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. 2011 Mar 28;2011:1717.

Vitiligo in adults and children

Rubeta Matin 1
PMCID: PMC3217714  PMID: 21439099

Abstract

Introduction

Vitiligo is an acquired skin disorder characterised by white (depigmented) patches in the skin, due to the loss of functioning melanocytes. The extent and distribution of vitiligo often changes during the course of a person's lifetime and its progression is unpredictable.

Methods and outcomes

We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of medical treatments, and of ultraviolet light treatments, for vitiligo in adults and in children? We searched: Medline, Embase, The Cochrane Library, and other important databases up to March 2010 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).

Results

We found 25 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.

Conclusions

In this systematic review we present information relating to the effectiveness and safety of the following interventions: corticosteroids (oral and topical), oral levamisole, topical immunomodulators, topical vitamin D analogues, ultraviolet A plus psoralen (PUVA [oral or topical]), and ultraviolet B (narrowband).

Key Points

Vitiligo is an acquired skin disorder characterised by white (depigmented) patches in the skin, caused by the loss of functioning melanocytes.

  • Vitiligo patches can appear anywhere on the skin, but common sites are usually around the orifices, the genitals, or sun-exposed areas such as the face and hands.

  • The extent and distribution of vitiligo often changes during the course of a person's lifetime, and its progression is unpredictable.

Limited courses of potent topical corticosteroids in adults and children are a safe and effective therapy for localised vitiligo and are often the first-choice treatment for this disorder.

  • The consensus is that adverse effects of oral corticosteroids in adults and children outweigh the benefits in vitiligo. There is currently insufficient RCT evidence available to assess their effectiveness.

Narrowband ultraviolet B in adults and children is considered a safe and effective therapy for moderate to severe generalised vitiligo and is often the first-choice treatment for this disorder.

Tacrolimus requires further evaluation, but is well tolerated in children and adults without the long-term adverse effects of topical corticosteroids.

  • There is currently insufficient RCT evidence available to assess other immunomodulators in vitiligo.

There is insufficient RCT evidence to fully assess levamisole or topical vitamin D analogues in vitiligo in children or in adults.

Consensus is that for the treatment of vitiligo in adults, oral psoralen plus ultraviolet A (PUVA) is effective, whereas topical PUVA is unlikely to be effective. However, topical PUVA has fewer adverse effects than oral PUVA. PUVA is likely to be harmful in children.

Vitiligo patches in certain body areas, such as the acral sites, palms and soles, lips, mucosa, and nipples, and segmental forms in any area are relatively resistant to all conventional treatment modalities.

  • In these cases, counselling and cosmetic camouflage become a priority, and often no treatments are advocated.

About this condition

Definition

Vitiligo is an acquired skin disorder characterised by white (depigmented) patches in the skin, caused by the loss of functioning melanocytes. The hair, and rarely the eyes, may also lose colour. Vitiligo patches can appear anywhere on the skin, but common sites are usually around the orifices, the genitals, or sun-exposed areas such as the face and hands. The disease is classified according to its extent and distribution, and can be subdivided into generalised or localised. In practice, there is considerable overlap between these types, and people often have vitiligo that cannot be categorised or that will change during the course of their lifetime. Therefore, for the purposes of this review, we have included all people diagnosed with vitiligo of any type. Children were defined as people aged 15 years and under.

Incidence/ Prevalence

Vitiligo is estimated to affect 1% of the world's population, regardless of age, sex, and skin colour. Anyone of any age can develop vitiligo, but it is very rarely reported to be present at birth. In a Dutch study, 50% of people reported that the disease appeared before the age of 20 years. It is difficult to assess the true prevalence of vitiligo as the estimate of between 0.5% and 1% prevalence worldwide varies according to cultural and social differences. In countries where more stigma is attached to the disease for cultural or social reasons or because it is more visible because of dark skin colour, more people with the disease are likely to consult a doctor than in other countries where this is not the case, thus reported estimates of prevalence may be high. Figures as high as 8.8% have been reported in India where stigma associated with the disease is high.

Aetiology/ Risk factors

The aetiology of vitiligo is uncertain although genetic, immunological, biochemical (including oxidative stress), and neurogenic factors may interact to contribute to its development. Although there are few epidemiological studies of vitiligo, it is believed that one third of people with vitiligo report close family members affected by the disorder, suggesting that genetic factors have an important role in the development of the disease, and this is supported by several genetic susceptibility studies. In particular, NALP-1 predisposes people to vitiligo as well as to various autoimmune diseases. However, certain triggers (e.g., trauma to the skin, hormonal changes, and stress) may be necessary for the disease to become apparent. Autoimmune mechanisms are thought to be responsible in the pathogenesis of vitiligo (especially in generalised or focal non-dermatomal vitiligo). This is supported by an increased incidence of antibodies found in people with vitiligo. Furthermore, vitiligo is often associated with autoimmune diseases, such as thyroid diseases, pernicious anaemia, and diabetes mellitus. Another indication that vitiligo may be caused by an autoimmune mechanism is that melanocyte antibodies have been found in people with vitiligo, and their incidence correlates with disease activity. Involvement of cellular immunity has been considered because T lymphocytes and macrophages in peri-lesional skin have also been frequently reported. Regarding segmental vitiligo, the neural hypothesis suggests that it is caused by an accumulation of a neurochemical substance, which decreases melanin production.

Prognosis

Vitiligo is not life threatening and is mostly asymptomatic, although it does increase the risk of sunburn of the affected areas. The association of vitiligo and skin cancer remains an area of controversy. The occurrence of skin cancer in long-lasting vitiligo is rare, although studies have demonstrated increased PUVA-associated skin cancers. A Swedish study, which followed up people treated with PUVA over 21 years, demonstrated an increased risk of squamous cell carcinomas. Furthermore, the risk of malignant melanoma increases among people treated with PUVA, approximately 15 years after the first treatment. The effects of vitiligo can be both cosmetically and psychologically devastating, resulting in low self-esteem and poor body image. The anxieties regarding the disease occur against a background of a lack of understanding of the aetiology and unpredictability of the course. Progression: The course of generalised vitiligo is unpredictable: lesions may remain stable for years or (more commonly) may progress alternating with phases of stabilisation, or (less commonly) may slowly progress for several years to cover the entire body surface. In some instances, people may undergo rapid, complete depigmentation within 1 or 2 years. In segmental vitiligo, lesions tend to spread rapidly at onset, and show a more stable course thereafter. Predicting treatment responsiveness: Certain disease characteristics help predict the outcome of treatment. Besides age, duration of disease, localisation, and extent of depigmentation, current disease activity should also be considered during clinical decision making. This is essential in people with vitiligo vulgaris, when the disease activity may fluctuate at a given time. Medical therapies and ultraviolet light treatments may be equally effective in active and stable disease, but this may not be true for other treatments (e.g., surgery). An associated skin manifestation is the phenomenon of "koebnerization", where pressure or friction on the skin can cause new lesions or worsen existing ones. Koebnerization occurs in most people with vitiligo, but elimination of frictional trauma, in the form of occlusive garments and jewellery, prevents occurrence of new lesions in the cosmetically important areas in cases of progressive vitiligo. Also, it has been reported that the presence of positive experimentally induced Koebner phenomenon is associated with active disease, but not necessarily more severe disease (that is, in terms of the extent of depigmentation). The presence of Koebner phenomenon may be a valuable clinical factor for assessing disease activity, and may predict responsiveness to certain treatments. A case series reported that people who were Koebner phenomenon positive (induced experimentally) were significantly more responsive to topical fluticasone propionate combined with UVA therapy; but, for narrowband UVB treatment, there was no difference in response, suggesting that people in active and stable stages of the disease may respond equally well to UVB.

Aims of intervention

To prevent formation of new skin lesions of the vitiligo; to achieve repigmentation of involved skin, thus improving the quality of life, with minimal adverse effects of treatments.

Outcomes

The degree of repigmentation that defines success has been arbitrarily set in many studies as 50% to 75% repigmentation, based largely on the global impression of the overall response. Other outcomes include percentage repigmentation, development of new lesions of vitiligo, and arrest of vitiligo spread. There is currently no validated quantitative scale that allows vitiligo to be characterised parametrically, but a model was developed in one RCT of a novel parametric tool, which, if used by clinicians, could provide a more quantifiable comparison of the effects of different interventions. Adverse effects of treatments.

Methods

Clinical Evidence search and appraisal March 2010. The following databases were used to identify studies for this systematic review: Medline 1966 to March 2010, Embase 1980 to March 2010, and The Cochrane Database of Systematic Reviews 2010, March issue (1966 to date of issue). When editing this review we used The Cochrane Database of Systematic Reviews 2010, issue 1. An additional search within The Cochrane Library was carried out for the Database of Abstracts of Reviews of Effects (DARE) and Health Technology Assessment (HTA). We also searched for retractions of studies included in the review. Abstracts of the studies retrieved from the initial search were assessed by an information specialist. Selected studies were then sent to the contributor for additional assessment, using predetermined criteria to identify relevant studies. Study design criteria for inclusion in this review were: published systematic reviews of RCTs and RCTs in any language, at least single blinded, and containing >20 individuals of whom >80% were followed up. There was no minimum length of follow-up required to include studies. We excluded all studies described as "open", "open label", or not blinded unless blinding was impossible. We included systematic reviews of RCTs and RCTs where harms of an included intervention were studied applying the same study design criteria for inclusion as we did for benefits. In addition we use a regular surveillance protocol to capture harms alerts from organisations such as the FDA and the MHRA, which are added to the reviews as required. To aid readability of the numerical data in our reviews, we round many percentages to the nearest whole number. Readers should be aware of this when relating percentages to summary statistics such as relative risks (RRs) and odds ratios (ORs). We have performed a GRADE evaluation of the quality of evidence for interventions included in this review (see table ). The categorisation of the quality of the evidence (into high, moderate, low, or very low) reflects the quality of evidence available for our chosen outcomes in our defined populations of interest. These categorisations are not necessarily a reflection of the overall methodological quality of any individual study, because the Clinical Evidence population and outcome of choice may represent only a small subset of the total outcomes reported, and population included, in any individual trial. For further details of how we perform the GRADE evaluation and the scoring system we use, please see our website (www.clinicalevidence.com).

Table 1.

