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| WHAT'S NEW IN VITILIGO?
W S Douglas* and M E Whitton+ |
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| *Former Consultant Dermatologist NHS Lanarkshire
+ Vitiligo Society & Cochrane Skin Group |
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Content of article originally published in DERMATOLOGY IN PRACTICE 2008; 16:1 |
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KEY POINTS
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| INTRODUCTION
Vitiligo is an acquired inflammatory disorder, with underlying genetic susceptibility, resulting in death or loss of function of skin melanocytes and hence the disappearance of the principal brown pigment of the skin, melanin. It is the most common hypopigmenting disease, affecting ~1% of the population worldwide, with considerable geographical/racial variation. Reported prevalence tends to be highest in dark-skinned populations where depigmentation is most visible and carries most stigma. The prevalence in pale-skinned populations could well be underestimated as vitiligo may only become apparent when unaffected skin becomes tanned. |
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| CLINICAL FEATURES Vitiligo appears as white macules, often with scalloped, convex margins, that may expand from a few mm in diameter to much larger patches. Macules may merge to form extensive geographical patterns. The margins of lesions may hyperpigment. Histology shows a variable chronic inflammatory infiltrate particularly in early lesions and slight erythema is occasionally seen at the margins of advancing lesions. In the absence of melanin, the principal skin pigment is haemoglobin and fully-evolved macules range from chalk-white to pink, depending on vascularity and vasodilatation. Variations in pigmentation occur in lesions that are developing or resolving (trichrome vitiligo). Repigmenting areas often show perifollicular foci of pigmentation which then expand and coalesce. When follicular melanocytes are affected, patchy depigmentation of hair - poliosis - is seen. This can sometimes precede the appearance of skin lesions. There may be increased susceptibility to sunburn, and itch occasionally accompanies developing lesions. The main symptom of vitiligo is the appearance of lesions, with an often distressing sense of disfigurement and associated stigma. Social isolation, reduced sense of worth, adverse effects on education, occupation, and personal relationships and depressive illness can be consequences. Dermatology Life Quality Index scores for vitiligo in women, though not in men, are similar to those for psoriasis - indicating disability comparable to diabetes or heart disease1. |
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| CLASSIFICATION and NATURAL HISTORY
Vitiligo may not be a single disease. It can be classified according to its extent and distribution. Generalized (bilateral) and unilateral variants are recognised. In the most common generalised variant, vitiligo vulgaris, macules develop symmetrically. The areas most frequently affected include eyelids, perioral skin, hands and wrists, feet and ankles, areolae, axillae and groins, and genitalia. The Koebner phenomenon influences the distribution – lesions occur at sites of trauma, pressure, or friction such as elbows, knees and waistline. Less common variants involve only the distal extremities, face, and skin around orifices. In about half of those who develop generalised vitiligo, the disease starts before the age of 20, but it can start at any age, affecting both sexes equally. There are phases of activity and quiescence but vitiligo is often gradually progressive. Rarely, it can spread rapidly to cover almost all of the skin. Improvement can also occur, particularly in childhood, but complete spontaneous recovery is rare. Unilateral types usually appear in childhood: focal, where lesions are haphazard in distribution; or segmental, where lesions occur in in several dermatomes, or follow Blaschko's lines. Halo naevus, in which a depigmented halo appears as a prelude to autodestruction of the naevus, may also be a variant of vitiligo. |
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| Differential Diagnosis and Investigation Differential diagnosis is from other depigmenting and hypopigmenting disorders (Table 1), and is largely clinical. Absence of scaling, induration, significant inflammation, and scarring are important. Ultraviolet light increases the contrast between fully depigmented and normal skin, but reduces the contrast where there is only partial loss of melanin. The most useful diagnostic tools are Wood’s light examination for diagnosis and UV photography for follow-up or teledermatological diagnosis. An easy and cheap alternative to UV photography is selection of the blue channel of a standard digital photographic image using photoediting software (Fig1). Other investigations may include: skin scrapings for microscopy where pityriasis versicolor is suspected; biopsy where one of the less common diseases is being considered. Vitiligo patients may have other concurrent autoimmune disease - thyroid function and B12 should be checked. |
