Therapeutic Options for Vitiligo

Davindra Singh, MD, FRCPC^1-4 and Huda AlSaffar, MD, FRCPC¹

¹Faculty of Medicine, University of Toronto, Toronto, ON
²Faculty of Medicine, Laurentian University, Sudbury, ON
³Faculty of Medicine, Lakehead University, Thunder Bay, ON
⁴Faculty of Medicine, Queen’s University, Kingston, ON

Introduction

Vitiligo affects approximately 1% of the population and is characterized by well demarcated, depigmented macules and patches that occur after destruction of melanocytes. It is an acquired disorder of unknown etiology. Vitiligo can appear at any time of life but is most common around the age of 20. It can be psychologically devastating, especially in patients with darker skin types. There is no cure but with appropriate management many patients can reduce its progression, achieve repigmentation, and attain cosmetically acceptable results. Recent guidelines have helped inform physicians in their approach to this disease.^1-3

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Epidemiology

• The prevalence of vitiligo is approximately 1% but can vary regionally. For example, Gujarat state in western India has the highest prevalence in the world at 8.8%.¹
• Men and women are equally affected.
• Average age of onset is 20 years.
• Women are more likely to seek treatment with vitiligo presenting earlier in the first decade of life versus the fifth decade of life for men.
• It is more frequently diagnosed in the spring and summer.
• There is a familial tendency in approximately 18% of cases.⁴

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Etiology

• The cause of vitiligo remains unknown.
• Several different pathophysiological mechanisms are likely involved.
• The autoimmune hypothesis is most favoured due to an association with other autoimmune diseases (e.g., thyroid disease, alopecia areata, diabetes mellitus, pernicious anemia, rheumatoid arthritis, and psoriasis). There are numerous genetic associations and linkage studies.⁵
• The neurohumoral hypothesis is also supported by the development of segmental vitiligo along the distribution of nerves.
• Cytotoxic and oxidative stress hypotheses also have moderate support.

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Quality of Life (QoL)

• Vitiligo can be psychologically devastating and comparable in impact to severe psoriasis.
• QoL assessments should be considered during the first clinic visit.
• Psychosocial impacts to patients can include feelings of embarrassment, depression and shame; negative emotional sequelae can result in sexual difficulties, sleep disturbance and anxiety.⁶
• Psychotherapy can be offered to select patients.

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Diagnosis

• Classic presentation consists of depigmented macules and patches with convex borders surrounded by normal skin.
• Common sites affected include face, hands, nipples, axillae, umbilicus, inguinal and anogenital regions.
• Slow progression can occur.
• Koebnerization is a common finding and this refers to the development of new lesions in areas affected by trauma.⁵
• Two general categories include segmental and non-segmental vitiligo:
  • Segmental vitiligo is unilateral, begins in childhood, usually involves one dermatome and tends to be stable.
  • Non-segmental vitiligo is more common, appears later in life, is symmetrical and can be progressive.
• There are several other uncommon variants (trichrome, quadrichrome, blue, ponctue and inflammatory vitiligo).
• Differential diagnosis:
  • Three of the most common mimickers include tinea versicolour, piebaldism, and idiopathic guttate hypomelanosis but many others can be considered.

Work-up

• Initial steps include a thorough clinical history and physical examination.
• Through emission of ultraviolet A light (365 nm), the Wood’s lamp can identify areas of depigmentation not readily visible to the naked eye, especially in lighter skin types.
• If diagnosis is still uncertain, lesional and normal skin should be biopsied for direct comparison with special staining to identify melanocytes.
• Bloodwork includes thyroid-stimulating hormone (TSH) and antinuclear antibody (ANA) as a minimum, with consideration for other autoimmune disease screening.
• Consider eye and ear exams as there is an association with hearing loss and ocular abnormalities.
• If part of a greater syndrome, referral to a geneticist should be considered.
• QoL assessment and referral for counselling has been shown to benefit patients.⁷

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Prognostic Features

• Certain features point to a poorer prognosis and should be identified early (e.g., mucosal involvement, family history of vitiligo, non-segmental disease, positive Koebner phenomenon).
• Certain features point to a more favourable response to treatment (e.g., younger patients, darker skin types, recent onset, lesions on the head, neck and trunk).

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Treatment

Vitiligo can be a lifelong disease and choosing the appropriate treatment can be difficult given the variety of options available. There are numerous medical, surgical, and light-based treatments for repigmentation. Options for depigmentation also exist. First-line treatments should be safe, effective, minimally invasive, and cost efficient. Advanced treatments are reserved for recalcitrant disease. Most treatments take time before an effect is evident, so patience on the part of the physician and patient is essential.

Oral Doxycycline

• Topical corticosteroids (TCS)
  • This is the usual first-line treatment
  • Optimal dosing parameters remain to be determined
  • High potency topical steroids (clobetasol, fluticasone) used for a two-month period appear to be safe
  • Side effects include atrophy, telangiectasia, striae, folliculitis, and hypertrichosis
• Topical calcineurin inhibitors (tacrolimus or pimecrolimus)
  • Provide almost equal results to topical steroids
  • Safe for short-term and intermittent long-term use.
  • The most common side effect is a transient burning sensation upon application
  • To date, there is no evidence to suggest an increased risk of lymphoma in adults or children using these products, refer to Canadian Dermatology Association position statement. Available at: http://www.dermatology.ca/wp-content/ uploads/2012/01/TopicalCalcineurinInhibitorsEN.pdf
• Vitamin D3 analogues (calcipotriol/calcipotriene)
  • Monotherapy is inferior to TCS and not recommended
  • When combined with TCS, efficacy increases and the fixed-dose combination of calcipotriol 0.005% and betamethasone dipropionate 0.05% once daily is a simple option
  • Vitamin D3 analogues are not recommended in combination with light therapy

