Interventions for vitiligo Edited (no change to conclusions)
Vitiligo is a chronic skin disorder characterised by patchy loss of skin colour. Some people experience itching before the appearance of a new patch. It affects people of any age or ethnicity, more than half of whom develop it before the age of 20 years. There are two main types: generalised vitiligo, the common symmetrical form, and segmental, affecting only one side of the body. Around 1% of the world's population has vitiligo, a disease causing white patches on the skin. Several treatments are available. Some can restore pigment but none can cure the disease.
To assess the effects of all therapeutic interventions used in the management of vitiligo.
We updated our searches of the following databases to October 2013: the Cochrane Skin Group Specialised Register, CENTRAL in The Cochrane Library (2013, Issue 10), MEDLINE, Embase, AMED, PsycINFO, CINAHL and LILACS. We also searched five trials databases, and checked the reference lists of included studies for further references to relevant randomised controlled trials (RCTs).
Randomised controlled trials (RCTs) assessing the effects of treatments for vitiligo.
Data collection and analysis
At least two review authors independently assessed study eligibility and methodological quality, and extracted data.
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.
Maxine E Whitton, Mariona Pinart, Jonathan Batchelor, Jo Leonardi‐Bee, Urbà González, Zainab Jiyad, Viktoria Eleftheriadou, Khaled Ezzedine
Plain language summary
Treatments for vitiligo
Vitiligo is a chronic skin disorder characterised by patchy loss of skin colour. Some people experience itching before the appearance of a new patch. It affects people of any age or ethnicity, more than half of whom develop it before the age of 20 years. There are two main types: generalised vitiligo, the common symmetrical form, and segmental, affecting only one side of the body. Recent genetic research suggests that generalised vitiligo is, at least in part, an autoimmune condition which destroys melanocytes (pigment cells). Although our understanding of vitiligo has increased, its causes are still poorly understood. Several treatments are available. Some can restore pigment but none can cure it or prevent its spread or recurrence. Vitiligo patches can have a major psychosocial impact, especially for people with dark or tanned skin or when the face or hands are affected. People with vitiligo can be stigmatised, often experiencing low self‐esteem and a lack of self‐confidence. Children with vitiligo may be teased and bullied at school. Despite this, we found only one study assessing psychological therapy for vitiligo.
What treatments work best to help manage vitiligo?
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.
Quality of the evidence
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.
Maxine E Whitton, Mariona Pinart, Jonathan Batchelor, Jo Leonardi‐Bee, Urbà González, Zainab Jiyad, Viktoria Eleftheriadou, Khaled Ezzedine
Implications for practice
Although some consensus exists among researchers as to the causes of vitiligo, there is still a wide variety of theories and so the trials performed in recent years examine a wide range of interventions. It is important to stress that, at present, there is neither a cure for vitiligo nor an effective method of limiting the spread of the disease. Current treatment practices tend to centre on whatever theory is believed to be the most important while newer, more controversial ideas take time to become established. The small numbers of participants and heterogeneity of design of the studies in this review makes it difficult to make firm statements regarding recommendations for clinical practice.
The ever‐expanding range of interventions being assessed in vitiligo randomised controlled trials (RCTs) is perhaps a reflection of the fact that there are still no interventions which are obviously superior to others. Of the interventions intended to induce repigmentation, we found low‐quality RCT evidence for a number of different interventions that produce a varying degree of repigmentation of unknown long‐term permanence.
There is moderate evidence for the use of topical corticosteroids, although long‐term use is likely to lead to adverse effects. When used as monotherapy, it may be preferable to use superpotent preparations to give a better chance of therapeutic response, but close monitoring for adverse effects will be necessary. The topical immunomodulator, tacrolimus, seems to be a reasonable alternative to topical corticosteroids, particularly on anatomical sites where there may be a higher risk of adverse effects with topical corticosteroids. Although clinical advice has usually been to exercise caution when combining topical immunomodulators with light therapies, due to the theoretical long‐term risk of skin cancer, these combinations may have benefit if used under close medical supervision.
In general, combination interventions were superior to monotherapies; the majority of analyses giving significant results were in favour of various combination treatments. Most of the studies that assessed combination interventions employed light therapies (UVA, PUVA, or UVB, particularly NB‐UVB) and laser light therapies. Our search uncovered limited to moderate evidence for various types and regimens of light therapy (UVA and UVB) used alone or in combination with psoralens, topical corticosteroids, vitamin D analogues, 5‐fluorouracil, azathioprine, and oral prednisolone, although adverse effects were common with the latter. There is some evidence that excimer laser is more effective in combination with topical interventions such as hydrocortisone 17‐butyrate, tacrolimus, or tacalcitol. There is also limited evidence for the benefit of oral Ginkgo biloba, and split thickness skin grafts plus PUVAsol. Surgical therapies can be effective for small areas in people with stable disease. Clinicians should bear in mind that suction blister grafts may result in adverse effects, the most significant of which is precipitation of new areas of vitiligo at donor sites, due to the Koebner phenomenon. Autologous transplantation of melanocytes is a promising novel therapy, giving superior cosmetic results compared to more conventional surgical therapies, but access to this treatment may be limited.
Although there is empirical evidence in the literature to support the use of cosmetic camouflage to improve the quality of life of people with vitiligo, we found no trials of this intervention. Depigmentation is sometimes used in severe cases of vitiligo but we found no RCTs of this intervention either. There may also be some people who require more in‐depth psychological support. As with the previous update, we found only one RCT comparing the use of cognitive‐behavioural therapy and person‐centred approaches and this study found little support for any particular psychological intervention; we could not perform statistical analysis of the study data. As things stand, although there is limited evidence for this kind of intervention anecdotal evidence strongly suggests that a form of psychological intervention or support could be of benefit to some individuals.
