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 question: What are the effects of surgical interventions for vitiligo in adults and in children? We searched: Medline, Embase, The Cochrane Library, and other important databases up to April 2014 (BMJ 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 four 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: blister grafts, cultured cellular transplantation, non-cultured cellular transplantation, punch/mini grafts, and split thickness skin grafts.
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.
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 medical treatment modalities. This is thought to be related to the lack of melanocyte reservoir in non-hair bearing sites.
In these cases, counselling and cosmetic camouflage become a priority, and often in these sites re-pigmentation is unlikely to be achieved unless surgical methods are used.
There are a variety of medical treatments used for vitiligo, but this review has focused on surgical therapeutic options as this is an expanding field worldwide. Surgery is considered in people with stable vitiligo unresponsive to standard medical therapies.
We do not know whether surgical treatments of vitiligo in adults and children (blister grafts, cultured cellular transplantation, non-cultured cellular transplantation, punch/mini grafts, split-thickness skin grafts) are effective, as we found limited evidence from RCTs and systematic reviews. The evidence found was of low or very low quality.
We searched for RCTs comparing blister grafts, cultured cellular transplantation, non-cultured cellular transplantation, punch/mini grafts, and split-thickness grafts with no active treatment or with each other.
There are significant challenges undertaking robust RCTs assessing surgical treatments, as it is difficult to offer suitable control treatments and the high cost of surgical studies can be limiting.
Clinical context
General background
Vitiligo is an acquired skin disorder characterised by white (depigmented) patches in the skin, caused by the loss of functioning melanocytes. It is difficult to assess the true prevalence of vitiligo as the estimate of prevalence worldwide, between 0.5% and 1.0%, varies according to cultural and social differences. Figures as high as 9% have been reported in India where stigma associated with the disease is high.
Focus of the review
There are a variety of medical treatments used for vitiligo, but this review has focused on surgical therapeutic options as this is an expanding field worldwide. Surgery is considered in people with stable vitiligo unresponsive to standard medical therapies.
Comments on evidence
The evidence found was of low or very low quality. There are significant challenges undertaking robust RCTs assessing surgical treatments, as it is difficult to offer suitable control treatments and the high costs of surgical studies can be limiting .
Search and appraisal summary
The update literature search for this review was carried out from the date of the last search, March 2010, to April 2014. A search back-dated to 1966 was performed for the new options added to the scope at this update. For more information on the electronic databases searched and criteria applied during assessment of studies for potential relevance to the review, please see the Methods section. Searching of electronic databases retrieved 30 studies. Appraisal of titles and abstracts led to the exclusion of 17 studies and the further review of 13 full publications. Of the 13 full articles evaluated, two systematic reviews and two RCTs were added at this update.
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. 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%]). Other treatments options include topical tacrolimus for localised vitiligo and narrowband ultraviolet light B (UVB) or oral psoralen plus ultraviolet light A (PUVA) for moderate to severe generalised vitiligo. Surgery is considered in people with stable vitiligo unresponsive to conservative medical therapies. Stable disease is generally defined as no new lesions, no change in existing lesions, absence of koebnerisation, and spontaneous re-pigmentation. The time period for this is undefined but can range from 6 months to 3 years. The approach taken by surgical therapies is to add melanocytes into the depigmented patches of skin, taken from other pigmented areas. Currently, two types of surgery are considered, tissue grafting or cellular grafting procedures. In this review we have included split-thickness skin grafts, blister grafts, and punch/mini-grafts, which are types of tissue grafting, and cultured and non-cultured cellular transplantation, as types of cellular grafting.
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 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 prevalence worldwide varies between 0.5% and 1.0% 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 due to 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 9% 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. 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 due to the absence of melanocytic photo-protection. 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 that followed up people treated with PUVA over 21 years for a range of benign skin conditions demonstrated an increased risk of squamous cell carcinomas. Furthermore, the risk of malignant melanoma increases among people treated with PUVA by 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 exist 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. Surgical therapies can be effective interventions for vitiligo, but are limited by the fact that they are invasive and require significant training and expertise to be performed successfully. Surgical treatments are contraindicated in patients who have a history of hypertrophic or keloid scars. An associated skin manifestation is the phenomenon of koebnerisation, where pressure or friction on the skin can cause new lesions or worsen existing ones. Koebnerisation 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 re-pigmentation of involved skin, thus improving the quality of life, with minimal adverse effects.
