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Vitiligo: more than just skin deep

Mark Greener
BSc(Hons)
Freelance Medical Writer, Journalist
and Editor
Former Research Pharmacologist

The psychological trauma associated with vitiligo can prompt sufferers to withdraw from social situations and may even trigger overt clinical depression.1 Indeed, a recent study found that 24.6% of a group of vitiligo patients scored over 10 on the Dermatology Life Quality Index. In other words, around a quarter of patients with vitiligo experience a severe reduction in their health-related quality of life.2

Unfortunately, the problems associated with vitiligo are relatively common in clinical practice. Around 1% of the UK population suffers from vitiligo and about half of sufferers develop the condition before the age of 20 years. Skin spontaneously repigments in around 30% of cases. However, spontaneous repigmentation is often slow and incomplete.1,3
Against this background, nurses can offer support and practical advice to reduce the emotional, social and psychological impact of the condition.

What causes depigmentation?
Melanocytes in the epidermis store melanin, the skin's main pigment. A pathway controlled by an enzyme, tyrosinase, produces melanin from the amino acid tyrosine. Melanocytes feed pigment into basal keratinocytes, the most common skin cell. In other words, two factors determine skin colour: first, the number and activity of melanocytes; and second, processing and storage of melanin by keratinocytes.3 

Vitiligo probably arises from an autoimmune reaction that destroys melanocytes and some keratinocytes. Autoimmune reactions describe cases where the immune system's ability to differentiate the body's healthy tissue from invading pathogens or abnormal cells breaks down. Several strands of evidence support suggestions that the immune system targets the skin, thereby producing areas of depigmentation. For example, immunoglobulin G (IgG) isolated from the serum of vitiligo patients can penetrate into melanocytes and trigger apoptosis (targeted cell suicide) of pigment cells. IgG extracted from healthy controls does not seem to trigger apoptosis.4 In healthy people, apoptosis is one way in which the body removes damaged and decrepit cells.

Furthermore, T-lymphocytes seem to mediate the eradication of melanocytes characteristic of vitiligo.5 The epidermis of vitiligo lesions also shows increased expression of tumour necrosis factor (TNF)-alpha and interleukin-6, two cytokines (proteins that carry messages between cells) that enhance inflammation and inhibit pigmentation. In contrast, the two cytokines were "practically undetectable" in skin taken from controls. In vitiligo patients, the lesions showed more apoptotic keratinocytes than skin from around the depigmented area. In contrast, the epidermis of control subjects did not express apoptotic keratinocytes. The authors suggest that increased TNF-alpha could contribute to keratinocyte apoptosis.

The excessive apoptosis characteristic of vitiligo would reduce the expression of cytokines produced by the keratinocyte that trigger the release of melanin. As a result, melanocytes disappear.6 While such studies begin to unravel the complex networks of molecules that cause depigmentation, biologists still have much to learn. Nevertheless, the identification of specific molecular targets – such as the cytokines – raises the prospect of developing targeted treatments.

Because of such immune reactions, melanin no longer reaches keratinocytes and the skin depigments. Occasionally, such as in some cases of depigmentation affecting the vulva, penis or neck, vitiligo remains localised. In most cases, however, vitiligo spreads symmetrically over the entire body. Nevertheless, the head and neck often depigment early in the disease's progression, while depigmentation of hair and eyes is rare. Obviously, vitiligo is more apparent on coloured than on fair skin. White-skinned people often present with vitiligo in the summer when sun exposure highlights differences in skin colour.1,3

The elusive trigger
The initial cause of the autoimmune reaction is unclear, although several clues have emerged. Of course, several factors could trigger the immune response that ultimately leads to skin depigmentation.

First, certain chemicals used in the rubber industry can trigger vitiligo. The hands and genitalia are usually the first parts of the body affected by occupational vitiligo. Genital depigmentation follows exposure to chemicals excreted in urine.3

Second, about a third of people with vitiligo report that at least one close family member also suffers from the disease.1 Clearly, genetic predisposition probably contributes to some cases of vitiligo.

Third, several autoimmune and other conditions increase the risk of developing vitiligo including diabetes, pernicious anaemia, Addison's disease, myxoedema and thyrotoxicosis.3 This reflects the overlap between autoimmune diseases.

Fourth, some researchers suggest that increased levels of free radicals trigger vitiligo. Recently, Indian researchers measured levels of the antioxidant enzymes superoxide dismutase (SOD) and catalase (CAT) in lesional and normal skin of vitiligo patients and in skin samples from normal controls. Levels of SOD in patients' vitiliginous and nonvitiliginous skin were elevated compared with controls. However, SOD levels did not differ between the lesional skin and nonlesional skin of vitiligo patients. CAT levels in patients' skin were significantly lower than controls. This pattern of changes suggests that the skin of people with vitiligo is subject to increased oxidative stress (high levels of free radicals).7

Finally, depigmentation often begins at sites of trauma, such as the knuckles, as a halo around a naevus or associated with striae.1,3,8 As this pathogenic diversity suggests, vitiligo may arise from the interaction of several mutually reinforcing factors, rather than a single cause. So, for example, a genetic predisposition could influence whether trauma or increased oxidative stress leads to depigmentation.

