- between the mean success rates of narrowband UV-B, ies on phenylalanine with UV-A, broadband UV-B, and broadband UV-B, and oral methoxsalen plus UV-A were narrowband UV-B did not report any systemic or local not significant. side effects. In 1 patient series with oral khellin, 7 (28%) of the 25 patients dropped out of the study because of Side Effects. Of the 46 included series, 40 (87%) re- (asymptomatic) elevation of liver transaminase levels. In ported side effects (Table 8 and Table 9). Of the oral the remaining 7 photochemotherapeutic modalities, the photochemotherapeutic modalities, methoxsalen had the side effects reported were all mild and transient and did highest proportion of patients who developed nausea (and not lead to discontinuation of the therapy in any of the vomiting) as a side effect (29%; 95% CI, 24%-35%), fol- patients described. The mean treatment duration of pho- lowed by khellin (9%; 95% CI, 2%-16%) and PS (8%; 95% tochemotherapies varied between 9 months for phenyl- CI, 2%-15%). Nausea was caused least often by bergap- alanine plus UV-A and 24 months for oral PS plus UV-A.

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©1998 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/29/2021 Table 6. Therapy for Generalized Vitiligo and Pooled ORs and 95% CIs (Random Effects Model)*

No. of Patients, Active Group, No. of Placebo Group, No. of Therapy Study, y Active + Placebo Responders/Total Responders/Total OR (95% CI)† Oral methoxsalen plus sun Pathak et al,31 1984 47 + 24 15/47 0/24 23.37 (1.33-409.93) Pathak et al,31 1984 39 + 24 7/39 0/24 11.31 (0.62-201.64) Ruiz Maldonado and 25 + 22 16/25 8/22 3.11 (0.94-10.25) Oral trioxsalen plus sun Tamayo Sanchez,32 1975 Pooled random effects 23/64 8/46 3.75 (1.24-11.29) (oral trioxsalen plus sun) Farah et al,33 1967 9 + 27 2/9 0/27 18.33 (0.79-424.37) Pathak et al,31 1984 37 + 24 11/37 0/24 21.26 (1.19-380.41) Oral PS plus sun Pooled random effects 97 13/46 0/51 19.87 (2.37-166.32) (oral PS plus UV-A) Antoniou et al,34 1989 11 + 10 5/11 0/10 17.77 (0.84-377.40) Orecchia and Perfetti,35 1992 12 + 6 0/12 0/6 0.52 (0.01-29.34) Siddiqui et al,36 1994 8 + 6 0/8 0/6 0.76 (0.01-43.93) Phenylalanine plus UV-A Al-Khawajah,37 1996 13 + 10 0/13 0/10 0.78 (0.01-42.55) Pooled random effects 76 5/44 0/32 2.24 (0.35-14.28) (phenylalanine plus UV-A) Oral khellin plus sun Abdel-Fattah et al,38 1982 30 + 30 5/30 0/30 13.16 (0.69-249.48)

*OR indicates odds ratio; CI, confidence interval; and PS, unsubstituted psoralen. †As a standard option, the computer program Meta-Analyst (Joseph Lau, Boston, Mass) corrects a 0 value by 0.5.

Table 7. Therapy for Generalized Vitiligo: Reason for Exclusion of Patient Series*

Methox- Triox- Phenyl- UV-B Oral salen + salen + Bergapten + PS + alanine + Khellin Cortico- UV-A UV-A UV-A UV-A UV-A +UV-A Broadband Narrowband steroids Total No. of patient series 70 39 9 20 30 17 2 9 35 231 identified No. (%) of series Included 6 (9) 8 (21) 4 (44) 1 (5) 15 (50) 5 (30) 1 (50) 1 (11) 5 (14) 46 (20) Excluded 64 (91) 31 (79) 5 (56) 19 (95) 15 (50) 12 (70) 1 (50) 8 (89) 30 (86) 185 (80) Reasons for exclusion of patient series, No. Double publication 5 5 0 5 1 0 0 6 0 22 Combined with another 10 1 1 1 3 0 1 0 11 28 (experimental) drug Obsolete drug or 20 14 0 3 0 1 0 0 0 38 dosage scheme Compared or placebo- 24 10 3 9 7 8 0 1 15 77 treated patient series Series of Ͻ5 patients 0 0 0 0 0 2 0 0 2 4 Inadequate or 51 1 1 4 1 0 1 216 insufficient data on effectiveness

*PS indicates unsubstituted psoralen.