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| AETIOLOGY
A major epidemiological study of people with vitiligo and their families has confirmed much of what has long been suspected about the inheritance of vitiligo and its links with autoimmunity2. About 30% of affected people have a family history of vitiligo, particularly those with early onset disease. First degree relatives have an increased risk of ~6%. Approximately 30% of vitiligo patients have thyroid disease, while Addison’s disease, pernicious anaemia, and systemic lupus erythematosus are also more frequent in vitiligo sufferers and their close relatives. An increasing number of vitiligo susceptibility genes are being identified, the majority associated with both vitiligo and other autoimmune disorders3. One of these is NALP1, a regulator of the innate immune response4. In addition, there is convincing evidence of both cellular and humoral autoimmune disease mechanisms in vitiligo. These include the presence in the circulation and in lesions of melanocyte-specific cytotoxic T-lymphocytes, and , in some patients, autoantibodies which react with melanocyte-specific components5. It now seems likely that these autoimmune mechanisms are pathogenic, but they could represent a reaction to abnormal melanocytes damaged by another mechanism. Both twins develop vitiligo in only 1 in 4 pairs of identical twins, indicating the importance of environmental trigger factors in the genetically susceptible. No equivalent autoimmune trigger in vitiligo has been shown to parallel that of Streptococcal infection in psoriasis, and evidence is purely clinical for other possible triggers such as injury and stressful life-events. However, melanocytes are known to be susceptible to damage from oxidising agents. Industrial “vitiligo” can be due to p-Tertiary butyl phenol (rubber & plastics industry) or hydroquinone (hairdressing). Endogenous hydrogen peroxide (H2O2) may have a similar effect, and, in vitiligo, the epidermis contains elevated levels of H2O2 and reduced activity of the enzyme catalase, a critical component of anti-oxidant defence6. Thus “oxidative stress” might be a mechanism by which environmental factors could alter the antigenicity of the melanocyte and initiate the autoimmune reaction7. |
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| Sunlight (and artificial UV) and Vitiligo Tanning makes vitiligo more obvious. Absence of melanin reduces the natural protection from sunlight thus increasing the risk of sunburn, skin ageing, and cancer. Advice about sun protection and avoidance as well as sunbed use should therefore be an important part of consultations for vitiligo. There is, however, a surprising lack of good data on vitiligo and cancer - only a few reports of individual cases have appeared in the literature. There probably is an increased risk of solar keratosis and squamous cell carcinoma - but much lower than was once thought, much less than in scarring disorders or albinism, and possibly little more than average for a given skin type. There is also evidence that increased immunological reactivity associated with vitiligo may protect against melanoma. |
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Treatment
We therefore suggest that priority be given to treating:
Careful assessment of the individual patient is very important: in this chronic condition it is particularly important to inform fully, and agree with the patient, the aims of treatment, taking into account:
Everyone should be provided with:
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| TOPICAL TREATMENTS
The evidence that vitiligo responds best to early treatment should encourage General Practitioners to initiate topical treatment, without awaiting specialist advice, despite the unlicensed status of all treatments. |
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Corticosteroids
with ongoing treatment for those showing a response, perhaps alternating every 4 weeks with another treatment to reduce the risk of steroid side-effects. There is no evidence to suggest that twice-daily topical corticosteroid or intralesional corticosteroids offers sufficient additional benefit to offset the greater risk of side-effects. |