A suitable case for treatment
Currently, vitiligo remains incurable. However, dermatologists can deploy an increasing range of drugs and other treatments that help reduce the signs of vitiligo and alleviate the social, psychological and emotional trauma associated with the disease. As a result, nurses should encourage patients to seek a referral to a dermatologist. Even if the patient's previous experiences suggest that treatment is suboptimal, the armamentarium is expanding steadily. This section offers some examples of the growing number of treatment options that allows dermatologists to tailor treatment to each patient.

Phototherapy
Patients have used sunlight to treat vitiligo for thousands of years.9 Ancient Egyptians, for example, treated the depigmentation with sunlight and preparations derived from the giant hogweed, a plant that produces photosensitising chemicals.1 More recently, dermatologists developed PUVA, which combines ultraviolet A light and the photosensitiser psoralen. A combination of trimethylpsoralen plus 8-methoxypsoralen increased the effect of natural sunlight almost 20 fold compared to placebo. Indeed, psoralen and UV light can induce remission in 50–60% of patients. However, the full benefit may require regular treatment over two to three years.1,3

Targeted phototherapy is a relatively recent innovation. One study assessed targeted broadband UVB phototherapy in 32 patients with localized vitiligo. Only 12.5% showed visible repigmentation after between 20 and 60 sessions. The repigmentation covered more than 75% of the affected area in two patients.10

Other studies report more promising results. For example, Welsh and colleagues assessed twice-weekly, broadband, UVB-targeted phototherapy in 12 patients with vitiligo affecting less than 10% of their body.11 After 30 sessions, an average of 66.3% of facial lesions and 31.5% of those on the neck, trunk and genitalia repigmented. However, UVB-targeted phototherapy did not repigment lesions on the extremities. While some patients reported side-effects, such as itching, a burning sensation, erythema, desquamation, transitory hyperpigmentation, minimal blistering and ulceration, the adverse events did not result in the investigators discontinuing treatment. Overall, phototherapy remains a valuable treatment for many patients.

Topical treatments
Patients may also benefit from a variety of topical treatments, such as topical calcipotriol, which may improve repigmentation rates from PUVA; steroids (especially in early or evolving disease); and calcineurin inhibitors (such as tacrolimus and pimecrolimus).1,3,12 First, for example, potent topical steroids produced better repigmentation than oral
psoralens plus sunlight (relative risk 4.70). Unfortunately, adverse events hinder long-term use of steroids.1

In an open pilot study that enrolled 26 patients with head and neck vitiligo, pimecrolimus repigmented half of the lesions after six months' treatment. On average, lesions showed around 73% repigmentation. A burning sensation at the application site emerged as the main adverse event.12

As a final example of the benefits offered by topical treatments, a recent study enrolled 17 patients with generalised vitiligo who applied 0.1% tacrolimus once daily to one lesion and twice a day to a second lesion for six months.13
Fifteen patients with 40 target lesions completed the study. Twice-daily treatment induced >75% repigmentation in two lesions as well as >25-50% and 1-25% repigmentation in four lesions each. Five lesions showed no response. Once-daily treatment resulted in >25-50% and 1-25% repigmentation in two and five lesions respectively. The remaining eight lesions showed no change. One out of 10 control lesions showed >25-50% repigmentation. The remainder were unchanged. Facial lesions showed the best response to tacrolimus and the authors advise offering "a guarded prognosis" for lesions on other parts of the body.

Surgical techniques
Several surgical techniques may also repigment areas affected by vitiligo. For example, surgeons can graft skin and follicles, and transplant melanocytes taken from unaffected skin into depigmented lesions. The effectiveness of surgery varies from 13% to 87%. Some forms of skin graft seemed to produce the best results, although further research needs to characterise the relative merits of the different approaches.14 Tattooing may be appropriate for small areas. For example, tattooing can offer a "relatively easy, safe and effective option for lip vitiligo". Typically, lip vitiligo does not respond well to medical therapies. However, the cosmetic outcome for lip tattooing seems to be better in people with dark complexions than in fair-skinned patients.15

Nurses' advice and support
Vitiligo is relatively common and often causes significant psychological, emotional and occupational distress. Nurses should suggest that anyone with vitiligo sees their doctor, especially as an increasing range of treatments is now available. Unfortunately, some people with vitiligo may feel that their doctor is "disinterested", regards the disease as cosmetic, and does not provide the support and understanding the patient feels they need.1 Nurses should also suggest that sufferers contact a patient support group for further advice (see Resources) - and don't underestimate the importance of the nurse's traditional "sympathetic ear".

