Depigmentation therapies for normal skin in vitiligo universalis

Depigmentation therapies for normal skin in vitiligouniversalis †Dermatology Department and ‡Vitiligo Research Chair, College of Medicine, King Saud University, Riyadh, Saudi Arabia*Correspondence: K.M. AlGhamdi. E-mail: kmgderm@yahoo.com If vitiligo involves most of the body, it might be easier to depigment the normal remaining skin rather than to attempt repigmentation. We reviewed the literature to date regarding available therapies for depigmenting the normal skin in vitiligo universalis. Our review revealed that the threshold regarding what percentage of body surface area qualifies as depigmentation is variable among practitioners. Monobenzyl ether of hydroquinone (MBEH) is the most widely used depigmenting agent and has few side-effects. Tretinoin in combination with MBEH is able to speed depigmentation of the skin. Monomethylether of hydroquinone has also been used successfully for depigmentation.
Eighty-eight per cent phenol is also effective in depigmenting the skin but its application on large areas is toxic for liver and kidney. Different types of lasers are also available to destruct the melanocytes selectively, but this technique can be painful and expensive. Cryotherapy is a cheap depigmenting therapy but, because of scarring risk, it should only be used by experienced dermatologists. No trials have compared the efficacy of the above-mentioned well-established depigmentation agents ⁄ techniques. Certain drugs such as imatinib, imiquimod and diphencyprone, which are used to treat other diseases, caused depigmentation as a side-effect. Some depigmentation agents used for branding cattle can also serve as topical depigmentation agents. In conclusion, comparative clinical trials are needed to compare the efficacy of various depigmentation agents ⁄ techniques. In particular, topical imatinib, imiquimod and diphencyprone may be considered as potential depigmenting agents, which require further investigation. This review revealed that MBEH is safe and effective depigmenting agent.
Received: 5 April 2010; Accepted: 21 September 2010 Keywords88% phenol, cryotherapy, depigmentation therapies, diphencyprone, imatinib, imiquimod, lasers, monobenzyl etherof hydroquinone, monomethylether of hydroquinone patches are sensitive during sunburns and may impair cosmetic In mammals, melanin controls pigmentation in the skin and hair.1 appearance and psychosocial functions.8 The disorder is primarily Melanin biosynthesis is initiated from hydroxylation of tyrosine treated by several medical therapies but complete repigmentation to 3,4-dihydroxyphenylalanine (DOPA) through action of the enzyme tyrosinase in melanocytes. This enzyme continuously oxi- The emotional impact of this cosmetically disfiguring condition dizes DOPA to DOPA-quinone. Through a series of oxido-reduc- on patients and their families is severe.9 Depression (10%), sleep tion reactions, the darkest and insoluble 5,6-dihydroxyindole disturbances (20%), suicidal thoughts (10%), and anxiety (3.3%) have been observed in those affected with vitiligo.10 Vitiligo can The loss of skin pigmentation resulting from disappearance of also lead to difficulties in forming relationships and avoidance of pigment cells because of the application of chemicals or because of certain social situations.11 Vitiligo can be confused with leprosy, immunological and genetic factors (e.g., vitiligo) is called depig- which also causes loss of pigment, thus further stigmatizing mentation.4 Vitiligo is a common depigmentation disorder occur- patients.12 Therefore, patients with extensive and resistant vitiligo ring in about 1% of the world’s population but the prevalence has may benefit from depigmentation therapy, which is designed to been reported to be as high as 4% in some countries.5–7 The dis- remove the remaining pigment rather than to regain pigment in ease causes the appearance of white patches on the skin. These the vitiliginous skin.13 Vitiligo universalis patients themselves are Journal of the European Academy of Dermatology and Venereology ª 2010 European Academy of Dermatology and Venereology often embarrassed by the remaining normally pigmented patches Table 1 Established and potential depigmenting agents on their exposed areas and wish to be depigmented rather than Generally, depigmentation therapy can be considered if vitiligo affects more than 60% to 80% of the body. A recent survey, how- ever, showed variation among dermatologists, where 32% of derma- tologists were in favour of depigmentation when vitiligo affects more than 75% of the body while 42% dermatologists were infavour of depigmentation when vitiligo affects more than 50% ofthe body.14 Expert consensus recommends that patient selection is side-effects and lead to permanent removal of pigment.20 There important in depigmentation treatment. In general, depigmentation are several well-established as well as potential depigmenting is undertaken only when the patient has more than 50% pigment agents, and certain chemical agents used for branding cattle, that loss in their skin because of vitiligo, or when the depigmentation is can cause depigmentation as a side-effect (Table 1).
extensive in the cosmetically sensitive areas of the hands and face.