In comparison with daily intake of corticosteroids, nificantly better results than placebo. Analysis based on oral minipulse therapy with corticosteroids was associ- patient series revealed that topical class 3 corticoste- ated with a lower mean proportion of patients with sys- roids and class 4 corticosteroids had the highest mean temic and cutaneous side effects (Table 9). The differ- proportion of patients with more than 75% repigmenta- ences among the rates of various side effects between daily tion. Treatment-specific side effects were reported mostly therapy and oral minipulse therapy were, however, not with topical psoralen and intralesional and class 4 cor- significant. The treatment duration for oral minipulse ticosteroids. In generalized vitiligo, the OR vs placebo therapy varied between 6 and 24 months, depending on was significant for oral methoxsalen plus UV-A and oral the number of courses given (each course lasted 5 weeks). PS plus UV-A. In the series, the highest mean success rates were achieved with narrowband UV-B, broadband UV-B, COMMENT and oral methoxsalen plus UV-A therapy. Oral methoxsalen plus UV-A was associated with the highest rates of Analysis of the available RCTs on therapies for localized side effects. No side effects were reported with narrow- vitiligo showed that only class 3 corticosteroids had sig- band or broadband UV-B therapy.

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©1998 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/29/2021 Databases are known to be only partially success- tion which and how many observers were involved in scor- ful in identifying relevant studies.17 Therefore, other ing of the repigmentation. For this reason, we have ex- sources were screened manually to optimize the results cluded studies that used ratings such as “repigmenta- of the search. In addition, leading authorities and phar- tion or no repigmentation” as outcome measures without maceutical firms were contacted to minimize publica- giving percentages of the observed repigmentation. Per- tion bias.42 However, publication bias cannot be ex- haps, in the future, computer image analysis may reflect cluded in our data set despite extensive efforts to gain more accurately the percentage of repigmentation vs de- all of the performed studies. Only a few studies report- pigmentation in patients with vitiligo.43 ing “negative findings” of a therapy were found.28,37 Other factors that may have influenced treatment out- We have separated treatment modalities indicated come are differences between patient populations in age for patients with localized vitiligo from those indicated and skin type. Although some authors had the impression for patients with generalized vitiligo. Nevertheless, se- that younger and dark-skinned patients gained better re- lection bias is likely to influence our findings since, be- sults, no definitive controlled study was performed to sup- tween studies, patients may have suffered from differ- port this observation. It was also disappointing that pa- ent severity of disease. Smaller lesions may have responded tient compliance was not reported in any of the studies that better to therapy than larger ones. Some studies using used phototherapy. Monitoring of compliance is relevant, oral PUVA also included patients with only localized viti- since phototherapy in vitiligo is time consuming and re- ligo lesions. quires continous high motivation of the patients. Further- It is likely that the way of assessing repigmentation more, the issue of whether the treatment had improved qual- also differed between studies. Most studies did not men- ity of life was not addressed in any of the studies. We therefore propose that future clinical trials in vitiligo should evaluate treatment outcome in relation to such 90 variables as localization and duration of the lesions, skin 80 70 type, age, quality of life, and compliance of the patients. 60 In addition, we support the performance of follow-up stud- 50 ies on the permanency of therapy-induced repigmenta- 40 30 tion, in particular for photoradiation. So far, only 3 stud- 20 ies have addressed this issue. However, all 3 studies