Camouflage cosmetics can cover affected areas and may be particularly appropriate for special social occasions. The local dermatology department should be able to place patients in touch with this service. However, many patients feel that camouflage cosmetics are too time-consuming for everyday use. Some light-skinned patients find that fake tans cover large, exposed areas – such as the arms and legs - and may be especially valuable during the summer. However, nurses need to reinforce the importance of using a high-factor sun block and other sun protection - depigmented patches burn easily.1,3

Apart from emphasising the importance of sun protection, nurses also need to stress that patients should avoid other types of skin damage – such as playing with animals that scratch. As mentioned above, skin trauma can trigger depigmentation.3 Some studies suggest that stress may contribute to the onset and exacerbation of vitiligo. So, nurses could advocate relaxation and other stress reduction techniques. Patients with particularly stressful lives or difficulties adjusting to the disease may benefit from sessions with the practice counsellor or a more formal psychological referral. However, a Cochrane review highlights the dearth of evidence assessing psychological treatments.1

Conclusion
Vitiligo remains a mysterious and incurable condition. However, dermatology and primary care teams can do much to improve a patient's appearance: a point nurses should reinforce to patients. Nevertheless, further research needs to improve dermatologists' ability to use existing treatments. For example, a Cochrane review noted the "pressing need" for high-quality, randomised trials that use standardised methods to measure repigmentation and that include outcomes such as quality
of life.1

Furthermore, studies should assess long-term outcomes and enrol a greater number of children.1 Nevertheless, recent studies into the causes of vitiligo can offer insights and molecular targets that could lead to a new generation of treatments. In the meantime, nurses can offer support and practical advice that reduces the physical and psychological toll imposed by this disfiguring and distressing disease.

Resource
The Vitiligo Society
W: www.vitiligosociety.org.uk

References
1. Whitton ME, Ashcroft DM, Barrett CW, Gonzalez U. Interventions for vitiligo. Cochrane Database Syst Rev 2006;25(1):CD003263.
2. Radtke MA, Schäfer I, Gajur A, Langenbruch A, Augustin M. Willingness-to-pay and quality of life in patients with vitiligo. Br J Dermatol 2009.
3. Ryan TJ, Sinclair R. Diseases of the skin. In: Warrell DA, Cox TM, Firth JD (eds). Oxford Textbook of Medicine. 4th edn. Oxford: Oxford University Press; 2005:849–51.
4. Ruiz-Argüelles A, Brito GJ, Reyes-Izquierdo P, Pérez-Romano B, Sánchez-Sosa S. Apoptosis of melanocytes in vitiligo results from antibody penetration. J Autoimmun 2007;29(4):281–6.
5. Van den Boorn JG, Konijnenberg D, Dellemijn TA et al. Autoimmune destruction of skin melanocytes by perilesional T cells from vitiligo patients. J Invest Dermatol 2009.
6. Moretti S, Fabbri P, Baroni G et al. Keratinocyte dysfunction in vitiligo epidermis: cytokine microenvironment and correlation to keratinocyte apoptosis. Histol Histopathol 2009;24(7):849-57.
7. Sravani PV, Babu NK, Gopal KV et al. Determination of oxidative stress in vitiligo by measuring superoxide dismutase and catalase levels in vitiliginous and non-vitiliginous skin. Indian J Dermatol Venereol Leprol 2009;75(3):268–71.
8. Verma SB. Striae: stretching the long list of precipitating factors for 'true koebnerization' of vitiligo, lichen planus and psoriasis. Clin Exp Dermatol 2009.
9. Millington GW, Levell NJ. Vitiligo: the historical curse of depigmentation. Int J Dermatol 2007;46(9):990–5.
10. Akar A, Tunca M, Koc E, Kurumlu Z. Broadband targeted UVB phototherapy for localized vitiligo: a retrospective study. Photodermatol Photoimmunol Photomed 2009;25(3):161–3.
11. Welsh O, Herz-Ruelas ME, Gómez M, Ocampo-Candiani J. Therapeutic evaluation of UVB-targeted phototherapy in vitiligo that affects less than 10% of the body surface area. Int J Dermatol 2009;48(5):529–34.
12. Boone B, Ongenae K, Van Geel N et al. Topical pimecrolimus in the treatment of vitiligo. Eur J Dermatol 2007;17(1):55–61.
13. Radakovic S, Breier-Maly J, Konschitzky R et al. Response of vitiligo to once- vs twice-daily topical tacrolimus: a controlled prospective, randomized, observer-blinded trial. J Eur Acad Dermatol Venereol 2009.
14. Rusfianti M, Wirohadidjodjo YW. Dermatosurgical techniques for repigmentation of vitiligo. Int J Dermatol 2006;45(4):411-7
15. Singh AK, Karki D. Micropigmentation: Tattooing for the treatment of lip vitiligo. J Plast Reconstr Aesthet Surg 2009.