Depigmentation is not recommended for children.15 In patients with extensive areas of depigmentation and ⁄ or disfig- Monobenzyl ether of hydroquinone is the mainstay of depigmen- uring lesions on the face who do not respond to repigmentation tation therapy. It is also referred to as monobenzone or by its therapies (e.g., phototherapy), depigmentation can be useful chemical name, p-(benzyloxy) phenol.21 MBEH is a topical prod- because complete repigmentation may never occur even after long uct used for the treatment of pigmentary disorders22 such as periods of phototherapy.16 Sometimes subtotal repigmentation melasma,23 solar lentigines and pigmented nevus.24 Arndt and may be achieved after patients undergo 150–200 sessions of psora- Fitzpatrick applied MBEH (10–20%) to the normally pigmented len plus ultraviolet A (PUVA) therapy with or without adjuvant areas surrounding vitiligo lesions to induce complete skin depig- therapy but there is always a possibility of depigmentation after ces- mentation, to achieve uniform skin tone.25,26 Ultimately 90–95% sation of PUVA therapy.17 Therefore, complete depigmentation of patients were fully bleached after the application of 20% MBEH rather than repigmentation therapy is recommended by many cream.27 If vitiligo has been stable for years, a longer duration of investigators in case of vitiligo universalis.13,16 During and upon therapy and higher concentration of MBEH may be required. The completion of the depigmentation therapy, patients are perma- process of depigmentation requires twice daily application of nently at risk for acquiring sunburn. Patients should therefore be cream and allotment of time each day. In general, depigmentation advised to minimize sun exposure and to apply broad-spectrum of particular site can require 5–12 months of therapy. If depig- sunscreens because recurrence of the pigment is also observed mentation does not occur over the course of 3–4 months of appli- within a few weeks of discontinuing successful depigmentation cation of 20% MBEH then concentration of MBEH can be therapy on sun-exposed sites.13 Oakley reported that repigmenta- increased upto 40% but MBEH concentration greater than 40% is tion occurred within a few weeks of discontinuing successful depig- mentation therapy with monobenzyl ether of hydroquinone In an animal study, MBEH produced significant cutaneous (MBEH) in a patient with extensive vitiligo.18 Patients undertaking depigmentation of guinea pig skin28 and its oral administration to depigmentation therapy should be warned about repigmentation.19 laboratory animals induced visually recognizable hypomelanosis in We aimed to systematically review the published scientific liter- the hair.29 MBEH is known to interfere with melanocyte activ- ature regarding different depigmenting agents such as depigment- ity.24,26,29 Recently, Hariharan et al. reported that MBEH can ing creams, lasers, cryotherapy, and systemic drugs, to compare induce cell death because of disintegration of cellular membranes their advantages and disadvantages for treatment of vitiligo uni- and release of cellular contents, without activating the caspase cas- versalis. Moreover, we aim to shed light on additional potential cade or DNA fragmentation.30 Therefore, the death pathway is depigmentation agents. We searched databases including MED- non-apoptotic. Release of high mobility group box-1 protein by LINE ⁄ PubMed, Embase and Google Scholar for vitiligo, leucoder- MBEH-treated human melanocytes and ultra-structural features, ma, depigmentation therapies and vitiligo universalis. We found such as disruption of the plasma membrane and the nuclear mem- no controlled studies that compared the efficacy or safety of vari- brane, further confirmed a necrotic death pathway mediated by MBEH.30 Riley postulated that MBEH diffuses into melanosomesof pigment cells where the enzyme tyrosinase converts it to toxic species such as quinones, which react with essential cellular macro- The ideal depigmenting compound should have a potent, rapid molecules such as proteins and DNA and cause melanocyte and selective effect on melanocytes, carry no short- or long-term death.31–33 Depigmentation induced by MBEH is generally Journal of the European Academy of Dermatology and Venereology ª 2010 European Academy of Dermatology and Venereology Depigmentation therapies for vitiligo universalis irreversible and is associated histologically with loss of melano- tion, these melanocytes in comparison with epidermal melano- somes and, eventually, loss of melanocytes.34,35 cytes are less susceptible to the compound.32 In many institutions worldwide, depigmentation therapy consists of the application of a bleaching agent containing MBEH.26,36–38 Application of MBEH is reserved for induction of Mild burning or itching, irregular leucoderma and skin irritation complete depigmentation in severely affected vitiligo patients who were reported with 4-MP.46,54 Patients should be advised that pig- cannot or do not choose to repigment, as well as those who wish ment may return and protection from sunlight is necessary.13 All-trans retinoic acid (RA), a vitamin A derivative primarily