GRADE evaluation of interventions for vitiligo

Important outcomes Treatment success (repigmentation), disease progression (development of new lesions), adverse effects
Number of studies (participants) Outcome Comparison Type of evidence Quality Consistency Directness Effect size GRADE Comment
What are the effects of medical treatments for vitiligo in adults?
3 (48) Treatment success Potent topical corticosteroids v placebo 4 −1 0 0 +2 High Quality point deducted for sparse data. Effect-size points added for OR >5
2 (33) Treatment success Very potent topical corticosteroids v placebo 4 −2 0 0 0 Low Quality points deducted for sparse data and incomplete reporting of results
1 (20) Treatment success Potent v very potent corticosteroids 4 −2 0 −2 0 Very low Quality points deducted for sparse data and incomplete reporting of results. Directness points deducted for no direct comparison between groups and no clear measurement of outcome
1 (67) Treatment success Potent topical corticosteroids plus UVA v topical corticosteroids alone 4 −2 0 0 0 Low Quality points deducted for sparse data and poor follow-up
1 (68) Treatment success Potent topical corticosteroids plus UVA v UVA 4 −2 0 0 0 Low Quality points deducted for sparse data and poor follow-up
1 (31) Treatment success Potent topical corticosteroids plus topical calcipotriol v topical calcipotriol alone 4 −1 0 −1 0 Low Quality point deducted for sparse data. Directness point deducted for inclusion of children
1 (18) Treatment success Pimecrolimus v placebo cream 4 −2 0 −1 0 Very low Quality points deducted for sparse data and incomplete reporting of results. Directness point deducted for inclusion of children
1 (60) Disease progression Levamisole plus potent topical corticosteroids v potent topical corticosteroids alone 4 −2 0 −2 0 Very low Quality points deducted for sparse data and poor follow-up. Directness points deducted for inclusion of children and uncertainty about size of lesions
1 (24) Treatment success Topical calcipotriol v placebo or no treatment 4 −2 0 −1 0 Very low Quality points deducted for sparse data and incomplete reporting of results. Directness point deducted for inclusion of children
1 (34) Treatment success Topical calcipotriol v topical betamethasone dipropionate 4 −2 0 −1 0 Very low Quality points deducted for sparse data and incomplete reporting of results. Directness point deducted for inclusion of children
1 (30) Treatment success Topical calcipotriol plus potent topical corticosteroids v potent topical corticosteroids 4 −1 0 −1 0 Low Quality point deducted for sparse data. Directness point deducted for inclusion of children
1 (35) Treatment success Topical calcipotriol plus PUVA v PUVA alone 4 −2 0 −1 0 Very low Quality points deducted for sparse data and incomplete reporting of results. Directness point deducted for inclusion of children
2 (57) Treatment success Topical calcipotriol plus NB-UVB v UVB 4 −2 0 −1 0 Very low Quality points deducted for sparse data and incomplete reporting of results. Directness point deducted for inclusion of children
1 (32) Treatment success Topical tacalcitol plus NB-UVB v NB-UVB 4 −2 0 0 0 Low Quality points deducted for sparse data and incomplete reporting of results
What are the effects of ultraviolet light treatments for vitiligo in adults?
1 (122) Treatment success Methoxsalen plus UVA v UVA alone 4 −2 0 −1 0 Very low Quality points deducted for sparse data and poor-quality studies. Directness point deducted for inclusion of children
1 (167) Treatment success Trioxysalen plus UVA v UVA alone 4 −2 0 −1 0 Very low Quality points deducted for sparse data and poor-quality studies. Directness point deducted for inclusion of children
3 (195) Treatment success Unsubstituted PUVA v UVA alone 4 −2 −1 −1 0 Very low Quality points deducted for sparse data and incomplete reporting of results. Consistency point deducted for conflicting results. Directness point deducted for uncertainty about applicability of results (sunlight variations)
1 (38) Treatment success Oral PUVA v topical PUVA 4 −2 0 0 0 Low Quality points deducted for sparse data and incomplete reporting of results
1 (at least 241 people) Treatment success Different oral PUVA derivatives v each other 4 −1 0 0 0 Moderate Quality point deducted for poor-quality studies
1 (at least 153 people) Treatment success Methoxsalen plus trioxysalen plus UVA v different psoralen derivatives plus UVA 4 −2 0 0 0 Low Quality points deducted for sparse data and poor-quality study
1 (56) Treatment success Oral PUVA v NB-UVB 4 −1 0 −1 0 Low Quality point deducted for sparse data. Directness point deducted for difference in number of treatments completed between groups
1 (22) Treatment success NB-UVB v placebo 4 −2 0 0 0 Low Quality points deducted for sparse data and for controlled trial
1 (22) Treatment success Oral PUVB (broadband) v oral PUVA 4 −2 0 −1 0 Very low Quality points deducted for sparse data and incomplete reporting of results. Directness point deducted for inclusion of children
1 (45) Treatment success Topical PUVA v no treatment 4 −1 0 0 0 Moderate Quality point deducted for sparse data
1 (106) Treatment success Topical PUVA v NB-UVB 4 −3 0 −1 0 Very low Quality points deducted for sparse data, incomplete reporting of results, and for quasi-RCT. Directness point deducted for inclusion of children
What are the effects of medical treatments for vitiligo in children?
1 (45) Treatment success Clobetasol propionate v PUVA 4 −1 0 0 0 Moderate Quality point deducted for sparse data
1 (20) Treatment success Clobetasol propionate v topical tacrolimus 4 −1 0 −1 0 Low Quality point deducted for sparse data. Directness point deducted for inclusion of children aged >15 years
What are the effects of ultraviolet light treatments for vitiligo in children?
1 (50) Treatment success Trioxysalen plus UVA v UVA alone 4 −1 0 −1 0 Low Quality point deducted for sparse data. Directness point deducted for applicability of results
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Type of evidence: 4 = RCT. Consistency: similarity of results across studies.Directness: generalisability of population or outcomes.Effect size: based on relative risk or odds ratio.NB-UVB, narrowband ultraviolet B.

Glossary

Active vitiligo

An extending vitiligo with enlarging lesions or development of new lesions.

Broadband ultraviolet B

290 nm to 320 nm wavelength ultraviolet radiation.

Ecchymoses

The escape of blood into the tissues from ruptured blood vessels marked by a livid black and blue or purple spot or area.

Generalised vitiligo

Characterised by multiple scattered lesions in a symmetrical distribution pattern. It occurs in acrofacial, periorifacial, and orifacial types, in which the distal extremities and face are involved. In the universal form, there is more than 80% depigmentation.

High-quality evidence

Further research is very unlikely to change our confidence in the estimate of effect.

Hypertrichosis

Excessive growth of hair.

Internally controlled trial

A trial in which the experimental intervention is compared with either a standard treatment for the disease, a placebo, or no treatment at all, in the same participant.

Koebner phenomenon

The development of vitiligo at sites of aspecifically traumatised skin.

Localised vitiligo

can consist either of focal lesions (macules appear in a non-dermatomal distribution) or a segmental form (macules are localised in a segmental distribution that is frequently not dermatomal, commonly seen in children).

Low-quality evidence

Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.

Moderate-quality evidence

Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.

Narrowband ultraviolet B

310 nm to 315 nm wavelength ultraviolet radiation.

PUVA

Combination therapy of ultraviolet A and topical or oral psoralen. The psoralen sensitises the skin to ultraviolet A and is taken or is applied a set period of time before the ultraviolet A exposure.

Parametrically

A set of measurable factors that define a condition and determine its course which are varied in a trial.

Segmental vitiligo

A form of localised vitiligo where one or more lesions of vitiligo arise in a quasidermatomal pattern.

Ultraviolet A

315 nm to 400 nm ultraviolet radiation.

Very low-quality evidence

Any estimate of effect is very uncertain.

Vitiligo vulgaris

A symmetrical type of generalised vitiligo in which scattered macules are seen over the entire body.

Disclaimer

The information contained in this publication is intended for medical professionals. Categories presented in Clinical Evidence indicate a judgement about the strength of the evidence available to our contributors prior to publication and the relevant importance of benefit and harms. We rely on our contributors to confirm the accuracy of the information presented and to adhere to describe accepted practices. Readers should be aware that professionals in the field may have different opinions. Because of this and regular advances in medical research we strongly recommend that readers' independently verify specified treatments and drugs including manufacturers' guidance. Also, the categories do not indicate whether a particular treatment is generally appropriate or whether it is suitable for a particular individual. Ultimately it is the readers' responsibility to make their own professional judgements, so to appropriately advise and treat their patients. To the fullest extent permitted by law, BMJ Publishing Group Limited and its editors are not responsible for any losses, injury or damage caused to any person or property (including under contract, by negligence, products liability or otherwise) whether they be direct or indirect, special, incidental or consequential, resulting from the application of the information in this publication.

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BMJ Clin Evid. 2011 Mar 28;2011:1717.

Corticosteroids (topical) in adults

Summary

TREATMENT SUCCESS Potent topical corticosteroids compared with placebo: Potent corticosteroids are more effective at 2 to 21 months at improving the proportion of people with >75% repigmentation of localised vitiligo ( high-quality evidence ). Very potent topical corticosteroids compared with placebo: We don't know whether very potent topical corticosteroids are more effective at improving the number of people with >75% repigmentation of their localised vitiligo ( low-quality evidence ). Potent compared with very potent corticosteroids: We don't know how effective potent topical corticosteroids and very potent corticosteroids are, compared with each other, at improving outcomes in people with vitiligo ( very low-quality evidence ). Potent topical corticosteroids plus UVA compared with topical corticosteroids alone: Topical fluticasone propionate plus UVA may be more effective at increasing the proportion of people achieving >75% repigmentation of affected lesions at 9 months (low-quality evidence). Potent topical corticosteroids plus UVA compared with UVA alone: We don't know how effective topical fluticasone propionate plus UVA and UVA alone are, compared with each other, at increasing the proportion of people achieving >75% repigmentation of affected lesions at 9 months (low-quality evidence). Potent topical corticosteroids plus topical calcipotriol compared with topical calcipotriol alone: Topical betamethasone diproprionate cream (0.05%) plus topical calcipotriol (0.005%) may be more effective at 3 months at increasing the proportion of adults and children who achieve >25% repigmentation (low-quality evidence). Topical betamethasone dipropionate compared with topical calcipotriol: Topical betamethasone dipropionate may be more effective at 3 months at improving the proportion of adults and children who achieve >25% repigmentation (very low-quality evidence). Potent topical corticosteroids plus topical calcipotriol compared with potent topical corticosteroids: We don't know how effective potent topical corticosteroids plus topical calcipotriol and potent topical corticosteroids alone are, compared with each other, at 3 months at improving the proportion of children and adults achieving >50% repigmentation; however potent topical corticosteroids plus topical calcipotriol may be more effective at decreasing the mean time to initial repigmentation (low-quality evidence). DISEASE PROGRESSION Levamisole plus potent topical corticosteroids compared with potent topical corticosteroids alone: We don't know how effective levamisole plus topical mometasone furoate and topical mometasone furoate alone are, compared with each other, at 6 months at preventing the development of new lesions in adults and children with slowly spreading vitiligo (very low-quality evidence). NOTE We found no clinically important results from RCTs about different strengths of topical corticosteroids compared with each other or comparing the efficacy of topical corticosteroids on different parts of the body in people with vitiligo. Corticosteroid use is associated with skin atrophy, drug-induced acne, and hypertrichosis. There is consensus that a limited course of potent and very potent topical corticosteroids in localised vitiligo is a useful first-line treatment, particularly in newly formed lesions.

Benefits

We found two systematic reviews (search dates 1998 and 2009). The second systematic review did not include a meta-analysis of the clinical outcomes of interest.