>75% Repigmentation 10 % of Patients Achieving described PUVA therapy with the use of a daily dosage 0 44-46 Methox- Triox- Bergap- PS + Phenyl- Khellin + Broad- Narrow- Cortico- Cortico- scheme, which is now considered obsolete. salen + salen + ten + UV-A alanine + UV-A band band steroids steroids UV-A UV-A UV-A (1/72) UV-A (5/65) UV-B UV-B Daily OMT Only a few RCTs that included both localized and (6/349) (8/412) (4/368) (15/392) (1/14) (1/51) (3/71) (2/72) Therapies for Generalized Vitiligo generalized vitiligo could be included in this analysis. No (No. of Patient Series Included/Total No. of Patients) RCT was found on topical psoralen, oral bergapten, and narrowband and broadband UV-B therapy. Therefore, cau- Figure 2. Effectiveness of therapies for generalized vitiligo. Analysis was based on patient series (sample size–weighted averages and 95% confidence tion is needed in the interpretation of the data. In RCTs intervals). PS indicates unsubstituted psoralen; OMT, oral minipulse therapy. on therapies for generalized vitiligo, only a small num-

Table 8. Photoradiation for Generalized Vitiligo: Side Effects*

Phenyl- UV-B Methoxsalen + Trioxsalen + Bergapten + PS + alanine + Khellin + UV-A UV-A UV-A UV-A UV-A UV-A Broadband Narrowband No. of included series 6 8 4 1 15 5 1 1 Treatment duration, 2-24 (15) 4-28 (19) 3-22 (14) 24 (24) 2-24 (9) 3-24 (10) 12 12 range (mean), mo No. of series with side 4 6 4 1 15 5 1 1 effects reported Total No. of patients 277 308 368 72 392 65 14 51 Patients with side effects† Nausea (and vomiting) 80 (29) [24-35] 6 (2) [0-3] 3 (1) [0-2] 6 (8) [2-15] 0 6 (9) [2-16] 0 0 Phototoxic reactions 69 (25) [20-30] 3 (1) [0-3] 22 (6) [4-8] 0 0 0 0 0 (erythema to burns) Abnormal liver function 5 (2) [1-4] 6 (2) [0-3] 1 (0) [0-2] 0 0 11 (17) [8-26] 0 0 test results Miscellaneous systemic 17 (6) [3-9] 18 (6) [3-8] 1 (0) [0-2] 17 (24) [14-33] 0 2 (3) [0-11] 0 0 (headache, dizziness) Miscellaneous cutaneous 86 (31) [26-37] 15 (5) [2-7] 4 (1) [0-3] 6 (8) [2-15] 0 1 (2) [0-8] 0 0 (pruritus) Increased contrast 27 (10) [6-13] 9 (3) [1-5] NA NA 0 0 0 0 between normal and depigmented skin

*PS indicates unsubstituted psoralen; NA, not available. †Data are reported as number of patients with sample size−weighted average percentages in parentheses and 95% confidence intervals in brackets.

