Key points

Introduction

Like many autoimmune diseases, vitiligo pathogenesis is influenced by genetic, stochastic, and environmental factors. This is clear from the fact that first-degree relatives of patients with vitiligo have a 5-fold to 6-fold increased risk of disease and identical twins have a 23-fold increased risk, clearly implicating genetics as an important risk factor for vitiligo. However, despite sharing almost all of their genes, identical twins are only 23% concordant for disease, meaning that if one has vitiligo the other will have it only 23% of the time. This clearly implicates other, nonheritable risk factors for developing vitiligo as well. Stochastic mechanisms, or the influence of random chance, likely play a role, particularly during the development of the immune system, which occurs through random recombination of T-cell receptors and antibodies. This process is responsible for “building” the autoreactive cells that ultimately attack melanocytes in vitiligo. The role of stochastic factors in developing vitiligo and other autoimmune diseases is not likely to account for all of the nongenetic risk, and so many believe that factors from the environment strongly influence the likelihood of developing autoimmunity.

Vitiligo is one of the few autoimmune diseases in which environmental factors are well-known, including the depigmenting effect of the chemical monobenzyl ether of hydroquinone (MBEH) discovered by Oliver and colleagues in a tanning factory, but includes many others as well. Some have been directly implicated via topical challenge through patch testing, others through large population studies, and still others more indirectly. This article summarizes the chemicals that have been clearly implicated as causing or exacerbating vitiligo, as well as the mechanism by which this occurs. Recognizing these chemicals and their implications for managing vitiligo is important during patient counseling and follow-up, both when thinking about disease prevention, as well as improving therapeutic responses.

Introduction

Like many autoimmune diseases, vitiligo pathogenesis is influenced by genetic, stochastic, and environmental factors. This is clear from the fact that first-degree relatives of patients with vitiligo have a 5-fold to 6-fold increased risk of disease and identical twins have a 23-fold increased risk, clearly implicating genetics as an important risk factor for vitiligo. However, despite sharing almost all of their genes, identical twins are only 23% concordant for disease, meaning that if one has vitiligo the other will have it only 23% of the time. This clearly implicates other, nonheritable risk factors for developing vitiligo as well. Stochastic mechanisms, or the influence of random chance, likely play a role, particularly during the development of the immune system, which occurs through random recombination of T-cell receptors and antibodies. This process is responsible for “building” the autoreactive cells that ultimately attack melanocytes in vitiligo. The role of stochastic factors in developing vitiligo and other autoimmune diseases is not likely to account for all of the nongenetic risk, and so many believe that factors from the environment strongly influence the likelihood of developing autoimmunity.

Vitiligo is one of the few autoimmune diseases in which environmental factors are well-known, including the depigmenting effect of the chemical monobenzyl ether of hydroquinone (MBEH) discovered by Oliver and colleagues in a tanning factory, but includes many others as well. Some have been directly implicated via topical challenge through patch testing, others through large population studies, and still others more indirectly. This article summarizes the chemicals that have been clearly implicated as causing or exacerbating vitiligo, as well as the mechanism by which this occurs. Recognizing these chemicals and their implications for managing vitiligo is important during patient counseling and follow-up, both when thinking about disease prevention, as well as improving therapeutic responses.

Chemicals directly implicated in inducing vitiligo

Dyes

Taylor and colleagues first reported the ability of hair dyes and, specifically, para-phenylenediamine (PPD) to induce depigmentation. They described 4 subjects who developed depigmentation of the scalp and hair after using hair dyes, and found that 3 of the subjects exhibited depigmentation following patch testing (2 with PPD and 1 with the hair dye itself). Three of the subjects at least partially repigmented after discontinuing use of the dyes. Other cases implicating PPD in hair dyes have been reported as well, although not all cases confirmed depigmentation through patch testing. One group published a case series of 3 subjects who developed depigmentation of the scalp that abruptly stopped at the hair line, but was independent from hair dye use. They postulated that scalp depigmentation alone did not necessarily implicate the use of hair dyes as causative. Patients may develop hair dye–induced depigmentation on the scalp or face, depending on the site of application ( Fig. 1 A, B ).

( A ) Man who used hair dyes and developed scalp depigmentation at the hairline. ( B ) Man with depigmentation on the face after treating his goatee with a comb-in dye. ( C ) Depigmentation of the feet in the distribution of sandal straps.

( Courtesy of [ A ] William James, MD, Philadelphia, PA; [ B ] Pearl E. Grimes, MD, Los Angeles, CA; and [ C ] Inbal Braunstein, MD, Baltimore, MD.)

Alta is a red dye solution used in India as a cosmetic coloring agent for the feet. The dye has been reported to induce vitiligo at the location of application, and patch testing in 1 subject implicated the dye components Crocein Scarlet MOO, or brilliant crocein, and rhodamine B, or tetraethyl rhodamine. Depigmentation was preceded by contact dermatitis in this subject, and she also developed remote depigmentation on the hands. Negative results were observed in more than 20 controls who were also patch tested with the dyes. The subject also developed a similar reaction to PPD, thought to be a well-known cross-reaction between the chemicals, as the alta contained no trace of PPD. All sites depigmented approximately 6 weeks after application of the patch tests, and repigmented after 6 months. Some have reported that depigmentation occurred following direct exposure to dyes in leather products and other clothing when in close contact with the skin, such as shoes, wallets, and sandals ( Fig. 1 C).