utilized for the treatment of acne, is shown to serve as a weak This solution is inexpensive and applied topically for chemical depigmenting agent when used for several weeks.41 However, use peelings. Protein coagulation is observed in the epidermis immedi- of this drug in combination with MBEH resulted in depigmenting ately after application of 88% phenol solution.55 It can penetrate activity in black guinea pigs.22 This combination induced signifi- deep in to the tissue, down to upper reticular dermis.56 All phenol cant depigmentation within 4–8 weeks.42 Nair et al. proposed that compounds have toxicity towards melanocytes. Transient or defi- RA might enhance the skin penetration of depigmenting agents.43 nite hypo-pigmentation after application of phenol is due to the Thus, RA increases the susceptibility of melanocytes to hydroqui- development of a melanocytic incapacity to normally synthesize none and 4-hydroxyanisole through the impairment of glutathi- melanin.57 On the other hand, other depigmenting agents, such as hydroquinone and MBEH, destruct the melanocytes. It is reported reducing melanogenesis activity in viable melanocytes.45 that hydroquinone causes depigmentation because of decreasetyrosinase activity by 90% and reversible inhibition of cellular metabolism by affecting both DNA and RNA synthesis of melano- Although the use of MBEH may lead to a satisfying degree of cytes.58 Additionally, unlike hydroquinone, MBEH almost always depigmentation in most patients, some disadvantages such as skin causes a nearby irreversible depigmentation of skin. It has been irritation, contact dermatitis and ocular side-effects have also been suggested that the mechanism of depigmentation by MBEH reported.27,40,46 In addition, exogenous ochronosis is also reported involves selective melanocytic destruction through free radical for- as a potential complication after application of MBEH in many mation and competitive inhibition of the tyrosinase enzyme sys- cases.47,48 In some cases MBEH resistance17 and recurrence of the tem.59 Eighty-eight per cent phenol solutions can be considered as pigment were also observed18 because of intense sun exposure.49 a therapeutic option to eliminate residual normally pigmented Therefore, the use of MBEH has been restricted in the Nether- areas in patients with generalized vitiligo.
lands, since 1990.13 However, MBEH remains the only drug thatthe Food and Drug Administration, USA has approved for depig- mentation therapy of advanced vitiligo.50,51 Generally, 88% phenol solution does not produce any complica-tions in experienced hands. However, sometimes 88% phenol solution produces complications such as non-aesthetic scar forma- This compound is a phenol derivative and also known as tion, dyschromia and development of herpetic eczema. High-dose ‘p-hydroxyanisole’ or ‘monomethylether of hydroquinone’. The phenol usage is toxic, so it should not be applied over large compound has been shown to have melanocytotoxic properties areas.60 Phenol exerts marked corrosive action on any tissue it that are comparable with those of MBEH.31,52 The effectiveness of contacts when ingested, inhaled or brought into contact with the 4-methoxyphenol (MP) was significantly correlated with the dura- skin. Its cellular uptake is both rapid and passive because of its tion of use of the cream; the longer the cream was used, the better lipophilic character and signs of systemic toxicity develop soon the results.13 However, compared with MBEH cream, a disadvan- after exposure. Phenol’s main target organs are liver, kidney, respi- tage of 4-MP was the longer time prior to the onset of visible ratory and cardiovascular systems. Cardiovascular shock, cardiac depigmentation (between 4 and 12 months), whereas it was previ- arrhythmias and bradycardia, as well as metabolic acidosis have ously reported that depigmentation with MBEH may already be been reported within 6 h of skin peeling procedures with phenol.61 evident after 1 month.26 Recently, a combination product of 2% Re-pigmentation may occur if patients do not protect themselves 4-hydroxyanisole (Mequinol) and 0.01% tretinoin was tested in a double-blind multicentre study and was found to significantlyimprove solar lentigenes and related hyperpigmented lesions of the face and hands after a twice-daily application of up to Depigmentation with strong bleaching creams, such as MBEH or MP, is very effective but several side-effects were also reported.63 It Melanocytes in the hair follicles may also be affected by 4-MP usually takes 10 months or more for a complete loss of pigment in a dose-response fashion, but because of their deeper localiza- to occur, with the possibility of only partial depigmentation and Journal of the European Academy of Dermatology and Venereology ª 2010 European Academy of Dermatology and Venereology a relatively high failure rate,26 as it is reported that success rate of MBEH for depigmentation is 69%.26 It was also observed that The main disadvantage of this therapy is that sometimes local repigmentation on sun-exposed sites may also occur after com- anaesthesia is required because it may be painful to the patients.