Systemic Medications

• Systemic corticosteroids
  • These can be effective in halting disease progression and inducing repigmentation but are not recommended due to an unacceptable risk of side effects
• Antioxidants
  • Theoretically, they may play a role in protecting melanocytes from reactive oxygen species
  • Gingko biloba, vitamin E, vitamin C and other antioxidants cannot be recommended as additional research is needed
• Tumor necrosis factor (TNF)-alpha inhibitors
  • Theoretically, they may play a role as TNF-alpha is a proinflammatory cytokine that can induce melanocyte death and inhibit melanocyte stem cell differentiation
  • Further research is necessary before recommendations can be made
• Other immunosuppressive agents
  • No recommendation can be made regarding azathioprine, cyclophosphamide or cyclosporine due to a lack of evidence

Phototherapy

• Phototherapy should be reserved for patients who fail topical treatment.
• Treatment requires a commitment from the patient as dosing varies from 2 to 3 times per week for several months.
• Phototherapy does not alter the natural history of vitiligo.
• The exact mechanism of action is unknown but believed to have immunosuppressive and melanocyte stimulating effects.
• Narrow band ultraviolet-B (nb-UVB) is superior and easier to administer than psoralen + UVA therapy (PUVA).
• Treatment limits are necessary to prevent the possibility of skin malignancies: an arbitrary limit of 200 treatments for nb-UVB and 150 treatments for PUVA has been suggested.
• Combination therapy with topical treatments can enhance results:
  • Topical corticosteroids are recommended
  • Topical calcineurin inhibitors are recommended⁸
  • Topical vitamin D analogues are NOT recommended

Laser Therapy

• Lasers provide targeted treatment to lesions and emit less overall radiation, thereby reducing adverse impacts on healthy skin.
• 308 nm monochromatic excimer laser is well studied and superior to conventional light therapy.
• This therapeutic modality for vitiligo is not readily available in Canada at this point in time.
• Combination therapy with topical treatments can enhance results:
  • Topical corticosteroids are recommended
  • Topical calcineurin inhibitors are recommended
  • Topical vitamin D analogues are NOT recommended

Surgical Treatments

• Surgical techniques are among the most effective treatment options but are not yet available in Canada.
• The concept is to transplant functioning melanocytes to the depigmented areas.
• Treatment is reserved for recalcitrant, segmental vitiligo in cosmetically sensitive areas that have been stable for at least one year without evidence of Koebner phenomenon:
  • Requires a donor site that may be subject to scarring and Koebnerization
  • Requires a recipient site that may be subject to scarring, graft failure, pigment mismatch, cobblestone appearance, infection, and Koebnerization
• Documented techniques include:
  • Punch graft
  • Suction blister graft
  • Split thickness skin graft
  • Autologous melanocyte transfer
    • Graft tissue is harvested and after exposure to enzymes, individual melanocytes are released into a suspension that is transplanted onto a de-epithelialized recipient site
    • The advantage is that a smaller graft site can result in a suspension that can cover much larger areas

Depigmentation Therapy

• Select patients may benefit from depigmentation therapy, including those who have >50% body surface area involvement, experienced failure with repigmentation therapy, and accept the permanence of this technique.
• Treatment can take many months before the effect is visible; however, the improvement may not be permanent.
• Side effects with topical agents are common and include irritation, contact dermatitis, and ocular changes.
• Topical agents include:
  • Monobenzyl ether of hydroquinone
  • 4-methoxyphenol
• The Q-switched ruby laser is also effective and has a more rapid onset of action; it can be used in combination with topical products.

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No Treatment and Non-pharmacologic Adjuncts

• No treatment is viable in patients with skin types I and II.
• All patients should be offered sunscreen to protect the depigmented skin and reduce contrast with surrounding tanned skin.

Camouflage

• All patients should be made aware of camouflage cosmetics as a noninvasive strategy to diminish the appearance of visible patches. Temporary options include makeup and selftanning agents containing dihydroxyacetone.
• Permanent options include tattooing but Koebnerization, colour mismatch, and scarring must be considered.

Psychotherapy

• Emotional and psychological effects from vitiligo can be severe.
• Cognitive behavioural therapy has been shown to improve QoL, self esteem, and perceived body image, but further work is needed to clearly define its role.⁷

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Conclusion

Vitiligo is a disease that presents with depigmented skin and is associated with significant psychosocial effects. Disease progression can occur and is unpredictable. Management is challenging and many options are available. Topical treatments are considered first-line and more advanced therapies are often necessary with recalcitrant disease. Further research is needed to define the exact cause and to investigate potential therapies. Recent guidelines are useful in assisting physicians to optimize their treatment approach.

References

1. Gawkrodger DJ et al. Br J Dermatol. 2008 Nov;159(5):1051-76.
2. Alikhan A et al. J Am Acad Dermatol. 2011 Sep;65(3):473-91.
3. Felsten LM et al. J Am Acad Dermatol. 2011 Sep;65(3):493-514.
4. Mason CP et al. Clin Exp Dermatol. 2005 Jul;30(4):344-5.
5. Le Poole IC et al. Exp Dermatol. 1993 Aug;2(4):145-53.
6. Augustin M et al. Dermatology. 2008;217(2):101-6.
7. Papadopoulos L et al. Br J Med Psychol. 1999 Sep;72 ( Pt 3):385-96.
8. Nordal EJ et al. J Eur Acad Dermatol Venereol. 2011 Dec;25(12):1440-3.