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| Calcineurin inhibitors As with topical corticosteroids, calcineurin inhibitors are topical immunosuppressives, and prolonged therapy may be required to achieve maximum response. Tacrolimus (Protopic®) ointment 0.1% (0.03% in children), applied twice daily, has limited RCT evidence showing near-equivalence of efficacy to very potent topical steroids and fewer short-term side-effects in children10. There is less evidence for the less potent pimecrolimus (Elidel®). Stinging after application tends to lessen with continued treatment, but caution is required in view of uncertainty about long-term potential to promote skin cancers. We suggest use in those, particularly children, who fail to improve with topical steroid at 8 weeks; on areas such as eyelids where ocular steroid side-effects are a particular risk; and as steroid-sparing agents in e.g. alternate month therapeutic regimes for those who are steroid-responsive but need longterm treatment. Used in this way tacrolimus has the potential to maximise response and minimise adverse effects in those who benefit from topical steroids. |
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| PHOTOTHERAPY Some people with vitiligo report temporary improvement after sun exposure, and climatotherapy, particularly at the Dead Sea, has been a popular, though untested, treatment for many years. In psoriasis, the therapeutic effect has been shown to be mainly via the effect of solar radiation shorn of its shorter, burning, wavelengths by passage through additional atmosphere to reach a sub-sea-level site. Dead Sea salts make little, if any, therapeutic contribution13. Topical or systemic psoralen does enhance the effect of sunlight and has been used for many decades in Africa to treat vitiligo. PUVA was developed from it in the 1970s, and was rapidly established as a standard treatment for vitiligo, psoriasis and other diseases. Narrowband UVB Phototherapy (311+-5nm) has now been shown to be superior to PUVA or psoralen/sunlight treatment, with higher response rates and improved skin colour matching, clearing up to 70% of lesions14. Optimum regimes have not yet been established, but it is usual to treat three times weekly for up to 12 months. Prolonged treatment periods are the norm but early follow-up studies are encouraging, suggesting that about half of those who respond maintain that response 2 years after a course of treatment15. There has to be some concern about possible long-term risk of phototherapy but, in contrast to psoriasis, reports of PUVA-related cancer are rare in vitiligo patients, especially in darker skin types. NB-UVB, with its safety advantages over PUVA, can now be recommended: short-term to stabilise extending vitiligo; and repeatedly for severe disease. UK dermatologists will usually continue topical steroids during phototherapy, but tend to be wary of regimes that combine calcineurin inhibitors with phototherapy. The excimer laser produces coherent UVB of similar wavelength (308nm). It has been shown to be of at least equal efficacy to NB-UVB16. High doses can be delivered to localised patches with the advantage that radiation exposure can be localised to affected skin. Its disadvantage is the difficulty and expense of treating extensive disease. Availability in the UK is very limited. |
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| OTHER TREATMENTS
Treatments that aim to restore antioxidant defence such as oral antioxidants17, and topical application of pseudocatalase18, have, so far, only been shown to be effective in combination with NB-UVB or Dead Sea heliotherapy, and it is unclear to what extent they offer added benefit to phototherapy alone. A number of trials have failed to confirm earlier reports of efficacy for Vitamin D analogues. They may have a minor role in combination with phototherapy. Surgery, such as grafting of autologous skin, works well for segmental vitiligo. Newer techniques, originally developed for treatment of burns, include application of cell suspensions or of skin constructs prepared from cultured melanocytes and keratinocytes20. These offer the promise of better results and wider availability. Oral or parenteral corticosteroid therapy, pulsed or continuous, may be of benefit in halting disease progression, but should be reserved for specialist use in exceptional, recalcitrant, cases. When vitiligo is very widespread it can occasionally be helpful to use monobenzyl ether of hydroquinone 20% to depigment the remaining normal skin. The effect is usually irreversible. |
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FURTHER READING
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| ACKNOWLEDGMENTS Photographs courtesy of the Department of Medical Illustration, Monklands Hospital, Airdrie, Lanarkshire ML6 0JS |
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REFERENCES
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Table 1 Hypopigmenting Disorders – Differential Diagnosis
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