Potent topical corticosteroids versus placebo:

The first systematic review identified three RCTs. The systematic review found that, compared with placebo, potent topical corticosteroids significantly improved the proportion of people with >75% repigmentation (3 RCTs, 48 people, ages not reported, localised vitiligo, treatment over 2–21 months; AR: 16/48 [33%] with potent corticosteroid v 0/48 [0%] with placebo; OR 14.32, 95% CI 2.45 to 83.72). The authors of the systematic review reported that potent topical corticosteroids were the most effective and safe therapies for localised vitiligo.

Very potent topical corticosteroids versus placebo:

The first systematic review identified two RCTs. It found no significant difference between very potent topical corticosteroids and placebo in the proportion of people with >75% repigmentation (2 RCTs, 33 people, age range not reported, localised vitiligo, no time frame for treatment reported; AR: 2/33 [6%] with very potent corticosteroid v 2/33 [6%] with placebo; OR 1.00, 95% CI 0.16 to 6.21).

Potent versus very potent corticosteroids:

The first systematic review identified one RCT. It found that very potent topical corticosteroids were less effective than potent corticosteroids, although no direct comparison was made (3/10 [30%] with potent corticosteroid v 1/10 [10%] with very potent corticosteroid; significance not reported). No comment was made by the authors as to the unusual result, but in view of the small size of the study, further RCTs are needed to clarify the results.

Potent topical corticosteroids plus UVA versus topical corticosteroids alone:

The second systematic review identified one internally controlled trial (135 people, of whom 96 were evaluable; 18–80 years of age; 2 equal, symmetrical, bilateral lesions on the arms, legs, or trunk). The trial compared topical fluticasone propionate (a potent corticosteroid, 0.05% fluticasone propionate cream applied at night) alone versus topical fluticasone propionate plus UVA (10-J/cm2 exposure twice weekly for 20 minutes) in 67 people; and compared topical fluticasone propionate plus UVA versus UVA alone in 68 people. It found that, compared with topical fluticasone propionate alone, topical fluticasone propionate plus UVA significantly increased the proportion of people achieving >75% repigmentation of affected lesions at 9 months (10/67 [15%] with fluticasone propionate plus UVA v 2/67 [3%] with fluticasone propionate alone; P = 0.008; intention-to-treat [ITT] analysis). Repigmentation was evaluated clinically by a single clinician against baseline photographs (0% = no repigmentation, 75% = significant repigmentation, 100% = complete repigmentation). The trial did not explain why only 96 of the 135 enrolled participants were evaluable.

Potent topical corticosteroids plus UVA versus UVA alone:

The second systematic review identified one internally controlled trial (135 people, see above). The trial compared topical fluticasone propionate alone versus topical fluticasone propionate plus UVA in 67 people and compared topical fluticasone propionate plus UVA versus UVA alone in 68 people. It found no significant difference between UVA alone and topical fluticasone propionate plus UVA in the proportion of people achieving >75% repigmentation of affected lesions at 9 months (AR: 8/68 [12%] with fluticasone propionate plus UVA v 3/68 [4%] with UVA alone; P = 0.06; ITT analysis).

Potent topical corticosteroids plus topical calcipotriol versus topical calcipotriol alone:

The second systematic review identified one three-armed RCT (49 people with vitiligo affecting 5% of their skin) comparing topical calcipotriol ointment and betamethasone dipropionate in combination or alone. The RCT found that topical betamethasone dipropionate cream (0.05% applied twice daily) plus topical calcipotriol cream (0.005% applied twice daily) significantly increased the proportion of people who achieved >25% repigmentation (assessed by clinical examination and comparison with baseline photographs) at 3 months compared with topical calcipotriol cream alone (31 people, age range 10–60 years, vitiligo affecting <5% body surface area; AR: 11/15 [73%] with betamethasone dipropionate plus calcipotriol v 6/16 [37%] with calcipotriol alone; P <0.01).

Potent topical corticosteroids plus topical calcipotriol versus potent topical corticosteroids alone:

See benefits of vitamin D analogues.

Topical calcipotriol versus topical betamethasone dipropionate:

See benefits of vitamin D analogues.

Potent topical corticosteroids plus levamisole versus potent topical corticosteroids alone:

See benefits of levamisole.

Harms

Potent topical corticosteroids versus placebo:

The systematic review reported adverse effects from 6 case series (235 people, treatment duration 2–21 months). It found that potent topical corticosteroid use was associated with atrophy (5/250 [2%]), corticosteroid-induced acne (16/228 [7%]), and hypertrichosis (2/200 [1%]). The RCTs included in the review gave no information on adverse effects.

Very potent topical corticosteroids versus placebo:

One RCT identified by the systematic review found that all the participants treated with 0.05% clobetasol propionate showed evidence of dermal atrophy. The other RCT identified by the review found striking ecchymoses (1/20 [5%]) and rosacea (1/10 [10%]) with topical betamethasone. It reported that the majority of people treated with topical corticosteroids (betamethasone or clobetasol) had varying degrees of atrophy of the treated skin. The systematic review (search date 1998) reported adverse effects from 7 case series (277 people, treatment duration 2–12 months). It found that very potent topical corticosteroid use was associated with atrophy (39/277 [14%]), telangiectasia (8/267 [3%]), corticosteroid-induced acne (25/277 [9%]), and hypertrichosis (1/100 [1%]).

Potent topical corticosteroids plus UVA versus topical corticosteroids/UVA alone:

The RCT reported no significant skin atrophy or atrophogenic changes on visual examination over 9 months.

Potent topical corticosteroids plus topical calcipotriol versus topical calcipotriol alone:

The RCT identified by the reviewreported hypertrichosis (1/15 [7%]) and lesional dryness (1/15 [7%]) in people treated with betamethasone dipropionate plus calcipotriol. The calcipotriol-treated group reported peri-lesional hyperpigmentation (1/15 [7%]) and an irritant reaction (1/15 [7%]).

Potent topical corticosteroids plus topical calcipotriol versus potent topical corticosteroids alone:

See harms of vitamin D analogues.

Topical calcipotriol versus topical betamethasone dipropionate:

See harms of vitamin D analogues.

Potent topical corticosteroids plus levamisole versus potent topical corticosteroids alone:

See harms of levamisole.

Comment

Clinical guide:

Observational evidence and decades of experience of their use in vitiligo have led to a consensus that topical corticosteroids are effective. Most clinicians prescribe a course of a moderately potent or potent corticosteroid for the face, and a potent or very potent topical corticosteroid for the body as first-line treatment in focal or segmental vitiligo. However, the long-term use of topical corticosteroids is not advocated because the adverse effects are irreversible (e.g., skin atrophy, striae, and telangiectasia). Long-standing lesions have been shown to be relatively resistant to local corticosteroid treatment — probably because of the depletion of melanocyte reserves in hair follicles. Guidelines based on a systematic review suggested a combination of potent topical corticosteroids plus UVA therapy for people with localised vitiligo. It has been suggested that a combination of calcipotriol with potent topical corticosteroids may mitigate the local adverse effects of topical corticosteroids alone, which may be particularly helpful in children.

Substantive changes

Corticosteroids (topical) in adults New evidence added. Categorisation unchanged (Beneficial).

BMJ Clin Evid. 2011 Mar 28;2011:1717.

Immunomodulators (topical) in adults

Summary

TREATMENT SUCCESS Pimecrolimus compared with placebo cream: Topical pimecrolimus cream (1%) may be no more effective at 6 months at reducing the size of lesions in children and adults with symmetrical vitiligo ( very low-quality evidence ). NOTE Topical pimecrolimus and tacrolimus may be associated with malignancy.

Benefits

Pimecrolimus versus placebo cream:

We found one systematic review (search date 2009), which identified one internally controlled (left–right) RCT (20 people with symmetrical vitiligo, children and adults aged 12–60 years, mean age 36.9 years) comparing pimecrolimus cream (1%) versus placebo. The RCT found no significant difference in size of target lesion (assessed by planimetry) between topical pimecrolimus cream (1% applied twice daily) and placebo cream (vehicle applied twice daily to equivalent contralateral lesion) at 6 months (18 people, 2 people lost to follow-up, maximum duration of disease 2 years, with at least one new lesion in the last year; AR for mean difference in size of target lesion: +90 mm2 [range –2046 mm2 to +509 mm2] with topical pimecrolimus v +114 mm2 [range –1230 mm2 to +615 mm2] with placebo; P = 0.5).

Harms

Pimecrolimus versus placebo cream:

The RCT reported no skin atrophy or adverse effects.

Comment

Pimecrolimus plus narrowband UVB versus narrowband UVB plus placebo cream:

The systematic review (search date 2009) identified one RCT (68 people, aged 15–72 years, with stable symmetrical vitiligo) comparing pimecrolimus cream (1% applied twice daily) plus narrowband UVB versus placebo cream (petroleum applied twice daily to equivalent contralateral lesion) plus narrowband UVB. However, the follow-up in this RCT was low (50/68 [73%]). The RCT found no significant difference in rates of repigmentation between the groups at 3 months' follow-up. It reported only self-limiting erythema and pruritus as adverse effects with treatments. We will address this intervention in full in future updates of this review.

Drug safety alerts:

The FDA issued a public health advisory to inform people about a potential malignancy risk from the use of topical tacrolimus and pimecrolimus. This concern is based on information from animal studies, case reports in a small number of people, and a theoretical risk of immunomodulators.

Clinical guide:

Pimecrolimus and tacrolimus are emerging as therapeutic alternatives for many immune-mediated dermatoses (e.g., atopic eczema). Observational studies in vitiligo report similar efficacy to topical corticosteroids, and they may be useful for treating facial skin or eyelids, where the risk of skin atrophy from topical corticosteroids or phototoxicity from phototherapy is very high. Further RCT evidence for their use in vitiligo is needed to confirm this, although from this small study it seems that pimecrolimus is unlikely to be an effective treatment for vitiligo, either as an independent agent or as an adjunct to narrowband UVB treatment. RCTs investigating the effects of imiquimod in vitiligo have not been undertaken.

Substantive changes

Immunomodulators (topical) in adults New evidence added. Categorisation unchanged (Unknown effectiveness) as there remains insufficient evidence to judge the effects of this intervention.

BMJ Clin Evid. 2011 Mar 28;2011:1717.

Levamisole (oral) in adults

Summary

DISEASE PROGRESSION Levamisole plus potent topical corticosteroids compared with potent topical corticosteroids alone: We don't know how effective levamisole plus topical mometasone furoate and topical mometasone furoate alone are, compared with each other, at 6 months at preventing the development of new lesions in adults and children with slowly spreading vitiligo ( very low-quality evidence ). NOTE We found no direct information from RCTs about the benefits of levamisole alone in repigmentation of skin.

Benefits

Levamisole versus placebo:

We found no RCTs determining the benefits of levamisole as a sole agent in the repigmentation of involved skin.

