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Clinical Updates

Depigmentation Therapy for Vitiligo

Tiffany Mayo, Amit G. Pandya, MD

Wednesday, January 18, 2012

Most patients with vitiligo desire repigmentation of the affected areas. Several treatments are available, including topical corticosteroids and phototherapy; however, these are mostly helpful for patients with small lesions of short duration. Patients with more extensive, long-standing lesions may have too much involvement for these treatments to be practical. As the outlook for significant repigmentation is poor in these individuals, depigmentation therapy may be chosen to remove the remaining pigment, eliminate the spottiness of the skin, and present an even appearance. In general, more than 50% depigmentation must be present on a body area in order for depigmentation therapy to be feasible. In this article, we discuss the use, mechanisms of action and side effects of several depigmentation therapies in patients with vitiligo.

Monobenzylether of Hydroquinone

Monobenzylether of hydroquinone (MBEH) has been the most commonly used depigmentation therapy in vitiligo treatment for over half a century. It is currently the only drug approved by the Food and Drug Administration (FDA) for depigmentation in the US.1 Its depigmentation properties were discovered incidentally when tannery workers reported the appearance of white patches on their arms and forearms. Patch testing revealed the causative agent to be Agerite Alba, an impure form of MBEH found in rubber gloves.2 Following this discovery, MBEH was found to improve many conditions of hyperpigmentation, such as melasma, post-inflammatory hyperpigmentation, nevi, and ephelides, and was even thought to be a "miracle cure" for these disorders.3,4 However, side effects such as irritation, depigmentation at distant sites, and dyschromia soon emerged.5 Hydroquinone - a molecule similar to MBEH - was introduced into the clinical setting after the side effects of MBEH surfaced. It was shown to be an effective treatment for hyperpigmentation without the risk of permanent depigmentation.6 Subsequently, the use of MBEH has been limited to only those who desire permanent depigmentation.5

The depigmentation success rate of MBEH is over 60%.5 Therapy involves twice daily application of MBEH cream and results in a progressive lightening of the skin (Figures 1 and 2). Full depigmentation may require 4-12 months of therapy and generally takes longer in those with darker skin.1,5

 

Figure 1. Left cheek of a patient with extensive vitiligo who desired depigmentation therapy.


Figure 2. Left cheek of the same patient seen in Figure 1 after 3 months of twice-daily topical monobenzylether of hydroquinone; the patient also used sunscreens and practiced sun avoidance.

Mechanism of Action

The mechanism of action of MBEH is not fully understood, but initial studies theorized that MBEH is converted to hydroquinone in the skin, thereby preventing melanin formation.7 Recently, it has been shown that MBEH induces necrosis of non-follicular human melanocytes, which probably accounts for the ability of MBEH to produce permanent depigmentation.8 So far, no studies have compared the degree of depigmentation seen with MBEH on different skin types, but melanin and tyrosinase have been identified as key factors affecting depigmentation. Correlative studies between melanin concentration and melanocyte viability after exposure to MBEH show that, as the concentration of melanin increases, less melanocyte death occurs.8 If melanin is protective against MBEH-induced cell death, this could explain the reduced MBEH-induced depigmentation response in patients with darker skin.

Conversely, other studies propose that tyrosinase is the enzyme responsible for MBEH-induced depigmentation by causing covalent interactions that consequently inactivate the melanin-producing enzyme.9 This would suggest a greater response in darker skin; however, it has been shown that there is little variation in the amount of tyrosinase protein among different skin types. The melanin content varies owing to the higher activity of tyrosinase in darker complexions, a result of tyrosinase-related protein-1.10

Side Effects

The most frequent side effect of MBEH in the treatment of vitiligo is irritant contact dermatitis in pigmented areas of skin.11 13% of patients using MBEH experience contact dermatitis, with reactions ranging from mild erythema to painful vesicular eruptions.5,12 Conjunctival melanosis has also been observed in some patients undergoing MBEH therapy.13 Although depigmentation is permanent in most cases, spontaneous and partial repigmentation can occur within weeks to years after discontinuation of therapy.5,14 Exposure to ultraviolet light is the major reason for repigmentation and often results in a freckle-like pigmentation appearing in areas of previously depigmented skin owing to residual melanocytes in follicles. Patients must be instructed to use sunscreens and practice sun avoidance during and after MBEH use in order to prevent this from occurring.

Other Depigmentation Agents

Although MBEH is the only FDA-approved therapy for depigmentation in the US, alternative depigmentation therapies being studied include other phenol derivatives, laser therapy, and cryotherapy.

Mequinol is a phenol derivative thought to produce similar results to MBEH but with a slower onset of depigmentation.15 Mequinol therapy is currently used in The Netherlands, where the use of MBEH has been restricted.

For rapid and selective depigmentation, laser therapy using a Q-switched ruby laser has also been studied. Pain was reported as the major side effect, and follicular depigmentation developed in some patients.16

Finally, cryotherapy has recently been introduced as a cost-effective method for depigmentation of pigmented macules in vitiligo, but lentigo-like macules developed in sun-exposed areas of some participants after treatment.17 Combination therapy has also been studied; however, none of these methods has been adopted as a mainstream therapy for depigmentation in patients with vitiligo.15,18

The desperation for treatment causes many patients suffering from vitiligo to consider potentially harmful products marketed as skin whiteners. For example, glutathione is marked as a skin whitener in some countries such as the Philippines; however, the Philippine government recently released a public warning on the harmful effects of glutathione, including fatal skin rashes, thyroid dysfunction, and potential kidney failure.19 Patients are often willing to purchase costly but ineffective products in an attempt to improve the spotty appearance of vitiligo. 97% of participants in one study reported that they would give an entire year's salary in search of a cure.20 It is important to discuss the ineffectiveness of many costly products and the potential harmful side effects of over-the-counter products with patients. 