plete depigmentation by MBEH.18 Unfortunately, in some cases, Therefore, this treatment is only possible in the clinic, rendering it permanent depigmentation is not achieved and irregular leuco- an expensive therapy.13 The QSR laser therapy may fail in perma- derma and severe irritation of the skin have been reported.46 The nently removing pigmented patches and after several months of laser apparatus is another form of depigmenting therapy for treatment both epidermal repigmentation and an increased num- vitiligo.63 Depigmentation therapy using lasers can be applied in ber of dermal macrophages have been observed.71,74 cases where patients do not respond well to the depigmentationcream or in areas, especially the face, where rapid depigmentation Cryotherapy is suitable for very small lesions and cannot be utilized Lasers have proven to be highly effective in selectively targeting if the surface area of pigmented lesions is more than a few centime- melanocytes for destruction, thus causing depigmentation. The tres.22 Cryotherapy has been suggested to depigment MBEH-resis- Q-switched ruby (QSR, 694 nm) and alexandrite (755 nm) lasers tant skin.17 Cryosurgery is melanocytotoxic and can easily kill are known to induce selective photothermolysis of pigmented melanocytes.75 Cryosurgery was used to remove normally pig- lesions because their wavelengths are between 600 nm and 800 nm, mented patches in patients with universal vitiligo.17,75 The melano- which are absorbed more easily by melanin than by haemoglobin.64 cytes in non-segmental vitiligo are particularly prone to Light emitted by both lasers is well absorbed by melanin.65 mechanical and thermal destruction due to isomorphic Koebner The QSR laser selectively targets melanosomes and destroys phenomenon, whereby local trauma to the skin (e.g. rubbing) can melanocytes and keratinocytes.66 Because of the QSR laser effects, induce depigmented patches. Although Koebner phenomenon is the more tan skin is, the more therapeutic the effects become.
more pronounced in progressive rather than stable vitiligo but still Tanning can induce activation of melanocytes in normal pig- the melanocytes in stable vitiligo are much more vulnerable to mented areas and these activated melanocytes are the target of thermal and mechanical damage than melanocytes in normal indi- selective photothermolysis performed with pigment-specific lasers.
viduals.17,75 As cryotherapy is commonly performed utilizing Therefore, QSR laser therapy after tanning can induce permanent liquid nitrogen, which is the most effective cryogen for clinical use.
damage in activated melanocyte-containing structures.67 There are Irreversible damage in treated tissue occurs because of intracellular many advantages to depigmentation therapy with QSR laser: the ice formation.76 Therefore, melanocytes are more sensitive to cryo- therapeutic effects are fast and safe; the duration of treatment is damage in comparison with other cutaneous cell components such short; and the area to be depigmented can be large, as compared as keratinocytes, fibroblasts and endothelial cells.75 The degree of with depigmentation performed using a bleaching agent.16,63,68 An damage depends on the rate of cooling and minimum temperature additional advantage of the QSR laser is that its beam reduces the achieved. Inflammation develops during the 24 h after treatment, further contributing to destruction of lesion through immunologi- The Q-switched alexandrite (QSA) laser has shown efficacy in cally mediated mechanisms.76 Mild freezing leads to a dermoepi- treating both naturally occurring pigmented lesions and exogenous dermal separation, which is useful in treating epidermal lesions.
pigment.69,70 The QSA therapy is safe, simple and effective in Cryotherapy has numerous advantages over other modalities.