Levamisole plus potent topical corticosteroids versus potent topical corticosteroids alone:

We found one systematic review (search date 2009), which found one poor-quality RCT, comparing oral levamisole (100–150 mg twice weekly) plus topical mometasone furoate 0.1% (applied once daily) versus topical mometasone furoate 0.1% alone. The RCT found no significant difference between treatments at 6 months in preventing the development of new lesions in people with "slowly spreading" vitiligo (1 RCT, 60 people [18 children and 42 adults], vitiligo covering <2% body surface, generalised [acrofacial] and focal; AR for not developing new lesions: 19/23 [83%] with levamisole plus mometasone v 12/20 [60%] with mometasone alone; P = 0.19). The study defined "slowly spreading" as developing one to 5 new lesions in the previous month or 6 to 15 new lesions in the previous 3 months. No indication was given regarding the size of depigmented areas, and the number of new areas was determined by one clinician. During the study, people with rapid progression of their vitiligo (>10 new lesions in 1 month) were withdrawn from the study (3/32 [9%] in the levamisole plus mometasone group v 1/28 [4%] in the mometasone group). In addition, 10 people were lost to follow-up for unknown reasons, one person discontinued levamisole owing to adverse effects (specific reason not reported), and two people did not complete 6 months of treatment. The RCT was probably underpowered to show a significant difference owing to an unexpected lack of disease progression in the control group.

Harms

Levamisole versus placebo:

We found no RCTs.

Levamisole plus topical potent corticosteroids versus potent topical corticosteroids alone:

The RCT found that, compared with mometasone alone, levamisole plus mometasone increased nausea and vomiting but not abdominal pain (nausea/vomiting: 3/23 [13%] with levamisole plus mometasone v 1/23 [4%] with mometasone alone; abdominal pain: 1/23 [4%] with levamisole plus mometasone v 1/23 [4%] with mometasone alone; significance assessment not performed). The RCT also found that levamisole plus mometasone was associated with dizziness (3/23 [13%]), anxiety (3/23 [13%]), change of taste (3/23 [13%]), insomnia (1/23 [4%]), and dyspepsia (2/23 [9%]), although no direct comparison was made with the group that received mometasone only.

Comment

Clinical guide:

In clinical practice, levamisole is sometimes used as an immunostimulant to prevent progression of disease, in conjunction with other treatments (e.g., potent topical corticosteroids).

Substantive changes

Levamisole (oral) in adults New evidence added. Categorisation unchanged (Beneficial).

BMJ Clin Evid. 2011 Mar 28;2011:1717.

Vitamin D analogues (topical) in adults

Summary

TREATMENT SUCCESS Topical calcipotriol compared with placebo or no treatment: Topical calcipotriol may be no more effective at improving skin repigmentation in adults and children with localised and generalised vitiligo and symmetrical lesions ( very low-quality evidence ). Topical calcipotriol compared with topical betamethasone dipropionate: Topical calcipotriol may be less effective at 3 months at improving the proportion of adults and children who achieve >25% repigmentation (very low-quality evidence). Topical calcipotriol plus potent topical corticosteroids compared with potent topical corticosteroids: We don't know how effective potent topical corticosteroids plus topical calcipotriol and potent topical corticosteroids alone are, compared with each other, at 3 months at improving the proportion of children and adults achieving >50% repigmentation; however potent topical corticosteroids plus topical calcipotriol may be more effective at decreasing the mean time to initial repigmentation ( low-quality evidence ). Topical calcipotriol plus potent topical corticosteroids compared with topical calcipotriol alone: Topical betamethasone diproprionate cream (0.05%) plus topical calcipotriol (0.005%) may be more effective at 3 months at increasing the proportion of adults and children who achieve >25% repigmentation (low-quality evidence). Topical calcipotriol plus PUVA compared with PUVA alone: Topical calcipotriol plus PUVA may be more effective at achieving complete repigmentation (75–100% repigmentation) of vitiliginous lesions in adults and children, and at lowering the dose and number of exposures of UVA used (very low-quality evidence). Topical calcipotriol plus UVB (narrowband) compared with UVB: Topical calcipotriol plus UVB (narrowband) may be no more effective at improving repigmentation (>25%) of lesions in adults and children with vitiligo (very low-quality evidence). Topical tacalcitol plus UVB (narrowband) compared with UVB (narrowband): Topical tacalcitol plus UVB (narrowband) may be more effective at 6 months at improving repigmentation scores in people with generalised vitiligo and symmetrical lesions (low-quality evidence). NOTE We found no direct information from RCTs about whether topical tacalcitol is better than no active treatment or no treatment in people with vitiligo.

Benefits

Topical calcipotriol versus placebo or no treatment:

We found no systematic review or RCTs of sufficient quality. We found one RCT (left–right, non-blinded, comparative study of a mixed population of adults and children), which found no significant difference in skin repigmentation at 3 to 6 months between topical calcipotriol and no treatment (24 people, aged 5–59 years [14 people aged under 15 years], duration of disease 0.5–52 years, localised and generalised vitiligo with symmetrical lesions). One child had 5% repigmentation (% estimated by clinical examination only), one child had 20% repigmentation on the treatment side and 20% repigmentation on the control side, and another had 30% repigmentation on the treatment side and 10% repigmentation on the control side. It is likely that the results may be extrapolated to adults and other children, but they would need to be confirmed by larger numbers of both adults and children.

Topical calcipotriol versus topical betamethasone dipropionate:

We found one systematic review (search date 2009), which identified one three-armed RCT (49 people with vitiligo affecting 5% of their skin) comparing topical calcipotriol ointment and betamethasone dipropionate in combination or alone. The RCT found that proportionally fewer people achieved >25% repigmentation (assessed by clinical examination and comparison with baseline photographs) with topical calcipotriol cream (0.005% applied twice daily) compared with topical betamethasone dipropionate cream (0.05% twice daily) at 3 months (34 people, age range 10–60 years; AR: 6/16 [38%] with calcipotriol v 9/18 [50%] with betamethasone dipropionate; P value not reported).

Topical calcipotriol plus potent topical corticosteroids versus potent topical corticosteroids alone:

We found one systematic review (search date 2009), which identified one three-armed RCT (49 people with vitiligo affecting 5% of their skin) comparing topical calcipotriol ointment and betamethasone dipropionate in combination or alone. The RCT found no significant difference at 3 months in people achieving >50% repigmentation (assessed by clinical examination and comparison with baseline photographs) with topical calcipotriol (0.005% applied twice daily) plus topical betamethasone dipropionate cream (0.05% applied twice daily) compared with betamethasone dipropionate cream alone (30 people, age range 10–60 years; AR: 4/15 [27%] with calcipotriol plus betamethasone dipropionate v 2/15 [13%] with betamethasone dipropionate alone; P >0.1). However, the RCT may have been too small to detect differences between groups. No one in the RCT achieved >75% repigmentation. The RCT found a significantly decreased mean time to initial repigmentation at 3 months with topical calcipotriol plus topical betamethasone dipropionate compared with topical betamethasone dipropionate alone (mean time: 5.17 ± 2.4 weeks with calcipotriol plus betamethasone dipropionate v 9.04 ± 2.0 weeks with betamethasone propionate; P <0.01).

Topical calcipotriol plus potent topical corticosteroids versus topical calcipotriol alone:

See benefits of corticosteroids (topical) in adults.

Topical calcipotriol plus PUVA versus PUVA alone:

We found one systematic review (search date 2009), which identified one internally controlled RCT (35 people, age range 16–64 years, duration of disease 2–20 years, 10–50% body surface involvement, treatment continued until cosmetically acceptable pigmentation was achieved in responsive areas, and stopped when repigmentation ceased, clinician assessment of repigmentation at weekly intervals, UVA dosage determined according to minimal erythema doses of UVA (range 0.75–10.2 J/cm2). It found that calcipotriol cream (0.05 mg/kg) plus PUVA (oral methoxsalen 0.5–0.6 mg/kg plus UVA units) twice weekly was more effective in reaching "complete repigmentation" (75–100% repigmentation) of vitiliginous lesions compared with PUVA plus placebo (AR: 17/35 [49%] with calcipotriol plus PUVA v 4/35 [11%] with placebo plus PUVA; P value not reported). For complete repigmentation, the mean cumulative UVA dose and number of UVA exposures were significantly lower for the calcipotriol-treated side than for the placebo-treated side (mean cumulative UVA dose: 232 J/cm2 for the calcipotriol-treated side v 260 J/cm2 for the placebo-treated side; number of UVA exposures: 30 for the calcipotriol-treated side v 27 for the placebo-treated side; P = 0.001), which equated to an approximately 26 J/cm2 lower cumulative UVA dosage, and approximately three fewer treatment exposures.

Topical calcipotriol plus UVB (narrowband) versus UVB (narrowband) alone:

We found one systematic review (search date 2009), which found one RCT, and we found one additional RCT.

The RCT (40 people with vitiligo) identified by the review compared topical calcipotriol plus narrowband UVB versus narrowband UVB alone. The RCT found no significant difference in achieving >25% repigmentation after 30 treatments (clinical response assessed by photographs and visual scoring) between narrowband UVB (initial dose 0.1 J/cm2 followed by increments of 0.05 J/cm2 as tolerated, 3 times weekly) plus calcipotriol (0.05% ointment applied twice daily after phototherapy) and narrowband UVB alone (34 people, aged 17–26 years, stable vitiligo affecting >10% of the body surface area; AR: 10/13 [77%] with calcipotriol plus narrowband UVB v 19/24 [79%] with narrowband UVB alone; P value not reported).

The additional RCT was a left–right comparison RCT, which found no significant difference in repigmentation of lesions between calcipotriol (0.005% cream applied 2 hours before and after UVB session) plus narrowband UVB (initial dose 0.25 J/cm2, increased by 20% for each treatment) and narrowband UVB alone (evaluated by blinded independent observers comparing photographs with baseline at 24-session intervals) for a total of 96 treatment sessions (20 people comprising 85 reference lesions, age range 14–49 years, range of disease duration 3–300 months, extensive vitiligo affecting >30% body surface area, bilateral symmetrical distribution, numbers not reported; P >0.05). The mean total UVB dose delivered was 110 ± 45 J/cm2. The authors felt that the 20% increments in the UVB treatment regimen were too aggressive, thus inhibiting a potential beneficial response of the addition of calcipotriol. The total number of people in the RCT achieving >50% repigmentation, irrespective of calcipotriol, was 11/20 [55%].

Topical tacalcitol plus narrowband UVB versus narrowband UVB alone:

We found one systematic review (search date 2009), which found one RCT (32 people with generalised vitiligo and symmetrical lesions) comparing topical tacalcitol plus narrowband UVB versus narrowband UVB alone. The RCT found significantly higher repigmentation scores at 6 months (clinical response assessed by single-blinded observer at baseline and end of study visually) in people treated with narrowband UVB (starting with 70% minimal erythema dose followed by 10–30% increments as tolerated) plus topical tacalcitol ointment (dose 10 mg/4 cm2 applied once daily to assigned areas as measured by microdosator) compared with narrowband UVB alone (absolute numbers not reported; P <0.0005).

Harms

Topical calcipotriol versus placebo or no treatment:

We found no RCTs of sufficient quality. The RCT (left–right, non-blinded, comparative study of a mixed population of adults and children) gave no information on adverse effects.

Topical calcipotriol versus topical betamethasone dipropionate:

The RCT identified by the review reported significantly fewer adverse effects with calcipotriol compared with betamethasone dipropionate (peri-lesional hyperpigmentation 1/15 [7%] and an irritant reaction 1/15 [7%] with calcipotriol v lesional atrophy 5/15 [33%], lesional soreness 4/15 [27%], lesional dryness 1/15 [7%], and hypertrichosis 1/15 [7%] with betamethasone dipropionate; P <0.05).