Although vitiligo commonly presents before the age of 20 years, only seven of the 96 included studies looked specifically at interventions for vitiligo in children. The remainder of the studies either included adults alone or had no specified age. Treatment in children is limited by compliance, tolerance of treatment and concerns regarding long‐term side effects. None of the studies had long‐term follow‐up beyond two years. These seven studies looked at a range of interventions including topical treatments such as tacrolimus and corticosteroids, NB‐UVB, PUVA, 308‐nm excimer laser and dermabrasion. Stigmatisation can be a particular problem in children with vitiligo and treatment options beyond topical therapies should be explored after a discussion regarding side effects, effectiveness and impact on quality of life. Although further evidence is required, psychological and cosmetic interventions may be of particular benefit in this population of patients.
Implications for research
Since the original review was carried out in 2006, there has been a rapid increase in the number of clinical trials, particularly randomised controlled trials, assessing interventions for vitiligo. However, it is still not clear which are the best interventions for this condition. Until the causes of vitiligo are better understood, treatments will continue to be based on the many theories that exist for this disease. Although there has been a noticeable increase in basic scientific research, more investment is needed so that new discoveries in experimental models can be systematically advanced to preclinical and clinical stages.
- Standardised methodologies for describing and classifying vitiligo and for assessing the effect of interventions need to be developed and used by trial investigators. The establishment of a Vitiligo European Task Force (VETF; Taïeb 2007) is an important step in this direction and the work of this group should hopefully lead to studies measuring repigmentation in a more standardised way. However, many studies still use their own measures, so the work of the VETF group needs to be disseminated as widely as possible.
- There is also a general need for better quality RCTs of treatments for vitiligo. Overall, it seems that there has been only a slight improvement in the quality of the methodology of RCTs since the last update of this review, and since the publication of the "Guidelines for Designing and Reporting Clinical Trials in Vitiligo" (González 2011), which were based on the last update.
- Specific recommendations from the "Guidelines for Designing and Reporting Clinical Trials in Vitiligo" (González 2011), which should be followed in order to ensure the best design and reporting of any future vitiligo trials, include the following.
- Participants: Clear description of inclusion and exclusion criteria; clear description of baseline characteristics of participants; clear description of study setting.
- Interventions: Adequate description of intervention(s); adequate choice and description of control group; adherence to treatment should be measurable and reported.
- Outcomes: Adequate follow‐up (at least one year) and frequency of data recording; standardised definition of treatment effect and measurement scales; clear definition of primary, patient‐centred outcomes, including quality of life measured using a validated tool and percentage repigmentation; clear definition of secondary outcomes, including cessation of spread or stabilisation of the disease and long‐term permanence of repigmentation. (There is currently an international group developing an agreed set of core outcomes for vitiligo trials, as part of the COMET initiative.)
- Study design: Adequate generation of randomisation sequence and concealment; detailed description of methodology of blinding of assessors and participants; calculation of sample size; clear reporting of losses to follow‐up and analysis of the total number of randomised participants.
- Data reporting: should follow CONSORT reporting guidelines.
- Study design should take into account variations in participant features, including skin colour, age or duration of the disease, extent and type of vitiligo, as well as the site of affected areas. These factors may determine the applicability of results in particular clinical settings and may cause the response to treatment to vary. There should also be larger, multi‐centre studies and fewer intra‐participant studies to allow comparison and meta‐analysis.
- Melanocytes are slow to grow and develop, so in order to properly assess the efficacy of an intervention, interventions should ideally be continued for long enough to allow complete repigmentation; this may need to be at least six months and possibly up to a year.
- Cessation of spread of vitiligo and long‐term permanence of repigmentation are very important outcome measures for people with vitiligo. Future studies should include these outcomes and should ideally include at least two‐years' follow‐up of participants.
- Patient‐rated outcome measures (especially measures of treatment success) should be incorporated into the design of future studies. Further work is needed to develop and validate suitable outcome measures that are meaningful to patients (Eleftheriadou 2012).
- The inclusion of health‐related quality of life measures such as the VitiQOL scale and the Dermatology Life Quality Index would not only improve the relevance of trials but could allow comparison between trials using different interventions.
- More studies are needed to establish the dosage, safety, and long‐term efficacy of NB‐UVB monotherapy in treating vitiligo. In particular, the possibility of long‐term skin damage and possible skin cancer following prolonged UV treatment for vitiligo needs to be researched.
- Topical tacrolimus appears to have a similar effect to topical corticosteroids, but with a better safety profile (Ho 2011). More studies are needed to establish it as a viable, cost‐effective alternative, particularly in combination with other interventions (e.g. light therapies).
- Larger studies are needed in order to provide stronger evidence for the many combination interventions that have shown promise in treating vitiligo. Because vitiligo is a disease affecting pigment cells, the use of some form of phototherapy may be necessary in order for these cells to proliferate and develop, thus giving faster repigmentation. Combination therapy may therefore be more desirable from both a clinician and participant point of view.
- Although there are some studies of complementary or psychological interventions at present, a greater number of well‐conducted RCTs in these areas would provide more useful evidence for their efficacy. Psychological interventions are particularly important in view of the fact that the main symptoms of vitiligo are not physical but psychosocial.
- Studies are needed on the use of cosmetic camouflage, which is often recommended with no other treatment. Although it helps to disguise the condition and can give some degree of self‐confidence, it cannot be used on large affected areas of skin and has to be reapplied frequently. It can also create anxiety in those whose vitiligo is actively spreading. There is no good evidence to show that cosmetic camouflage improves the quality of life of people with vitiligo in the long term.