treating recalcitrant pigmentation after depigmentation therapy in Preparation time is short and treatment requires no other expen- vitiligo patients. The QSA laser is advantageous over the QSR laser sive supplies or injectable anaesthesia. In addition, the risk of because it has a faster pulse frequency, which allows for more infection is low and wound care is minimal.77 This technique is rapid therapy. In addition, it also has a higher wavelength of used to remove many melanocytic lesions including simple or 755 nm, as compared with the 694 nm QSR laser, which facilitates solar lentigines, junctional nevi and cafe´-au-lait spots without greater tissue penetration and improves results.71 causing permanent damage to other cell structures or scarring in Other potential Q-switched lasers that can selectively destruct melanocytes include neodymium:yttrium aluminium garnet This method is simple, easy to perform, safe, efficacious and (Nd:YAG) laser (1064 nm) and the frequency-doubled Nd:YAG cost effective.78 Therefore, it may be superior to other medical and laser (532 nm).72 Anderson and Parrish postulated that selective surgical methods. Depigmentation developed by cryotherapy is photothermolysis could be predicted by choosing appropriate permanent, not scar forming, if performed by experienced derma- wavelength, pulse duration and pulse energy for a particular tar- tologists. The technique yields excellent cosmetic results.17 get.66 Melanin absorbs light of shorter wavelengths more efficientlywithin the range from 250 nm to 1200 nm.73 Therefore, melanin can be selectively destroyed by 532 nm wavelengths because this If cryotherapy is performed aggressively, it can lead to permanent wavelength is strongly absorbed by melanin resulting destruction scarring.79 Cryotherapy should be used by experienced person of melanocytes, thus causing depigmentation.
Journal of the European Academy of Dermatology and Venereology ª 2010 European Academy of Dermatology and Venereology Depigmentation therapies for vitiligo universalis involving the myeloid differentiation factor 88-dependent path-way, upregulation of nuclear factor-jB and protein kinases. These signals evoke the T-helper (Th)1 response and increase production Imatinib is used for the treatment of leukaemia. Vitiligo-like of pro-inflammatory cytokines, mainly IFN-a, TNF-a and IL-12, depigmentation of the skin was observed as a side-effect of treat- all of which play a role in the pathogenesis of vitiligo. In addition, ment with this drug in several patients with chronic myeloid imiquimod promotes secretion of IL-6, IL-8 and IL-10, which are leukaemia (CML). Skin hypo-pigmentation was noted in five pro-inflammatory and pro-apoptosis cytokines that can cause viti- patients with CML who were treated with imatinib mesylate.80 ligo.95 Imiquimod augments the type 1 helper T-cell (TH1) Imatinib mesylate is a tyrosine kinase inhibitor and selectively inhi- response via the stimulation of these cytokines, which is found to bits the constitutive activity of this enzyme, resulting in decreased be prominent in both the antitumour pathways and the pathogen- pigmentation of the skin. After patients begin receiving imatinib esis of vitiligo.96–98 In promoting the regression and clearance of mesylate, hypo-pigmentation can be observed within 12 weeks.81 BCC, imiquimod can also induce changes that enhance the pro-pensity towards apoptotic mechanisms by decreasing Bcl-2 expres- sion, stimulating inflammatory infiltrate to the surrounding area The side-effects of imatinib mesylate (Table 3) are periorbital and increasing expression of FasR on BCC cells.99,100 oedema, fluid retention, diarrhoea and myelosuppression.82 In However, it is known that Bcl-2 is an antiapoptotic protein that addition, a number of dermatological side-effects have been docu- protects cell viability without promoting proliferation. In normal mented, such as follicular mucinosis, erythroderma and lichenoid epidermis, Bcl-2 expression is confined to the basal cell compart- eruption. Imatinib mesylate can also induce local or generalized ment and may serve to protect these cells from apoptosis.101 On the contrary, Bcl-2 protein expression and the apoptotic indexwere gradually modified during the course of the treatment with imiquimod because of many factors: a decrease