Topical calcipotriol plus potent topical corticosteroids versus potent topical corticosteroids:

The RCT identified by the review reported a significantly decreased number of adverse effects with betamethasone dipropionate plus calcipotriol compared with betamethasone dipropionate alone (hypertrichosis 1/15 [7%] and lesional dryness 1/15 [7%] with calcipotriol plus betamethasone dipropionate v lesional atrophy 5/15 [33%], lesional soreness 4/15 [27%], lesional dryness 1/15 [7%], and hypertrichosis 1/15 [7%] with betamethasone dipropionate alone; P <0.05).

Topical calcipotriol plus potent topical corticosteroids versus topical calcipotriol alone:

See harms of corticosteroids (topical) in adults.

Topical calcipotriol plus PUVA versus PUVA alone:

The RCT identified by the review reported mild to moderate erythema, xerosis, and itching for both active treatment and placebo (2/35 [6%] with calcipotriol v 3/35 [9%] with placebo; significance not stated).

Topical calcipotriol plus UVB (narrowband) versus UVB (narrowband) alone:

The RCT, identified by the review reported transient itching and erythema. The additional RCT reported erythema, irritation, and mild vesiculation (1/20 [5%]) in the calcipotriol-treated sides.

Topical tacalcitol plus narrowband UVB versus narrowband UVB:

The RCT identified by the review reported minimal adverse effects (mild erythema and itching) in the combination therapy group.

Comment

Topical tacalcitol plus sunlight (UVA) versus placebo plus sunlight (UVA):

The systematic review (search date 2009) identified one RCT (80 people with non-segmental vitiligo) comparing topical tacalcitol (applied at night) plus sunlight (30 minutes exposure daily) versus placebo plus sunlight. The RCT found no significant difference in overall repigmentation rates between the two groups at 16 weeks. All responses obtained with tacalcitol and sunlight were <25% repigmentation of treated areas compared with baseline (graded as poor). The RCT reported higher rates of transient erythema and mild contact dermatitis with tacalcitol plus sunlight compared with placebo plus sunlight. It found similar rates of itching between groups. We will assess this comparison in full in future updates of this review.

Clinical guide:

In the treatment of psoriasis, calcipotriol has a light-saving effect when used in combination with UVB, and response is achieved at a lower dose of UVB, but calcipotriol does not increase the overall effectiveness of UVB treatment. However, the role of tacalcitol in the treatment of vitiligo is yet to be determined. We found no RCTs investigating the effects of other topical vitamin D (calcitriol) in vitiligo.

Substantive changes

Vitamin D analogues (topical) in adults New evidence added. Categorisation unchanged (Unlikely to be beneficial).

BMJ Clin Evid. 2011 Mar 28;2011:1717.

Corticosteroids (oral) in adults

Summary

We found no direct information from RCTs about oral corticosteroids in the treatment of people with vitiligo. There is consensus that the adverse effects associated with oral corticosteroids far outweigh any benefit that may be achieved in people with vitiligo.

Benefits

We found no systematic review or RCTs.

Harms

We found no RCTs. One case series (29 people with vitiligo [24 with generalised vitiligo and 5 with acrofacial vitiligo, and 25 with progressive and 4 with stable disease]; age range 20–54 years) found that one or more adverse events were reported in 20/29 [69%] participants at a mean treatment period of 5.2 weeks, including weight gain, arterial hypertension, insomnia, acne, agitation, menstrual disturbance, and hypertrichosis.

Comment

Clinical guide:

Further RCTs into the effects of oral corticosteroids are unlikely to be undertaken. On the basis of observational evidence and experience, oral corticosteroids may arrest the progression of vitiligo, but fail to induce repigmentation. However, there is consensus that adverse events are common and can be severe; oral corticosteroids are therefore not commonly used in practice.

Substantive changes

No new evidence

BMJ Clin Evid. 2011 Mar 28;2011:1717.

PUVA (oral) in adults

Summary

TREATMENT SUCCESS Methoxsalen plus UVA compared with UVA alone: Methoxsalen plus UVA may be no more effective at achieving >75% repigmentation of all vitiliginous macules at 2 years in adults and children ( very low-quality evidence ). Trioxysalen plus UVA compared with UVA alone: Trioxysalen plus UVA may be no more effective at achieving >75% repigmentation of all vitiliginous macules at 2 years in adults and children (very low-quality evidence). Unsubstituted PUVA compared with UVA alone: We don't know whether PUVA is more effective at improving repigmentation of affected lesions in adults and children at 18 to 24 months (very low-quality evidence). Oral PUVA compared with topical PUVA: Oral PUVA may be no more effective at 18 months at achieving >50% repigmentation of all vitiliginous macules ( low-quality evidence ). Different oral PUVA derivatives compared with each other: Different derivatives and doses of psoralens (methoxsalen, unsubstituted psoralen, trioxysalen) plus UVA are equally effective at improving repigmentation of >75% of all vitiliginous macules at 2 years ( moderate-quality evidence ). Oral PUVA compared with UVB (narrowband): We don't know how effective oral PUVA and UVB (narrowband) are, compared with each other, at improving repigmentation rates in adults with vitiligo (low-quality evidence). Methoxsalen plus trioxysalen plus UVA compared with different psoralen derivatives plus UVA: Methoxsalen plus trioxysalen plus UVA may be more effective than unsubstituted PUVA at improving repigmentation of >75% of all vitiliginous macules at 2 years (low-quality evidence). Oral PUVA compared with oral PUVB (broadband): Oral PUVB (broadband) may be less effective in producing 50% to 60% repigmentation of extensive vitiligo in adults and children (very low-quality evidence). NOTE There is consensus that PUVA is effective for vitiligo.

Benefits

We found two systematic reviews (search dates 1998 and 2009). They found that the quality of the methods and reporting of included studies was poor.

Methoxsalen plus UVA versus UVA alone:

Both reviews identified one RCT, which compared sunlight plus oral methoxsalen, sunlight plus oral unsubstituted psoralen, sunlight plus oral trioxysalen, and placebo over 2 years (596 people, of whom 366 completed 2 years' treatment with follow-up; age range 12–70 years; most people with generalised vitiligo with 10–70% skin involvement; duration 1–50 years; people were exposed in prone and supine positions to the sun [2 hours post-ingestion] for 45–60 minutes in gradually increasing doses, three times weekly). The degree of repigmentation was rated visually by two independent investigators against photographs at enrolment and at 6-monthly intervals. People were randomly assigned to one of the following groups: methoxsalen 0.3 mg/kg (47 people), methoxsalen 0.6 mg/kg (49 people), trioxysalen 0.8 mg/kg (39 people), trioxysalen 1.8 mg/kg (61 people), trioxysalen 3.6 mg/kg (43 people), methoxsalen 0.3 mg/kg plus trioxysalen 1.8 mg/kg (55 people), unsubstituted psoralen 0.6 mg/kg (35 people), unsubstituted psoralen 1.2 mg/kg (37 people), and placebo (24 people). All 8 groups were exposed to UVA (sunlight). The RCT identified by the systematic reviews found no significant difference in repigmentation of >75% of all vitiliginous macules at 2 years between oral methoxsalen plus UVA and UVA alone (see table 1 ).

Table 1.

Methoxsalen, trioxysalen, unsubstituted PUVA versus placebo.

Comparison Outcome Result
Methoxsalen (0.3 mg/kg) plus UVA vUVA alone Repigmentation in >75% of all vitiliginous macules at 2 years (degree of repigmentation assessed visually by clinician against baseline photographs at 6-monthly intervals) AR: 12/49 [24%] with oral methoxsalen plus UVA v 0/24 [0%] with placebo; RR 12.50, 95% CI 0.77 to 202.63
 
Methoxsalen (0.6 mg/kg) plus UVA vUVA alone Repigmentation in >75% of all vitiliginous macules at 2 years (degree of repigmentation assessed visually by clinician against baseline photographs at 6-monthly intervals) AR: 12/49 [24%] with oral methoxsalen plus UVA v 0/24 [0%] with placebo; RR 12.50, 95% CI 0.77 to 202.63
 
Methoxsalen (any dose) plus UVA vUVA alone Repigmentation in >75% of all vitiliginous macules at 2 years (degree of repigmentation assessed visually by clinician against baseline photographs at 6-monthly intervals) AR: 24/98 [24%] with oral methoxsalen plus UVA v 0/24 [0%] with placebo; RR 12.37, 95% CI 0.78 to 196.56
 
Trioxysalen (0.8 mg/kg) plus UVA vUVA alone Repigmentation in >75% of all vitiliginous macules at 2 years (degree of repigmentation assessed visually by clinician against baseline photographs at 6-monthly intervals) AR: 7/39 [18%] with trioxysalen plus UVA v 0/24 [0%] with placebo; RR 9.38, 95% CI 0.56 to 157.09
 
Trioxysalen (1.8 mg/kg) plus UVA vUVA alone Repigmentation in >75% of all vitiliginous macules at 2 years (degree of repigmentation assessed visually by clinician against baseline photographs at 6-monthly intervals) AR: 9/61 [15%] with trioxysalen plus UVA v 0/24 [0%] with placebo; RR 7.66, 95% CI 0.46 to 126.70
 
Trioxysalen (3.6 mg/kg) plus UVA vUVA alone Repigmentation in >75% of all vitiliginous macules at 2 years (degree of repigmentation assessed visually by clinician against baseline photographs at 6-monthly intervals) AR: 8/43 [19%] with trioxysalen plus UVA v 0/24 [0%] with placebo; RR 9.66, 95% CI 0.58 to 160.37
 
Trioxysalen (any dose) plus UVA vUVA alone Repigmentation in >75% of all vitiliginous macules at 2 years (degree of repigmentation assessed visually by clinician against baseline photographs at 6-monthly intervals) AR: 24/143 [17%] with trioxysalen plus UVA v 0/24 [0%] with placebo; RR 8.51, 95% CI 0.53 to 135.43
 
Unsubstituted PUVA (0.6 mg/kg) vUVA alone Repigmentation in >75% of all vitiliginous macules at 2 years (degree of repigmentation assessed visually by clinician against baseline photographs at 6-monthly intervals) AR: 3/35 [9%] with 40 mg unsubstituted PUVA v 0/24 [0%] with placebo; RR 4.86, 95% CI 0.26 to 90.03
 
Unsubstituted PUVA (1.2 mg/kg) vUVA alone Repigmentation in >75% of all vitiliginous macules at 2 years (degree of repigmentation assessed visually by clinician against baseline photographs at 6-monthly intervals) AR: 11/37 [30%] with 1.2 mg/kg unsubstituted PUVA v 0/24 [0%] with placebo; RR 15.13, 95% CI 0.93 to 245.39
 
Unsubstituted PUVA (any dose) vUVA alone Repigmentation in >75% of all vitiliginous macules at 2 years (degree of repigmentation assessed visually by clinician against baseline photographs at 6-monthly intervals) AR: 14/72 [19%] with unsubstituted PUVA v 0/24 [0%] with placebo; RR 9.93, 95% CI 0.61 to 160.47
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Trioxysalen plus UVA versus UVA alone:

The RCT identified by the systematic reviews (see above) found no significant difference in repigmentation of >75% of all vitiliginous macules at 2 years between oral trioxysalen plus UVA and UVA alone (see table 1 ).