Outcomes
Treatment success (re-pigmentation) the degree of re-pigmentation that defines success has been arbitrarily set in many studies as 50% to 75% re-pigmentation, based largely on the global impression of the overall response. Disease progression, including development of new lesions 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. Quality of life measured using a validated tool. Adverse effects.
Methods
BMJ Clinical Evidence search and appraisal April 2014. The following databases were used to identify studies for this systematic review: Medline 1966 to April 2014, Embase 1980 to April 2014, and The Cochrane Database of Systematic Reviews, issue 4, 2014 (1966 to date of issue). Additional searches were carried out in the Database of Abstracts of Reviews of Effects (DARE) and Health Technology Assessment (HTA) database. We also searched for retractions of studies included in the review. Titles and abstracts of the studies identified by the initial search, run by an information specialist, were first assessed against predefined criteria by an evidence scanner. Full texts for potentially relevant studies were then assessed against predefined criteria by an evidence analyst. Studies selected for inclusion were discussed with an expert contributor. All data relevant to the review were then extracted by an evidence analyst. Study design criteria for inclusion in this review were published RCTs and systematic reviews of RCTs in the English language, any level of blinding, and containing at least 20 individuals (at least 10 per arm), of whom at least 80% were followed up. There was no minimum length of follow-up. We included RCTs and systematic reviews of RCTs where harms of an included intervention were assessed, 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 (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.
GRADE Evaluation of interventions for Vitiligo in adults and children: surgical interventions.
| Important outcomes | Disease progression, Quality of life, Treatment success | ||||||||
| Studies (Participants) | Outcome | Comparison | Type of evidence | Quality | Consistency | Directness | Effect size | GRADE | Comment |
| What are the effects of surgical treatments for vitiligo in adults and children? | |||||||||
| 1 (20) | Treatment success | Blister grafts versus split thickness skin grafts | 4 | –2 | 0 | –1 | 0 | Very low | Quality point deducted for sparse data and absolute numbers not reported; directness point deducted for applicability of results |
| 1 (41) | Treatment success | Blister grafts versus non-cultured cellular transplantation | 4 | –1 | –1 | –1 | 0 | Very low | Quality point deducted for sparse data; consistency point deducted for different results depending on outcome measured; directness point deducted for use of co-intervention |
| 1 (41) | Quality of life | Blister grafts versus non-cultured cellular transplantation | 4 | –1 | 0 | –1 | 0 | Low | Quality point deducted for sparse data; directness point deducted for use of co-intervention |
| 1 (28) | Treatment success | Non-cultured cellular transplantation plus ultraviolet light versus placebo plus ultraviolet light | 4 | –2 | 0 | –2 | 0 | Very low | Quality points deducted for sparse data and absolute numbers not reported; directness points deducted for applicability of results and use of co-intervention |
| 1 (64) | Treatment success | Punch/mini grafts plus PUVAsol versus split-thickness skin grafts plus PUVAsol | 4 | –1 | 0 | –1 | 0 | Low | Quality point deducted for sparse data; directness point deducted for use of co-intervention |
We initially allocate 4 points to evidence from RCTs, and 2 points to evidence from observational studies. To attain the final GRADE score for a given comparison, points are deducted or added from this initial score based on preset criteria relating to the categories of quality, directness, consistency, and effect size. Quality: based on issues affecting methodological rigour (e.g., incomplete reporting of results, quasi-randomisation, sparse data [<200 people in the analysis]). Consistency: based on similarity of results across studies. Directness: based on generalisability of population or outcomes. Effect size: based on magnitude of effect as measured by statistics such as relative risk, odds ratio, or hazard ratio.
Glossary
- Active vitiligo
An extending vitiligo with enlarging lesions or development of new lesions.
- 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.
- 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.
- 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.
- PUVAsol
A combination topical or oral psoralen with natural sunlight 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 can arise.
- 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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