Products indirectly implicated in vitiligo induction through population-based studies

The critical importance of commercial products in the induction of vitiligo became evident in the summer of 2013 when Kanebo, a Japanese cosmetics company, was forced to recall a new skin-lightening cream after more than 16,000 users developed vitiligo (∼2% of all users). The active ingredient was rhododendrol. A large retrospective analysis of users revealed that most experienced depigmentation only at the site of exposure to the cream; however, a small percentage (5%) experienced depigmentation at remote sites as well. Data acquired through questionnaires of affected individuals reported that following discontinuation of the cream, 7% of lesions had completely resolved, 27% had improved by more than half, 38% were improved by less than half, 25% were unchanged, and 2% had increased in size (1% could not be determined). Many patients (67%) improved even without therapy, whereas slightly more (77%) reported improvement when treated with standard therapies for vitiligo. Lesions induced by rhododendrol were mostly indistinguishable from vitiligo clinically and histologically, although 1 report suggested that melanocytes were largely reduced in number but not always completely absent in chemical-induced lesions. Some affected users developed eczematous reactions after using the cosmetic, and 14% reacted to rhododendrol patch testing with pruritus and erythema, although the number of those who depigmented at the location of the patch has not been reported.

A large, prospective population-based study reported that the use of hair dyes increased the risk of developing vitiligo. This group queried a database from the Nurses Health Study, established in 1976, in which a cohort of more than 68,000 participants provided information on their health conditions and exposures on a yearly basis. The study had a more than 90% response rate to biennial questionnaires, and validated accurate reporting of the incidence of vitiligo. The investigators found that women who started using hair dyes before the age of 30 and those who used hair dyes for more than 5 years (regardless of the starting age) had a 50% higher risk of developing vitiligo. This used an unbiased approach in a large cohort to support earlier case studies that implicated hair dyes in causing vitiligo. One caveat of the study was that it could not rule out an association between early hair graying and vitiligo, which has been reported previously, as the causative factor in the use of hair dyes at a young age.

Household products thought to induce vitiligo

A variety of common household products have been reported to induce and/or worsen vitiligo in patients; however, the offending chemical ingredients have not necessarily been identified. This has resulted in numerous lawsuits against the manufacturers, but no option for making safer products or educating patients about which ingredients to avoid. Phenol was used as the first surgical antiseptic by Joseph Lister in 1865. Because it is inexpensive, water-soluble, mildly acidic, and highly reactive, phenol derivatives are used to produce a wide variety of common household products, including disinfectants, cosmetics, diaper creams, detergents, cosmetic dyes, adhesives, pharmaceutical drugs, and others. According to a search of the Household Products Database (US Department of Health and Human Services), 44 unique phenols are used as ingredients in more than 8400 household products sold by 81 distinct manufacturers.

Outside of patch testing a specific suspected chemical, as described previously, it is difficult, if not impossible, to definitively implicate a product as a causative initiator of vitiligo, because there are currently no ways to distinguish this from spontaneous or idiopathic vitiligo. Thus, causation by a commercial product can be strongly inferred only based on patient history, physical examination, exposures, and knowledge about the chemical content of suspected products. Ghosh and Mukhopadhyay reported the largest study of the role of exposures in patients with vitiligo. They extensively interviewed all patients with vitiligo over a 5-year period and identified 864 cases in which they strongly suspected chemically induced disease. They reported that of these cases, 66% were thought to be initiated by the exposure, whereas 34% had preexisting vitiligo that was thought to be exacerbated by use of the product. Depigmentation was limited to the site of exposure in 74%, whereas 26% developed lesions remote from the site of contact. Although pruritus was present in 22% of cases, only a minority (5%) had evidence of contact dermatitis through an eczematous eruption at the site of contact and depigmentation. Hair dye was the most commonly implicated product (27%), and this was presumably due to PPD. Other products contained 4-TBP, MBEH, and Azo dyes, previously implicated by patch testing in other studies (see earlier in this article). The investigators reported that a better response to therapy was observed in patients with depigmentation localized to the site of chemical contact (de novo vitiligo) than those with preexisting vitiligo, suggesting that identifying and eliminating the chemical improved treatment responses.

Interestingly, the investigators noted the presence of “confetti macules” in most (89%) of their suspected patients with chemical-induced vitiligo, and suggested their presence as a distinct sign of chemical-induced vitiligo. This had previously been described by Ortonne and colleagues as well. However, the presence of confetti-like depigmentation was recently reported to be a clinical sign of highly active vitiligo. I have personally observed these macules to be widely distributed in patients with rapidly progressing disease, in areas distinct from exposure to chemicals or products (Harris JE, personal observations, 2016). Thus, I suspect that confetti macules are not necessarily indicative of chemical-induced vitiligo, but rather that chemical-induced vitiligo is often rapidly progressing, which is why it may be marked by the presence of confetti macules.

Other products reported to have induced vitiligo through case reports and case studies are prevalent in the literature, and include condoms, colored strings, herbal oils, detergents, footwear, hair color, dental acrylics, nylon thread, Vick’s Vaporub, compounded phenol-containing cream, a methylphenidate patch, electrocardiogram pads, synthetic leather wallets, ornamental Azo dyes, cinnamon toothpaste, eye drops, rubber, and “black henna” tattoos (although the reaction was likely due to PPD in the product, as black henna is not actual henna, which is orange or red). All of these reported cases occurred through topical exposures, which theoretically deliver a high concentration of the chemical to melanoyctes in their epidermal niche. It is unknown whether systemic exposures to similar agents (through diet, medications, or supplements) could result in a similar effect. If so, it could have serious implications for individuals who use future “skin-whitening candy” or other supplements, which appear to contain phenols. One study found that intramuscular injection of 4-TBP in black rabbits and dogs caused depigmentation, whereas there are conflicting reports of depigmentation after feeding MBEH to guinea pigs.