Other Considerations

The goal for depigmentation therapy is to obtain an even skin appearance; however, it is important to consider the possible disadvantages of permanent depigmentation. One such disadvantage is the possibility of a vitiligo cure being found in the future. Major discoveries have recently been made in the genetic causes and pathogenesis of vitiligo, which might lead to breakthroughs in future treatment options. Permanent depigmentation may not allow a patient to take advantage of such future therapies. This is especially important for younger patients. Additionally, the social effects of vitiligo are psychologically and emotionally distressing; however, depigmentation therapy in patients with darker skin types can result in exacerbation of social and cultural misunderstanding, as in the case of the African-American pop superstar Michael Jackson, who sought out permanent depigmentation of his skin.

Conclusions

Repigmentation is the optimal target for patients with vitiligo; however, depigmentation therapy is the only current treatment option for patients with severe, universal vitiligo. Research into various depigmentation methods such as cryotherapy, laser therapy, and combination therapy are on the horizon, but MBEH currently remains the mainstay therapy for depigmentation in patients with vitiligo.

References

  1. Bolognia JL, Lapia K, Somma S. Depigmentation therapy. Dermatol Ther. 2001;14:29-34.
  2. Oliver EA, Schwartz L, Warren LH. Occupational leukoderma. Arch Dermatol & Syphil. 1940;42:993-1014.
  3. Pollock JH. Hyperpigmentation improved by treatment with monobenzylether of hydroquinone. Arch Dermatol & Syphil.  1950;61:873-875.
  4. Lerner AB, Fitzpatrick TB. Treatment of melanin hyperpigmentation. JAMA. 1953;152:577-582.
  5. Mosher DB, Parrish JA, Fitzpatrick TB. Monobenzylether of hydroquinone. Br J Dermatol. 1977;97:669-679.
  6. Spencer MC. Hydroquinone bleaching. Arch Dermatol.  1961;84:181-184.
  7. Denton CR, Lerner AB, Fitzpatrick TB. Inhibition of melanin formation by chemical agents. J Invest Dermatol.  1952;18:119-135.
  8. Hariharan V, Klarquist J, Reust M, et al. Monobenzylether of hydroquinone and 4-tertiary butyl phenol activate markedly different physiologic responses in melanocytes: relevance to skin depigmentation. J Invest Dermatol. 2010;130:211-220.
  9. van Den Born JG, Picavet DI, van Swieten PF, et al. Skin-depigmenting agent monobenzone induces potent t-cell autoimmunity toward pigmented cells by tyrosinase haptenation and melanosome autophagy. J Invest Dermatol.  2011;131:1240-1251.
  10. Alaluf S, Barrett K, Blout M, Carter N. Ethnic variation in tyrosinase and TYRP1 expression in photoexposed and photoprotected human skin. Pigment Cell Res. 2003;16: 35-42.
  11. Nordlund JJ, Forge B, Kirkwood J, Lerner A. Dermatitis produced by application of monobenzone in patients with active vitiligo. Arch Dermatol. 1985;121:1141-1144.
  12. Lyon CC, Beck, MH. Contact hypersensitivity to monobenzyl ether of hydroquinone used to treat vitiligo. Contact Dermatitis 1998;39:132-133.
  13. Hedges TR 3rd, Kenyon KR, Hanninen LA, Mosher DB. Corneal and conjunctival effects of monobenzone in patients with vitiligo. Arch Ophthalmol. 1983;101:64-68.
  14. Oakley AM. Rapid repigmentation after depigmentation therapy: vitiligo treated with monobenzylether of hydroquinone. Australas J Dermatol. 1996;37;96-98.
  15. Njoo MD, Vodegel RM, Westerhof W. Depigmentation therapy in vitiligo universalis with topical 4-methoxyphenol and the Q-switched ruby laser. J Am Acad Dermatol 2000;42:760-769.
  16. Thissen M, Westerhof W. Laser treatment for further depigmentation in vitiligo. Int J Dermatol. 1997;36:386-388.
  17. Radmanesh M. Depigmentation of the normally pigmented patches in universal vitiligo patients by cryotherapy. J Eur Acad Dermatol Venereol. 2000;14:149-152.
  18. Nuzzo SD, Masotti A. Depigmentation therapy in vitiligo universalis with cryotherapy and 4-hydroxyanisole. Clin Exp Dermatol. 2010;35;215-216.
  19. Lazo SH. "Safety of the off-label use of glutathione solution for injection (IV)." DOH-FDA Advisory, 2011. Republic of the Philippines Department of Health Food and Drug Administration, 2011. [Available from: www.doh.gov.ph/files/DOH-FDA%20Advisory%20No.%202011-004.pdf]
  20. Ongenae K, Dierckxsens L, Brochez L, et al. Quality of life and stigmatization profile in a cohort of vitiligo patients and effect on the use of camouflage. Dermatology. 2005;210:279-285.
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