Unsubstituted PUVA versus UVA alone:

The systematic reviews both identified two RCTs. Pooled results from the first systematic review found that, compared with sunlight alone, oral unsubstituted PUVA significantly improved repigmentation of affected skin (97 people; age range not reported; generalised vitiligo; exposure to midday sun 2 hours after oral psoralen; exposure time increased according to tolerance; degree of repigmentation assessed visually by observer and participant at 18 months in one RCT and by comparison with initial photographs by two independent investigators at 2 years in the other; 2 RCTs; AR: 13/46 [28%] with oral unsubstituted PUVA v 0/51 [0%] with UVA alone; OR 19.87, 95% CI 2.37 to 166.32; P value not reported). The second RCT identified by the reviews found no significant difference in repigmentation of >75% of all vitiliginous macules at 2 years between oral PUVA (at any dose) and UVA alone (see table 1 ).

Oral PUVA versus topical PUVA:

The systematic review identified one RCT. It found no significant difference between oral and topical PUVA (dose and psoralen derivative not specified) in achieving repigmentation in >50% of all vitiliginous macules at 18 months (AR: 2/20 [10%] with oral unsubstituted PUVA v 2/18 [11%] with topical psoralen; RR 0.90, 95% CI 0.14 to 5.74; P value not reported).

Different oral PUVA derivatives versus each other:

The systematic review identified one RCT, which found no significant difference between different derivatives and doses of psoralen (methoxsalen, unsubstituted psoralen, trioxysalen) plus UVA versus each other in repigmentation of >75% of all vitiliginous macules at 2 years (see table 2 ). The same RCT found that a combination of methoxsalen plus trioxysalen plus UVA significantly improved the repigmentation of >75% of vitiliginous macules at 2 years when compared with UVA alone, but was no more effective compared with methoxsalen plus UVA or trioxysalen plus UVA, and less effective compared with unsubstituted PUVA (see table 3 ).

Table 1.

Different oral PUVA derivatives versus each other.

Comparison Outcome Result
Methoxsalen plus UVA vTrioxysalen (any dose) plus UVA Repigmentation in >75% of all vitiliginous macules at 2 years (degree of repigmentation assessed visually by clinician against baseline photographs at 6-monthly intervals) AR: 24/98 [24%] with oral methoxsalen plus UVA v 24/143 [17%] with trioxysalen; RR 1.46, 95% CI 0.88 to 2.42
 
Methoxsalen plus UVA vUnsubstituted PUVA (any dose) Repigmentation in >75% of all vitiliginous macules at 2 years (degree of repigmentation assessed visually by clinician against baseline photographs at 6-monthly intervals) AR: 24/98 [24%] with oral methoxsalen plus UVA v 14/72 [19%] with unsubstituted PUVA; RR 1.26, 95% CI 0.70 to 2.26
 
Trioxysalen (any dose) plus UVA vMethoxsalen plus UVA Repigmentation in >75% of all vitiliginous macules at 2 years (degree of repigmentation assessed visually by clinician against baseline photographs at 6-monthly intervals) AR: 24/143 [17%] with trioxysalen plus UVA v 24/98 [24%] with methoxsalen; RR 0.69, 95% CI 0.41 to 1.13
 
Trioxysalen (any dose) plus UVA vUnsubstituted psoralen plus UVA Repigmentation in >75% of all vitiliginous macules at 2 years (degree of repigmentation assessed visually by clinician against baseline photographs at 6-monthly intervals) AR: 24/98 [24%] with trioxysalen plus UVA v 14/72 [19%] with unsubstituted PUVA; RR 1.26, 95% CI 0.70 to 2.26
 
Trioxysalen plus UVA vUnsubstituted PUVA (any dose) Repigmentation in >75% of all vitiliginous macules at 2 years (degree of repigmentation assessed visually by clinician against baseline photographs at 6-monthly intervals) AR: 14/72 [19%] with trioxysalen plus UVA v 24/143 [17%] with unsubstituted psoralen (any dose); RR 1.16, 95% CI 0.64 to 2.10
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Table 1.

Methoxsalen plus trioxysalen plus UVA versus placebo/different PUVA derivatives.

Comparison Outcome Result
Methoxsalen plus trioxysalen plus UVA vplacebo Repigmentation in >75% of all vitiliginous macules at 2 years (degree of repigmentation assessed visually by clinician against baseline photographs at 6-monthly intervals) AR: 21/55 [38%] with oral methoxsalen plus trioxysalen plus UVA v 0/24 [0%] with placebo; RR 19.20, 95% CI 1.21 to 304.50
 
Methoxsalen plus trioxysalen (any dose) plus UVA vMethoxsalen plus UVA Repigmentation in >75% of all vitiliginous macules at 2 years (degree of repigmentation assessed visually by clinician against baseline photographs at 6-monthly intervals) AR: 21/55 [38%] with methoxsalen plus trioxysalen plus UVA v 24/98 [24%] with oral methoxsalen plus UVA; RR 0.64, 95% CI 0.40 to 1.04
 
Methoxsalen plus trioxysalen (any dose) plus UVA vTrioxysalen plus UVA Repigmentation in >75% of all vitiliginous macules at 2 years (degree of repigmentation assessed visually by clinician against baseline photographs at 6-monthly intervals) AR: 21/55 [38%] with methoxsalen plus trioxysalen plus UVA v 24/98 [24%] with trioxysalen plus UVA; RR 0.64, 95% CI 0.40 to 1.04
 
Methoxsalen plus trioxysalen (any dose) plus UVA vUnsubstituted PUVA Repigmentation in >75% of all vitiliginous macules at 2 years (degree of repigmentation assessed visually by clinician against baseline photographs at 6-monthly intervals) AR: 21/55 [38%] with methoxsalen plus trioxysalen plus UVA v 14/72 [19%] with unsubstituted PUVA; RR 0.51, 95% CI 0.29 to 0.91
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Oral PUVA versus UVB (narrowband):

The systematic review identified one RCT (56 people, aged 18 years or older, with symmetrical vitiligo affecting 2–70% of body surface area), which compared oral PUVA (8-methoxypsoralen 25 mg/m2 or 5-methoxypsoralen 50 mg/m2 given 3 hours before phototherapy with UVA given at an initial dose of 0.5 J/cm2 with 0.25 J/cm2 increments) twice weekly versus narrowband UVB (initial dose 0.1 J/cm2 with 20% increments) twice weekly. The RCT found no significant difference in repigmentation rates with oral PUVA compared with narrowband UVB at the end of treatment (AR: 16/25 [64%] with oral PUVA v 9/25 [36%] with narrowband UVB; RR 0.50, 95% CI 0.10 to 2.49; P = 0.4). However, the RCT commented that people in the oral PUVA-treated group received a significantly smaller median number of treatments compared with the narrowband UVB-treated group, and so results should be interpreted with caution.

Oral PUVA versus oral PUVB (broadband):

We found one left–right comparison RCT, which found that fewer treatments with oral methoxsalen (0.7 mg/kg) plus UVA (PUVA 320–400 nm; initial dose of UVA 0.5 J/cm2 increased by 0.5 J/cm2 at alternate sessions) were required compared with oral methoxsalen plus broadband UVB (PUVB 290–320 nm; initial dose of UVB of 0.03 J/cm2 increased by 0.03 J/cm2 at each session) to produce 50% to 60% repigmentation (evaluated clinically by 5 clinicians, 1 of whom was blinded) at weekly intervals for 30 sessions of treatment (24 people, age range 8–50 years, 3 sessions weekly, extensive vitiligo affecting >30% body surface area, bilateral symmetrical distribution; AR: 15/22 [68%] with PUVA v 11/22 [50%] with PUVB; P value not reported). The mean number of sessions needed to achieve 50% to 60% repigmentation was 25 ± 4 with PUVA and 26 ± 3 for PUVB. To achieve 50% to 60% repigmentation of vitiligo, the mean cumulative dose of UVA was 45 ± 16 J/cm2, and for UVB was 4.6 ± 1.9 J/cm2.

Oral PUVA plus topical calcipotriol versus PUVA alone:

See benefits of vitamin D analogues in adults.

Harms

Methoxsalen plus UVA versus UVA alone:

One RCT found that methoxsalen plus UVA increased nausea and pruritus compared with UVA alone (nausea: 20% with methoxsalen plus UVA v 10% with UVA alone; pruritus: 20% with methoxsalen plus UVA v 10% with UVA alone; significance assessment not performed, absolute numbers not reported). It also reported that methoxsalen was associated with gastrointestinal discomfort (8%).

Trioxysalen plus UVA versus placebo:

The RCT reported fewer adverse effects with trioxysalen compared with all other psoralen derivatives. It reported dizziness (7/58 [12%]), pruritus (5/58 [9%]), and nausea (2/58 [3%]) across both groups, but reported a greater number of adverse effects with the higher dose of trioxysalen compared with the lower dose.

Unsubstituted PUVA versus UVA alone:

The systematic reviews identified two RCTs. The first RCT did not search for or report any adverse effects. The second RCT found that a similar proportion of people taking unsubstituted psoralen 0.6 mg/kg and placebo had nausea and pruritus (nausea: 9% with unsubstituted psoralen v 10% with UVA alone; pruritus: 9% with unsubstituted psoralen v 7% with UVA alone; significance assessment not performed, absolute figures not reported). The RCT also reported that people taking unsubstituted psoralen experienced headaches (14%), dizziness (9%), and miscellaneous complaints (14%). People receiving a higher unsubstituted psoralen dose (1.2 mg/kg) were not evaluated.

Oral PUVA versus topical PUVA:

The RCT did not search for or report any adverse effects.

Different psoralen derivatives plus UVA versus each other:

The RCT reported nausea (6/35 [17%]), pruritus (13/35 [37%]), dizziness (2/35 [6%]), and headaches (1/35 [3%]) in people given the combination of methoxsalen plus trioxysalen. The placebo group reported nausea (2/24 [8%]) and pruritus (1/24 [4%]). The methoxsalen groups reported dizziness (8/96 [8%]), pruritus (19/96 [20%]), nausea (19/96 [20%]), and vague gastrointestinal discomfort (8/96 [8%]). The trioxysalen groups reported dizziness (7/58 [12%]), pruritus (5/58 [9%]), and nausea (2/58 [3%]). The low-dose psoralen group reported dizziness (3/35 [9%]), pruritus (3/35 [9%]), nausea (3/35 [9%]), headaches (5/35 [14%]), and miscellaneous complaints (5/35 [14%]).

Oral PUVA versus UVB (narrowband):

The RCT reported that erythema occurred significantly more often with oral PUVA compared with UVB (narrowband) (24/25 [96%] with oral PUVA v 17/25 [68%] with narrowband UVB; P = 0.02).