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©1998 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/29/2021 studies are needed to confirm the good results and to es- Table 9. Side Effects of Oral Corticosteroids Given Daily vs tablish its long-term side effects. Oral Minipulse Therapy (OMT) Analysis of the side-effect profiles in the patient series showed that treatment with psoralen (both orally and Daily OMT topically) is not easy to perform. Severe phototoxic reac- No. of included series 3 2 tions can be avoided by careful monitoring of UV expo- Treatment duration, range 4-6 (5) 6-24 (15) sures. Nausea can be avoided by concomitant ingestion (mean), mo 3 No. of series with side effects 12 of low-fat food or milk. The use of oral khellin was asso- reported ciated with elevated transaminase levels in a high propor- Total No. of patients 34 72 tion of the patients. Moreover, in 1 series, 28% of the pa- Patients with side effects* tients terminated the therapy because of this adverse effect. Moon face 7 (21) [7-34] 1 (1) [0-8] Therefore, we do not advise khellin as 1 of the drugs of Weight gain 5 (15) [5-31] 5 (7) [2-16] Acne 1 (3) [0-15] 2 (3) [0-10] choice. On the other hand, no side effects were reported Miscellaneous (systemic) 3 (9) [2-24] 11 (15) [7-24] with the use of phenylalanine plus UV-A, broadband UV-B, or narrowband UV-B. Figure 2 shows that phenylalanine *Data are reported as number of patients, with sample size−weighted plus UV-A is a relatively ineffective therapy. However, one average percentages in parentheses and 95% confidence intervals in may prefer UV-B (narrowband or broadband) therapy over brackets. oral methoxsalen plus UV-A therapy when comparing the side effects. Other advantages of UV-B therapy over oral ber of the patients treated with placebo had achieved suc- PUVA include no need for oral intake of psoralens, shorter cessful repigmentation. A possible explanation may be treatment sessions, and applicability in pregnant women that in vitiligo, spontaneous repigmentation rarely oc- and children younger than 12 years.48 curs and is never complete. Some even believe that “spon- Guidelines on the use of photochemotherapeutic mo- taneous” repigmentation does not exist and is in fact UV- dalitiesinvitiligoshouldalsogiverecommendationsonmaxi- induced repigmentation.8 In therapies for localized vitiligo, mum treatment duration. Both PUVA and UV-B (broadband repigmentation observed in patients treated with place- and narrowband) therapies need not be continous, since bos can therefore also be attributed to either sun expo- these modalities are well known for their carcinogenic sure (studies with class 4 corticosteroid and intrale- properties.49-51 In patients with psoriasis, long-term PUVA sional corticosteroid) or combined UV-A irradiation therapy was found to be associated with an increased risk (studies with topical 2%-5% khellin plus UV-A). for skin cancer, especially squamous cell carcinoma.52 To Analysis of RCTs and of the patient series showed date, only 2 patients with vitiligo have been described with that class 3 corticosteroid was the most effective and saf- squamous cell carcinoma after prolonged PUVA therapy.53,54 est therapy for localized vitiligo. We do not advise topi- This relatively low incidence may be explained by the fact cal class 4 corticosteroids and intralesional corticoste- that, in contrast to patients with psoriasis, those with viti- roids because of the significantly higher rates of atrophy. ligo receive lower cumulative PUVA dosages, do not expose Topical psoralen plus UV-A was shown to be associated themselves to extra sun rays, and do not use tar prepara- with a high risk of phototoxic events (erythema, blister- tions, cystostatic drugs (methotrexate), or immunosuppres- ing) and is therefore to be prescribed under strict pre- sive drugs (cyclosporine). Nevertheless, we suggest that cautions.7 Despite the absence of side effects with the use guidelines for maximum cumulative PUVA doses in viti- of topical khellin plus UV-A, we do not recommend this ligo should follow those recommended for psoriasis.55 With option because the drug is not shown to be effective in regard to UV-B therapy (both broadband and narrowband), the analysis of RCTs and the analysis of patient series. there are presently still insufficient epidemiological data The choice of therapy in generalized vitiligo can also available on humans to provide evidence-based advice be made after consideration of the reported effectiveness regarding a safe maximum dose. However, by means of a andsafetyprofiles.Moststudiesonphotoradiationconcluded dose-response model it has been calculated that long-term that more than 75% repigmentation could be achieved only narrowband UV-B therapy may carry substantially less risk when patients were treated on a regular basis and for longer for skin cancer than PUVA therapy.49 periods.Forphotoradiation,atleast1yearofcontinoustreat- The use of oral corticosteroids is still considered con- ment was required. These observations indicate that only troversial by many authors,4-7 since systemic side effects well-motivated, highly compliant patients are suitable for (such as moon face and weight gain) are associated with photoradiation. “Complete” repigmentation was rarely this therapy.56-58 Our results are in agreement with those reported with the use of oral photochemotherapeutic mo- of these authors, since the drug is relatively ineffective dalities. Most authors attributed this to the observation that and is related with a high rate of side effects. certain skin areas, such as the distal dorsal surfaces of the On the basis of the results of this review, the fol- hands and feet, tips of fingers and toes, areas of bony promi- lowing recommendations can be made concerning the nences, palms, soles, nipples, and lips scarcely repigment choice of the most effective and safest therapy. For pa- at all. Estimation of the response judged by overall body re- tients with localized vitiligo, class 3 corticosteroid is ad- pigmentation may have led to lower response rates because vised as first-choice therapy. When patients exhibit gen- the above-mentioned nonresponding areas were included eralized vitiligo, UV-B (narrowband or broadband) therapy in the calculations. Broadband UV-B and narrowband UV-B or oral methoxsalen plus UV-A is recommendend. This were described in only 1 study each.47,48 Narrowband UV-B review may be used as a basis for the development of evi- therapy is considered a novel phototherapy in vitiligo. More dence-based guidelines for the management of vitiligo.