of the antiapoptot- Imiquimod (1-(2-methylpropyl)-1H-imidzo[4,5-c]quinolin-4- ic factors (Bcl-2) and ⁄ or an increase in the proapoptotic stimulus amine), a low molecular weight imidazoquinolinamines, has [cytotoxic T lymphocytes, natural cytotoxic T cells ⁄ killer cells, potent antiviral and antitumour properties and approved from granzymes B, Fas, tumour necrosis factor (TNF), Bax, etc.].102 Food and Drug Administration, USA84 for the topical treatment Schon et al. also reported that imiquimod induced apoptosis in of external anogenital warts caused by human papillomavirus squamous cell carcinoma cell lines and HaCaT cells because of the (HPV) and for the skin cancers such as superficial basal cell car- activation of several caspases and Bcl-2-dependent cytosolic trans- cinoma (BCC) and actinic keratosis in a 5% cream (Aldara) for- location of cytochrome c from the mitochondria into the cyto- mulation85 but during treatment permanent postinflammatory plasm and subsequent cell death.103 Therefore, BCC cells become hypo-pigmentation has been reported as a side-effect.86 Imiqui- more susceptible to apoptosis through decreased Bcl-2 expression mod is an immune response modifier and acts on the immune system by stimulating monocytes ⁄ macrophages and plasmacy- In a recent study, Kim et al. also reported about development toid dendritic cells in the epidermis and dermis to produce of vitiligo-like hypo-pigmentary lesions after topical application of interferon-a and other immunostimulatory cytokines that stim- imiquimod because of the activation of caspase-3, Bcl-2 and mito- ulate cell-mediated immunity87 such as macrophages and the gen-activated protein kinase expression in melanocytes, i.e., initia- release of oxygen-reactive intermediates and other toxic mole- tion of apoptotic activity.104 Therefore, these results might cules, finally leading to apoptosis of tumour cells.88 Topical indicate that imiquimod can induce apoptosis of melanocytes, imiquimod has been found to be effective for clearing superficial which will result in the loss of pigment cells.104 Thus, imiquimod BCC in 85% of cases when used 3–5 times weekly for 6 weeks,89 represents a potential depigmenting agent (Tables 1 and 2).
and many studies have demonstrated that this regimen provides88% histological clearance rate.84,90,91 Therefore, prolonged use of imiquimod may lead to increased occurrences of localized The most common side-effects of imiquimod (Table 3) are burn- ing, itching, pain at the target site, local skin reactions (i.e. ery- Imiquimod stimulates CD8 cells to become cytotoxic and thema, erosion and scabbing ⁄ crusting)105 and hypo-pigmentation, induces maturation of Langerhans cells leading to enhancement of which occur more frequently with twice-daily application.86 antigen presentation.93 Similarly, vitiligo may be mediated throughantigen presentation by activated Langerhans cells with resultant destruction of melanocytes by cytotoxic T lymphocytes directed to Diphencyprone or diphenylcyclopropenone (DPCP) is used to melanocytes surface antigens,94 thus, causing depigmentation.
treat dermatological conditions resulting from an altered immu- Imiquimod binds to Toll-like receptors (TLR) 7 and 8, which nological state, such as extensive alopecia areata (AA). AA has are cell-surface receptors. TLR7 activates a signalling cascade been treated with DPCP since 1976 without serious adverse Journal of the European Academy of Dermatology and Venereology ª 2010 European Academy of Dermatology and Venereology Table 2 Comparison of established agents for depigmentation of normal skin in vitiligo universalis MBEH, monobenzyl ether of hydroquinone.
Table 3 Comparison of potential depigmenting agents for depigmenting the normal skin in vitiligo universalis blistering, regionallymphadenopathy andcontact urticaria events, except for the induction of hypo- or depigmentation.106 As above explained, all three drugs are either toxic and ⁄ or DPCP-induced vitiligo is rare and may represent a Koebner expensive. Eligibility criteria for these drugs are not clear. There- phenomenon in predisposed individuals.107 The initial depig- fore, we suggest further research to investigate topical formulation mented patch usually arises at the site of DPCP application.
of these agents as possible depigmenting therapies.