Oral PUVA versus oral PUVB (broadband):

We found no systematic review on the harms of broadband UVB. One RCT comparing broadband oral PUVB versus PUVA reported a phototoxic reaction with both treatments (4/22 [18%] with broadband oral PUVB v 5/22 [23%] with PUVA) and skin thickening (6/22 [27%] with broadband oral PUVB v 6/22 [27%] with PUVA).

Oral PUVA plus topical calcipotriol versus PUVA alone:

See harms of vitamin D analogues in adults.

Comment

Prognostic factors:

The following prognostic factors are thought to predict improved response rates independently of the psoralen derivative used: duration of therapy (duration exceeding 9–12 months correlated with improved repigmentation rate), regular treatment, minimal phototoxicity, and vitiligo site (face and neck responded best, followed by trunk and back, whereas bony prominences responded worst).

Treatment duration:

Long-term therapy is needed for successful repigmentation of vitiliginous skin. Between 15 and 25 treatments are necessary before perifollicular repigmentation is apparent. Between 100 and 300 treatments are required for complete repigmentation of the neck, trunk, and proximal limbs, with the face repigmenting faster. At 4 years' follow-up, people neither developed cutaneous malignancies nor developed abnormal liver function values.

UVA source:

It is important to remember that, in studies using sunlight as the source of UVA, variable factors (compliance, degree of sun exposure, country where the trial was conducted) can limit the interpretation and applicability of results. Where possible, reliable forms of light therapy such as UV light devices should be used in trials, but this is not always accessible or feasible in resource-poor countries. No RCTs have been carried out using different UVA light devices.

Clinical guide:

The consensus among clinicians is that oral PUVA is effective for vitiligo, and that methoxsalen is the most effective psoralen derivative. Methoxsalen and 5-methoxypsoralen are the most commonly used psoralen derivatives in UK; however, no RCTs studying 5-methoxypsoralen or comparing it with methoxsalen in vitiligo were found. 5-Methoxypsoralen is not available in the US, but is thought to be associated with a lower incidence of phototoxicity and gastrointestinal adverse effects compared with methoxsalen. Trioxysalen is extremely phototoxic for some individuals, and this limits its use. Individualisation of treatment is essential. None of the psoralen derivatives overcomes the limitation of poor response of the fingers, toes, palms, soles, nipples, ankles, and lips. There is limited evidence for the use of broadband UVB in vitiligo. RCTs would be feasible and should be undertaken, especially comparison studies with narrowband UVB.

Substantive changes

PUVA (oral) in adults New evidence added. Categorisation unchanged (Likely to be beneficial).

BMJ Clin Evid. 2011 Mar 28;2011:1717.

Ultraviolet B (narrowband) in adults

Summary

TREATMENT SUCCESS Narrowband UVB compared with placebo: Narrowband UVB may be more effective at 6 months at increasing mean repigmentation of affected lesions in adults with vitiligo ( low-quality evidence ). Compared with topical PUVA: We don't know whether narrowband UVB is more effective at 4 months at improving repigmentation of vitiliginous lesions ( very low-quality evidence ). Narrowband UVB compared with oral PUVA: We don't know how effective oral PUVA and narrowband UVB are, compared with each other, at improving repigmentation rates in adults with vitiligo (low-quality evidence). Narrowband UVB plus topical calcipotriol compared with UVB: Topical calcipotriol plus narrowband UVB may be no more effective at improving repigmentation (>25%) of lesions in adults and children with vitiligo (very low-quality evidence). Narrowband UVB plus topical tacalcitol compared with narrowband UVB: Topical tacalcitol plus narrowband UVB may be more effective at 6 months at improving repigmentation scores in people with generalised vitiligo and symmetrical lesions (low-quality evidence).

Benefits

Narrowband ultraviolet B (UVB) versus placebo:

We found one internally controlled trial, which found that, compared with placebo, narrowband UVB significantly increased mean repigmentation of affected lesions after 6 months (70% minimal erythema doses, increased by 10% increments, 3 times weekly or 60 treatments; 22 people, age range 23–77 years; duration of disease range 4–51 years; extent of vitiligo determined by Vitiligo Area Scoring Index [developed in this study as product of area of vitiligo in hand units and extent of residual depigmentation] and validated by global participant and clinician scoring using baseline photographs; AR: 43% repigmentation with narrowband UVB v 3% repigmentation with placebo; P <0.001; absolute numbers not reported). Lower extremities responded best, but feet responded worst.

Narrowband UVB versus topical PUVA:

See benefits of topical PUVA in adults.

Narrowband UVB versus oral PUVA:

See benefits of oral PUVA in adults.

Narrowband UVB plus vitamin D analogues versus narrowband UVB alone:

See benefits of vitamin D analogues in adults.

Harms

Narrowband UVB versus placebo:

We found one RCT, which reported hyperpigmentation with narrowband UVB, resulting in one person withdrawing from the study, and mild phototoxic effects.

Narrowband UVB versus topical PUVA:

The RCT did not report any adverse effects with narrowband UVB treatment.

Narrowband UVB versus oral PUVA:

See harms of oral PUVA in adults.

Narrowband UVB plus vitamin D analogues versus narrowband UVB alone:

See harms of vitamin D analogues in adults.

Comment

Clinical guide:

Despite only weak RCT evidence to support its use, narrowband UVB is considered safe and effective by clinicians in the treatment of generalised vitiligo. Because it has relatively few adverse effects, it is considered to be the first-line treatment of choice for people with moderate or severe generalised disease. One report recommended (on the basis of a number of case series only) a minimum treatment duration of 6 months with responsive people, with a maximum treatment duration of 24 months. After the first course of 1 year, a resting period of 3 months was recommended, to minimise the annual cumulative dose of UVB. Further research is necessary to determine the relative effectiveness of different treatment regimens.

Substantive changes

Ultraviolet B (narrowband) in adults New evidence added. Categorisation unchanged (Likely to be beneficial).

BMJ Clin Evid. 2011 Mar 28;2011:1717.

PUVA (topical) in adults

Summary

TREATMENT SUCCESS Compared with no treatment: Topical PUVA is no more effective at 18 months at achieving >50% repigmentation of vitiliginous lesions ( moderate-quality evidence ). Compared with oral PUVA: Topical PUVA may be no more effective at 18 months at achieving >50% repigmentation of all vitiliginous macules in adults and children ( low-quality evidence ). Compared with narrowband UVB: We don't know whether topical PUVA is more effective at 4 months at improving repigmentation of vitiliginous lesions in adults and children ( very low-quality evidence ).

Benefits

Topical PUVA versus no treatment:

We found one systematic review (search date 2009), which identified one RCT (88 people; age range not reported; generalised vitiligo). The RCT had 4 arms: oral PUVA (sunlight), topical unsubstituted PUVA (sunlight), oral PUVA (sunlight) plus triamcinolone, and no treatment (cosmetic camouflage). It found no significant difference between topical unsubstituted PUVA (dosage and brand of psoralens not reported; sunlight) and no treatment in the repigmentation of >50% of vitiliginous lesions at 18 months (exposure to midday sun immediately after topical application of psoralen, with increasing exposure time according to the person's tolerance of sunlight; degree of repigmentation assessed visually by observer and participant; AR: 2/18 [11%] with topical PUVA v 0/27 [0%] with placebo; RR 7.37, 95% CI 0.37 to 145.06).

Oral PUVA versus topical PUVA:

See benefits of oral PUVA.

Topical PUVA versus narrowband UVB:

We found one quasi-RCT (106 people, age range 7–70 years [mean age 36.7 years with PUVA and 36 years with UVB], active and generalised vitiligo of more than 3 months' duration, 10–50% body surface involved), which compared topical unsubstituted PUVA 0.005% versus narrowband UVB 311 nm treatment twice weekly for 4 months (psoralen administered 15 minutes before UVA; UVA initial dose 0.5 J/cm2, increased in 20% increments until erythema and then continued at same dose; narrowband UVB initial dose 0.075 J/cm2, increased in 20% increments until erythema). It found that, compared with narrowband UVB, topical PUVA reduced repigmentation of vitiliginous lesions at 4 months (treatments assigned alternately; assessment of response by two uninvolved blinded clinicians using total-body photographs at each visit by means of planimetry: AR: 13/28 [46%] with topical PUVA v 52/78 [67%] with narrowband UVB, significance assessment not performed). The study reported that, in general, better repigmentation was observed on the face than on the trunk, with very little on the extremities. There was no subgroup analysis performed.

Harms

Topical PUVA versus placebo:

The first RCT did not search for or report any adverse effects.

Oral PUVA versus topical PUVA:

See harms of oral PUVA.

Topical PUVA versus UVB (narrowband):

The RCT reported erythema (3/28 [11%]), scaling (3/28 [11%]), and itching (3/28 [11%]) with PUVA. Difficulties in uniformly applying the aqueous gel resulted in linear burns of the vitiliginous skin as well as of the normally pigmented skin. In pigmented skin, hyperpigmented stripes remained.

Comment

Clinical guide:

Studies in psoriasis suggest that topical PUVA is the more acceptable treatment because of nausea as an adverse effect of oral PUVA, and because of a lower cumulative radiation dose with topical PUVA. Despite weak evidence for the use of both oral and topical psoralens in vitiligo, clinicians are more likely to recommend oral psoralens over topical psoralens because of the consensus that oral PUVA is more effective than topical PUVA.

Substantive changes

PUVA (topical) in adults Search updated for already included systematic review. No new evidence added. Categorisation unchanged (Unlikely to be beneficial).

BMJ Clin Evid. 2011 Mar 28;2011:1717.

Corticosteroids (topical) in children

Summary

TREATMENT SUCCESS Clobetasol propionate compared with PUVA: Clobetasol propionate is more effective at increasing the proportion of children achieving >75% repigmentation at 6 months ( moderate-quality evidence ). Clobetasol propionate compared with topical tacrolimus: We don't know how effective clobetasol propionate and topical tacrolimus are, compared with each other, at 2 months at increasing the proportion of children achieving >75% repigmentation ( low-quality evidence ).

Benefits

We found one systematic review (search date 2009), which did not include a meta-analysis for the clinical outcomes of interest. It identified two RCTs.

Clobetasol propionate versus PUVA:

The first RCT identified by the review compared clobetasol propionate (0.05% cream applied twice daily) versus topical PUVA (0.1% methoxsalen ointment applied 45 minutes before UVA exposure) three times weekly. It found that, compared with topical PUVA, clobetasol propionate significantly increased the proportion of children achieving >75% repigmentation at 6 months (50 children under 12 years old; AR: 9/22 [41%] with clobetasol propionate v 2/23 [9%] with topical PUVA; RR 4.7, 95% CI 1.14 to 19.39; P value not reported). The best response was seen on the face and neck, followed by the trunk and proximal parts of the extremities.