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©1998 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/29/2021 Accepted for publication August 6, 1998. 27. Orecchia G, Perfetti L. Photochemotherapy with topical khellin and sunlight in This work was supported by a grant from the Com- vitiligo. Dermatology. 1992;184:120-123. 28. Procaccini EM, Riccio G, Monfrecola G. Ineffectiveness of topical khellin in pho- mission for Guidelines for Clinical Practice, Academic Medi- tochemotherapy of vitiligo. J Dermatol Treatment. 1995;6:117-120. cal Centre, University of Amsterdam, Amsterdam, the Neth- 29. Procaccini EM, Riccio G, Viola L, Monfrecola G. Evaluation of topical khellin pho- erlands. tochemotherapy for vitiligo. Ann Ital Dermatol Clin Sperimentale. 1993;47: Presented at the Second Stichting Nederlands Insti- 275-278. tuut voor Pigmentstoornissen Symposium, Amsterdam, No- 30. Koga M. Vitiligo: a new classification and therapy. Br J Dermatol. 1977;97:255-261. 31. Pathak MA, Mosher DB, Fitzpatrick TB. Safety and therapeutic effectiveness of vember 21, 1997. 8-methoxypsoralen, 4,5,8-trimethylpsoralen, and psoralen in vitiligo. Natl Can- We thank Hele´ne Dyserinck, clinical librarian, for her cer Inst Monogr. 1984;66:165-173. assistance with the bibliographic database searches. 32. Ruiz Maldonado R, Tamayo Sanchez L. 4-5-8 Trimethylpsoralen in vitiligo: con- A complete list of all of the studies identified is avail- trolled clinical study of its therapeutic and toxic effect in children. Actas Dermo- able on request from the authors. sifiliograficas. 1975;66:513-526. 33. Farah FS, Kurban AK, Chaglassian HT. The treatment of vitiligo with psoralens Corresponding author: M. D. Njoo, MD, Netherlands and triamcinolone by mouth. Br J Dermatol. 1967;79:89-91. Institute for Pigmentary Disorders, Instituut voor Weten- 34. Antoniou C, Schulpis H, Michas T, et al. Vitiligo therapy with oral and topical phe- schappely¨k Onderzoek Building, Academic Medical Cen- nylalanine with UVA exposure. Int J Dermatol. 1989;28:545-547. ter, Meibergdreef 35, 1105 AZ Amsterdam, the Nether- 35. Orecchia G, Perfetti L. Photochemotherapy with topical khellin and sunlight in lands (e-mail: [email protected]). vitiligo. Dermatology. 1992;184:120-123. 36. Siddiqui AH, Stolk LM, Bhaggoe R, Hu R, Schutgens RB, Westerhof W. L- phenylalanine and UVA irradiation in the treatment of vitiligo. Dermatology. 1994; REFERENCES 188:215-218. 37. Al-Khawajah MM. The failure of L-phenylalanine and UVA in the treatment of vitiligo. J Dermatol Treatment. 1996;7:181-182. 1. Srivastava G. Introduction: vitiligo update. Asian Clin Dermatol. 1994;1:1-4. 38. Abdel-Fattah A, Aboul-Enein MN, Wassel GM, El-Menshawi BS. An approach to 2. Porter J, Beuf AH, Lerner AB, Nordlund JJ. Response to cosmetic disfigure- the treatment of vitiligo by khellin. Dermatologica. 1982;165:136-140. ment: patients with vitiligo. Cutis. 1987;39:493-494. 3. Ortonne JP. Psoralen therapy in vitiligo. Clin Dermatol. 