Abstract: This update of the 2010 review includes 96 studies, 57 from the previous update and 39 new studies, totalling 4512 participants. Most of the studies, covering a wide range of interventions, had fewer than 50 participants. All of the studies assessed repigmentation, however only five reported on all of our three primary outcomes which were quality of life, > 75% repigmentation and adverse effects. Of our secondary outcomes, six studies measured cessation of spread but none assessed long-term permanence of repigmentation resulting from treatment at two years follow-up. Most of the studies assessed combination therapies which generally reported better results. New interventions include seven new surgical interventions. We analysed the data from 25 studies which assessed our primary outcomes. We used the effect measures risk ratio (RR), and odds ratio (OR) with their 95% confidence intervals (CI) and where N is the number of participants in the study. We were only able to analyse one of nine studies assessing quality of life and this showed no statistically significant improvement between the comparators. Nine analyses from eight studies reported >75% repigmentation. In the following studies the repigmentation was better in the combination therapy group: calcipotriol plus PUVA (psoralen with UVA light) versus PUVA (paired OR 4.25, 95% CI 1.43 to 12.64, one study, N = 27); hydrocortisone-17-butyrate plus excimer laser versus excimer laser alone (RR 2.57, 95% CI 1.20 to 5.50, one study, N = 84); oral minipulse of prednisolone (OMP) plus NB-UVB (narrowband UVB) versus OMP alone (RR 7.41, 95% CI 1.03 to 53.26, one study, N = 47); azathioprine with PUVA versus PUVA alone (RR 17.77, 95% CI 1.08 to 291.82, one study, N = 58) and 8-Methoxypsoralen (8-MOP ) plus sunlight versus psoralen (RR 2.50, 95% CI 1.06 to 5.91, one study, N = 168). In these three studies ginkgo biloba was better than placebo (RR 4.40, 95% CI 1.08 to 17.95, one study, N = 47); clobetasol propionate was better than PUVAsol (PUVA with sunlight) (RR 4.70, 95% CI 1.14 to 19.39, one study, N = 45); split skin grafts with PUVAsol was better than minipunch grafts with PUVAsol (RR 1.89, 95% CI 1.25 to 2.85, one study, N = 64). We performed one meta-analysis of three studies, in which we found a non-significant 60% increase in the proportion of participants achieving >75% repigmentation in favour of NB-UVB compared to PUVA (RR 1.60, 95% CI 0.74 to 3.45; I² = 0%). Studies assessing topical preparations, in particular topical corticosteroids, reported most adverse effects. However, in combination studies it was difficult to ascertain which treatment caused these effects. We performed two analyses from a pooled analysis of three studies on adverse effects. Where NB-UVB was compared to PUVA, the NB-UVB group reported less observations of nausea in three studies (RR 0.13, 95% CI 0.02 to 0.69; I² = 0% three studies, N = 156) and erythema in two studies (RR 0.73, 95% CI 0.55 to 0.98; I² = 0%, two studies, N = 106), but not itching in two studies (RR 0.57, 95% CI 0.20 to 1.60; I² = 0%, two studies, N = 106). Very few studies only assessed children or included segmental vitiligo. We found one study of psychological interventions but we could not include the outcomes in our statistical analyses. We found no studies evaluating micropigmentation, depigmentation, or cosmetic camouflage. This review has found some evidence from individual studies to support existing therapies for vitiligo, but the usefulness of the findings is limited by the different designs and outcome measurements and lack of quality of life measures. There is a need for follow-up studies to assess permanence of repigmentation as well as high-quality randomised trials using standardised measures and which also address quality of life.

Plain-language summary: In this update search we found 39 new randomised controlled trials which, added to the 57 studies included previously, makes a total of 96 studies with 4512 participants. Twenty-one (21/39, 54%) of the new studies assessed new treatments, most of which involved the use of light. Narrowband UVB (NB-UVB) light was used in 35/96 (36% of all included studies), either alone or in combination with other therapies and achieved the best results. There were 18 surgical studies and 31 studies compared active treatment versus placebo. Half of the studies lasted longer than six months. Most of them 69/96 (72%) had fewer than 50 participants. Only seven studies assessed children and one study only recruited men. The majority of studies (53/96, 55%), most of which were of combination treatments with light, assessed more than 75% repigmentation. Eight studies reported a statistically significant result for this outcome, including the following four results: topical corticosteroids were better than PUVAsol (psoralen with sunlight), hydrocortisone plus laser light was better than laser light alone, ginkgo biloba was better than placebo and oral minipulse of prednisolone (OMP) plus NB-UVB was better than OMP alone. None of the studies reported the long-term benefit of the treatment i.e. two years' sustained repigmentation. The maximum follow-up time, reported in only one study, was one year post-treatment. Only 9/96 (9%) reported the quality of life of participants, but the majority of all studies (65/96, 68%) reported adverse effects, mainly for topical treatments, some of which caused itching, redness, skin thinning, telangiectasia and atrophy. Neither mometasone furoate nor hydrocortisone produced adverse effects. Some NB-UVB studies reported phototoxic reaction and Koebnerisation whereas some PUVA (psoralen with artificial light UVA as a light source) studies caused dizziness and nausea. Six studies reported cessation of spread of vitiligo, one of which showed that ginkgo biloba was more than twice as likely to stop vitiligo spreading than placebo. This review has highlighted the recent surge in vitiligo research providing insights into its causes. The majority of the studies reporting successful repigmentation were combinations of various interventions with light, indicating this is an effective, though not necessarily permanent, treatment for generalised vitiligo. In view of the fact that vitiligo has no cure, providing ways of coping with it could be of benefit to patients and should be part of standard care. Better designed studies, consensus on how to measure treatment success, more studies involving children and studies assessing psychological interventions, are needed. Since the last update (2010), the design and reporting of vitiligo trials have not greatly improved. Only five studies met the criteria for a well-designed trial. Poor design, the number and complexity of the treatments and the fact that many of the studies assessed individual vitiligo patches in the same participant, made comparison of the studies difficult. Consequently, we could only perform one meta-analysis of three studies comparing NB-UVB with PUVA which showed that NB-UVB has fewer side effects and is marginally better than PUVA.