Clobetasol propionate versus topical tacrolimus:

The second RCT identified by the review (20 children, aged 4–17 years [4 aged 15 years and over], symmetrical vitiligo lesions, mean duration of disease 2.2 years, variable localisation, segmental and mucosal vitiligo excluded) was a left–right comparison of topical clobetasol propionate (0.05%) versus topical tacrolimus (0.1%) twice daily. It found no significant difference between topical clobetasol and topical tacrolimus in achieving >75% repigmentation of affected areas at 2 months (grade of repigmentation evaluated by colour slides at baseline and analysed every 2 weeks by blinded clinicians not involved in study, and by morphometric digitalised computer program; AR: 5/20 (25%) with clobetasol v 5/20 (25%) with topical tacrolimus 0.1%; P = 1.00).

Potent topical corticosteroids plus topical calcipotriol versus either topical corticosteroid or calcipotriol alone:

We found no RCTs in children only. See benefits of topical corticosteroids in adults and vitamin D analogues in adults.

Topical betamethasone dipropionate versus topical calcipotriol:

We found no RCTs in children only. See benefits of vitamin D analogues in adults.

Harms

Clobetasol propionate versus PUVA:

The first RCT identified by the review reported mild atrophy (4/22 [18%]), telangiectasia (2/22 [9%]), hypertrichosis (1/22 [5%]), and corticosteroid-induced acne (2/22 [9%]) with topical corticosteroids. It reported blistering in two people receiving PUVA, requiring cessation of treatment for 1 month.

Clobetasol propionate versus topical tacrolimus:

The second RCT identified by the review reported atrophy (3/20 [15%]) and telangiectasia (2/20 [10%]) with clobetasol. It reported a burning sensation (2/20 people [10%]), which did not preclude the continuation of therapy, with tacrolimus, during the first 2 weeks of therapy.

Potent topical corticosteroids plus topical calcipotriol versus topical calcipotriol alone:

We found no RCTs in children only. See harms of topical corticosteroids in adults and vitamin D analogues in adults.

Topical betamethasone dipropionate versus topical calcipotriol:

We found no RCTs in children only. See harms of vitamin D analogues in adults.

Comment

Clinical guide:

In developing guidelines for the management of vitiligo, a consensus was agreed among clinicians that topical corticosteroid therapy would be chosen as first-line treatment for localised vitiligo (11/14 respondents [79%]), generalised vitiligo (11/14 respondents [79%]), and stable vitiligo (12/14 respondents [86%]).

Substantive changes

Corticosteroids (topical) in children Search updated for already included systematic review. No new evidence added. Categorisation unchanged (Beneficial).

BMJ Clin Evid. 2011 Mar 28;2011:1717.

Immunomodulators (topical) in children

Summary

TREATMENT SUCCESS Topical tacrolimus compared with clobetasol propionate: We don't know how effective topical tacrolimus and clobetasol propionate are, compared with each other, at 2 months at increasing the proportion of children achieving >75% repigmentation ( low-quality evidence ). NOTE We found no direct information from RCTs about whether tacrolimus, pimecrolimus, or imiquimod are better than no active treatment in the management of children with vitiligo. Topical pimecrolimus and tacrolimus may be associated with malignancy.

Benefits

Topical tacrolimus versus placebo:

We found no systematic review or RCTs.

Topical tacrolimus versus clobetasol propionate:

See benefits of topical corticosteroids in children.

Topical pimecrolimus versus placebo:

We found no RCTs in children only. See benefits of immunomodulators in adults.

Topical imiquimod versus placebo:

We found no systematic review or RCTs.

Harms

Topical tacrolimus versus placebo:

We found no RCTs.

Topical tacrolimus versus clobetasol propionate:

See harms of topical corticosteroids in children.

Topical pimecrolimus versus placebo:

We found no RCTs in children only. See harms of immunomodulators in adults.

Topical imiquimod versus placebo:

We found not RCTs.

Comment

See comment in immunomodulators in adults for comment and drug safety alert on possible malignancy risk with topical immunomodulators. However, long-term results in children have not demonstrated an increase in carcinogenicity with topical tacrolimus use, but further studies are required. The manufacturing company recommends photoprotection while being treated with tacrolimus and contraindicates application to malignant or premalignant lesions.

Substantive changes

Immunomodulators (topical) in children Search updated for already included systematic review. No new evidence added. Categorisation unchanged (Unknown effectiveness).

BMJ Clin Evid. 2011 Mar 28;2011:1717.

Vitamin D analogues (topical) in children

Summary

We found no direct information from RCTs about the effects of vitamin D analogues in children with vitiligo only.

Benefits

Topical calcipotriol versus placebo:

We found no systematic review or good-quality RCTs in children only. See benefits of vitamin D analogues in adults.

Topical calcipotriol plus PUVA versus PUVA:

We found no RCTs in children only. See benefits of vitamin D analogues in adults.

Topical calcipotriol plus UVB versus UVB:

We found no RCTs in children only. See benefits of vitamin D analogues in adults.

Harms

Topical calcipotriol versus placebo:

We found no RCTs.

Topical calcipotriol plus PUVA versus UVA:

We found no RCTs in children only. See harms of vitamin D analogues in adults.

Topical calcipotriol plus UVB versus UVB:

We found no RCTs in children only. See harms of vitamin D analogues in adults.

Comment

One RCT of poor quality (including adults and children with vitiligo) found no significant difference in percentage repigmentation between topical calcipotriol and no treatment at 4 months. We found no RCTs investigating the effects of other topical vitamin D analogues (tacalcitol) or vitamin C (calcitriol) in children.

Substantive changes

No new evidence

BMJ Clin Evid. 2011 Mar 28;2011:1717.

Corticosteroids (oral) in children

Summary

We found no direct information from RCTs about the effects of oral corticosteroids in children with vitiligo. There is consensus that the adverse effects associated with oral corticosteroids far outweigh any benefit that may be achieved in people with vitiligo.

Benefits

We found no systematic review or RCTs.

Harms

We found no RCTs.

Comment

Clinical guide:

The use of oral pulsed corticosteroids in children has been reported to be successful in uncontrolled trials in arresting the progression of vitiligo, but is not advised by dermatologists because of the risks of suppression of the adrenal cortex, and systemic adverse effects associated with this therapy (such as facial oedema, weight gain, and growth retardation).

Substantive changes

No new evidence

BMJ Clin Evid. 2011 Mar 28;2011:1717.

Ultraviolet B (narrowband) in children

Summary

We found no direct information from RCTs about the effects of narrowband UVB in children with vitiligo only. The consensus is that narrowband UVB is safe and effective in children, and may improve quality of life.

Benefits

Narrowband ultraviolet B (UVB) versus placebo:

We found no systematic review or RCTs.

Narrowband UVB versus topical PUVA:

We found no systematic review or RCTs in children only. We found one RCT in a mixed population of adults and children. See benefits of topical PUVA in adults.

Harms

Narrowband UVB versus placebo:

We found no RCTs.

Narrowband UVB versus topical PUVA:

We found no systematic review. We found one RCT, which did not report any adverse effects with UVB treatment.

Comment

We found no controlled trials investigating narrowband or broadband UVB in the management of vitiligo in children. We found one prospective cohort study, which found that narrowband UVB (310–315 nm, initial dose 0.25 J/cm2, increased by 20% increments, twice weekly) resulted in >75% repigmentation at 1 year in about half the participants (51 children, age range 4–16 years, generalised vitiligo affecting >5% body surface area, clinician assessment using baseline photography; AR: 27/51 [53%] with narrowband UVB, significance assessment not performed, no control). The best response was seen on the face and neck, with the poorest response seen in the acral sites (fingers, feet), areas of bony prominences, and areas of lower hair-growth density (wrists, ankles, joints). The study reported pruritus (4/51 [8%]) and xerosis with thickening of lesional skin (2/20 [10%]) with narrowband UVB. The safe duration of narrowband UVB and maximum cumulative dose compared with other treatment modalities remains undetermined, but the consensus is that this form of treatment is safe and effective in children, and may improve their quality of life. UVB phototherapy has the advantage of not requiring photoprotective goggles post-treatment. Furthermore, there is consensus that the risk of developing skin cancers from light treatments is lowest with narrowband UVB and highest with PUVA.

Substantive changes

No new evidence

BMJ Clin Evid. 2011 Mar 28;2011:1717.

PUVA (oral or topical) in children

Summary

TREATMENT SUCCESS Trioxysalen plus UVA compared with UVA alone: UVA (sunlight or sun lamp) plus oral trioxysalen may be more effective at 8 months at achieving cure or clear improvement in skins of children affected by vitiligo ( low-quality evidence ). Topical PUVA compared with clobetasol propionate: Topical PUVA is less effective at increasing the proportion of children achieving >75% repigmentation at 6 months ( moderate-quality evidence ). NOTE There is consensus that PUVA is not recommended in children under the age of 12 owing to the risk of cataract formation, and an increased risk of skin cancer.

Benefits

Trioxysalen plus UVA versus UVA alone:

We found one systematic review (search date 2009), which did not include a meta-analysis for the clinical outcomes of interest. It identified one RCT, which found that, compared with oral placebo plus UVA (sunlight/sun lamp), trioxysalen (10–30 mg/day) plus UVA (sunlight/sun lamp) significantly achieved cure/clear improvement in skin affected by vitiligo at 8 months (50 children, average age 9–10 years [minimum of 5% skin affected]; AR: 16/25 [64%] with trioxysalen plus UVA v 7/25 [28%] with UVA alone; RR 2.29, 95% CI 1.14 to 4.58; P value not reported). Trioxysalen was given 3 hours before exposure, or in two doses after breakfast and lunch for those using sunlight. Exposure time to UVA was 3 to 30 minutes daily until erythema appeared in the vitiligo patches.

Topical PUVA versus UVB (narrowband):

See benefits of UVB (narrowband) in children.

Topical PUVA versus clobetasol propionate:

See benefits of topical corticosteroids in children.

Harms

Trioxysalen plus UVA versus UVA alone:

One RCT reported severe pruritus (1/25 [4%]), hyperpigmentation of uninvolved skin (1/25 [4%]), and blisters (2 people using sun lamp) in those taking trioxysalen plus UVA. There was no evidence of liver or blood toxicity in either control or treatment group.

Topical PUVA versus UVB (narrowband):

The RCT reported erythema (3/28 [101%]), scaling (3/28 [11%]), and itching (3/28 [11%]) with PUVA. Difficulties in uniformly applying the aqueous gel resulted in linear burns of the vitiliginous skin as well as of the normally pigmented skin. In pigmented skin, hyperpigmented stripes remained.

Topical PUVA versus UVB (narrowband):

See harms of UVB (narrowband) in children.

Topical PUVA versus clobetasol propionate:

See harms of topical corticosteroids in children.

Comment

Clinical guide:

In general, PUVA is not recommended for children under the age of 12 years. Results from studies carried out in mixed-age groups should not be extrapolated to children. The phototoxic potential of psoralens is of great concern in children, where avoidance of excessive sun exposure may be difficult to regulate. PUVA therapy is not advocated in children under the age of 12 years because of the risk of cataract formation (because the eye is not fully developed until the age of 12 years), and because of the increased risk of skin cancer. See also comment on oral PUVA in adults.

Substantive changes

PUVA (oral or topical) in children Search updated for already included systematic review. No new evidence added. Categorisation unchanged (Likely to be ineffective or harmful).

Articles from BMJ Clinical Evidence are provided here courtesy of BMJ Publishing Group

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