1989;7:120-135. 39. Petzoldt D, Reich AL. Oral treatment of vitiligo with 8-methoxypsoralen and tri- 4. Antoniou C, Katsambas A. Guidelines for the treatment of vitiligo. Drugs. 1992; amcinolone. Hautarzt. 1974;25:191-194. 43:490-498. 40. El Zawahry M, Soliman M, El Ansary M, El Zawahry MB, Mahdy Rady EAA. A 5. Nordlund JJ, Halder RM, Grimes PE. Management of vitiligo. Dermatol Clin. 1993; clinical and immunological study of the effect of the different modalities of treat- 11:27-33. ment on vitiligo patients. J Pan Arab League Dermatol. 1997;8:63-75. 6. Grimes PE. Vitiligo: an overview of therapeutic approaches. Dermatol Clin. 1993; 41. Drake LA, Ceilly RI, Dorner W, et al. Guidelines of care for phototherapy and pho- 11:325-338. tochemotherapy. J Am Acad Dermatol. 1994;31:643-648. 7. Drake LA, Dinehart SM, Farmer ER, et al. Guidelines of care for vitiligo. JAm 42. Easterbrook PJ, Berling JA, Gopalan R, Matthews DR. Publication bias in clini- Acad Dermatol. 1996;35:620-626. cal research. Lancet. 1991;337:867-872. 8. Westerhof W, Njoo MD, Schallreuter KU. Vitiligo: Weiterbildung. Hautarzt. 1997; 43. Kanthraj GR. Comparison of computer-aided design and rule of nines methods 48:677-693. in the evaluation of the extent of body involvement in cutaneous lesions. Arch 9. Huth EJ. Needed: review articles with more scientific rigor. Ann Intern Med. 1987; Dermatol. 1997;133:922-923. 106:470-471. 44. Elliott JA, Charlotte NC. Methoxsalen in the treatment of vitiligo: an appraisal of 10. Mulrow CD. The medical review article: state of the science. Ann Intern Med. 1987; the permanency of the repigmentation. Arch Dermatol. 1958;79:237-243. 104:485-488. 45. Kenney JA Jr. Vitiligo treated by psoralens: a long-term follow-up study of the 11. Antman EM, Lau J, Kupelnick B. A comparison of results of meta-analysis of ran- permanency of repigmentation. Arch Dermatol. 1971;103:475-480. domized controlled trials and recommendations of clinical experts. JAMA. 1992; 46. Theodoridis A, Tsambaos D, Sivenas C, Capetanakis J. Oral trimethylpsoralen in 268:240-248. the treatment of vitiligo. Acta Derm Venereol. 1976;56:253-256. 12. Oxman AD, Guyatt GH. The science of reviewing research. Ann N Y Acad Sci. 47. Ko¨ster W, Wiskemann A. Phototherapy with UV-B in vitiligo. Z Hautkr. 1990;65: 1993;703:125-134. 1022-1024. 13. Evidence-Based Medicine Working Group. Evidence-based medicine: a new ap- 48. Westerhof W, Nieuweboer-Krobotova L. Treatment of vitiligo with UVB (311 nm) proach to teaching the practice of medicine. JAMA. 1992;268:2420-2425. versus topical PUVA. Arch Dermatol. 1997;133:1525-1528. 14. Sackett DL, Rosenberg WM, Gray JAM, Haynes RB, Richardson WS. Evidence 49. Slaper H, Schothorst AA, van der Leun JC. Risk evaluation of UVB therapy for based medicine: what it is and what it isn’t. BMJ. 1996;312:71-72. psoriasis: comparison of calculated risk for UVB therapy and observed risk in 15. Ladhani S. The need for evidence-based management of skin diseases. Int J Der- PUVA treated patients. Photodermatology. 1986;3:271-283. matol. 1997;36:17-22. 50. Sterenborg HJCM, van Weelden H, van der Leun JC. The dose-response rela- 16. Mulrow CD. Rationale for systematic reviews. BMJ. 1994;309:597-599. tionship for tumorigenesis by UV radiation in the region 311-312 nm. J Photo- 17. Dickersin K, Scherer R, Lefebvre C. Identifying relevant studies for systematic chem Photobiol B. 1988;2:179-194. reviews. BMJ. 1994;309:1286-1291. 51. Young AR. Photocarcinogenicity of psoralens used in PUVA treatment: present 18. Eddy DM. Practice policies: what are they? JAMA. 1990;263:877-880. status in mouse and man. J Photochem Photobiol B. 1990;6:237-247. 19. Cook DJ, Greengold NL, Ellrodt AG, Weingarten SR. The relation between sys- 52. Stern RS, Lange R, members of the Photochemotherapy Follow-up Study. Non- tematic review and practice guidelines. Ann Intern Med. 1997;127:210-216. melanoma skin cancer occurring in patients treated with PUVA five to ten years 20. Altman DG. Comparing groups: categorical data. In: Altman DG, ed. Practical Sta- after first treatment. J Invest Dermatol. 1988;91:120-124. tistics for Medical Research. London, England: Chapman & Hall; 1997:268-271. 53. Buckley DA, Rogers S. Multiple keratoses and squamous carcinoma after PUVA 21. DerSimonian R, Laird NM. Meta-analysis in clinical trials. Control Clin Trials. 1986; treatment of vitiligo. Clin Exp Dermatol. 1996;21:43-45. 7:177-188. 54. Takeda H, Mitsuhashi Y, Kondo S. Multiple squamous cell carcinomas in situ in 22. Koopmans-van Dorp B, Goedhart-van Dijk B, Neering H, van Dijk E. Treatment vitiligo after long-term PUVA therapy. J Am Acad Dermatol. 1998;38: of vitiligo by local application of betamethasone 17-valerate in a dimethyl sulf- 268-270. oxide cream base. Dermatologica. 1973;146:310-314. 55. British Photodermatology Group. British Photodermatology Group guidelines for 23. Kandil E. Treatment of vitiligo with 0-1% betamethasone 17-valerate in isopro- PUVA. Br J Dermatol. 1994;130:246-255. pyl alcohol: a double-blind trial. Br J Dermatol. 1974;91:457-460. 56. Imamura S, Tagami H. Treatment of vitiligo with oral corticosteroids. Dermato- 24. Bleehen SS. The treatment of vitiligo with topical corticosteroids: light and elec- logica. 1976;153:179-185. tron microscopic studies. Br J Dermatol. 1976;94(suppl 12):43-50. 57. Pasricha JS, Khaitan BK. Oral mini-pulse therapy with betamethasone in vitiligo 25. Clayton R. A double-blind trial of 0.05% clobetasol proprionate in the treatment patients having extensive or fast-spreading disease. Int J Dermatol. 1993;32: of vitiligo. Br J Dermatol. 1977;96:71-73. 753-757. 26. Vasistha LK, Singh G. Vitiligo and intralesional steroids. Indian J Med Res. 1979; 58. Moon TK, Im SB, Hann SK, Cho SH, Park YK. The effect of small doses of oral 69:308-311. corticosteroids in vitiligo patients. Korean J Dermatol. 1995;33:880-885.

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