Electron microscopic studies have confirmed that the depig-mentation is not postinflammatory, evidence which supports the Potential agents for depigmentation used for isomorphic phenomenon.108 It has been reported that patients can develop vitiligo even which DPCP concentrations as low as Denton et al. identified compounds that had depigmenting prop- erties for branding cattle.29 Subsequently, several depigmentingcompounds have been experimentally discovered and tested in laboratory animals for branding purposes, without painful side- Adverse effects include (Table 3) local eczema with blistering, effects during or after application.110 In one study, eight com- regional lymphadenopathy, hyper-pigmentation, hypo-pigmenta- pounds were selected on the basis of their known depigmenting effects, including: hydroquinone (H), 4-ethoxyphenol (4-EP), Journal of the European Academy of Dermatology and Venereology ª 2010 European Academy of Dermatology and Venereology Depigmentation therapies for vitiligo universalis 4-methylcatechol (4-MC), 4-tert-butylcatechol (4-t-BC), 4-meth- review, we also proposed few potential depigmentation agents for oxyphenol (4-MP), monobenzone (M), hydroquinone bis (2-hy- further research (Table 3) such as Imatinib, Imiquimod and Diph- droxyethyl)-ether (HHEE) and catechol (C). These compounds encyprone. These agents were used for curing some other diseases were injected into animal skin as 10% and 20% solutions dissolved but as side-effects they caused depigmentation on the skin. We in 95% ethanol. Six of the eight compounds tested showed posi- propose that these agents and some depigmentation agents used tive depigmenting effects at 10% except C and HHEE.111 These for branding cattle to be investigated as topical potential depig- results also revealed that compounds screened at concentrations of menting agents. In addition, this review has revealed that MBEH 10% were superior to those injected at 20% because of their ability is the most safe and effective depigmenting agent.
to produce a depigmenting effect with minimal necrosis.111 Both 4-MC and 4-MP were also applied topically in a cream (liposome) base onto the same animal previously used to screen The authors would like to thank Dr Davinder Parsad for eight compounds at 10% according to the technique that has been kindly critically reviewing the manuscript.
previously described by Bangham et al. for incorporating thesecompounds into a liposome base.112 This liposome preparations were applied in a rub-in form on the same animal after it had 1 Wick MM, Hearing VJ, Rorsman H. Biochemistry of melanization. In been clipped and swabbed as described previously. A stencil held Fitzpatrick TB, Eisen AZ, Wolff K, Freedberg IM, Austen KF, eds.
Dermatology in General Medicine, Vol. 1. McGraw-Hill, New York, tightly against the skin was used as a guide in which 0.5 mL of preparation was rubbed into the skin with a cotton swab until all 2 Hearubg VJ, Jimenez M. Analysis of mammalian pigmentation at the the material had been absorbed. The cream base was applied alone molecular level. Pigment Cell Res 1989; 2: 75–85.
in the same manner beneath the treatment site to serve as a con- 3 Luo LH, Kim HJ, Nguyen DH et al. Depigmentation of melanocytes by (2Z, 8Z)-Matricaria acid methyl ester isolated from Erigeron brevi- trol. At the end of the experiment, it was observed that there was scapus. Biol Pharm Bull 2009; 32: 1091–1094.
no visible depigmentation of the epidermis as result of topical 4 Mishima Y, Kawasaki H, Pincus H. Dendritic cell dynamics in pro- application of compounds, possibly because an inadequate gressive depimentations. Distinctive cytokinetics of a-dendritic cellsrevealed by electron microscopy. Arch Dermatol Forsch 1972; 243: 67– amount of compounds was absorbed into the skin. Shafer-Korting et al. also explained about the lack of penetration of drugs into the 5 Whitton ME, Ashcroft DM, Barrett CW, Gonzalez U. Interventions for skin due to failure of the drug to penetrate the horny layer of the vitiligo [systematic review]. Cochrane Database Syst Rev 2007.
skin and low absorption rates due to drugs remaining in the lipo- 6 Parsad D, Pandhi R, Juneja A. Effectiveness of oral Ginkgo bilobain treating limited, slowly spreading vitiligo. Clin Exp Dermatol 2003; 28: Certain of these compounds should be further investigated as 7 Sehgal VN, Srivastava G. Vitiligo: compendium of clinico-epidemilogi- topical depigmenting agents for use in humans with vitiligo uni- cal features. Indian J Dermatol Venereol Leprol 2007; 73: 149–156.
8 Nordlund JJ, Ortonne JP. Vitiligo vulgaris. In Nordlund JJ, Biossy RE, Hearing VJ, King RA, Ortonne JP, eds. The Pigmentary System: Physi-ology and Pathophysiology. Oxford University Press, New York, 1998: Inflammation was observed at both 10% and 20% concentrations 9 Porter J, Beuf A, Nordlund JJ, Lerner AB. Personal response of for the 4-MC, 4-MP and M. Substantial dermal necrosis was patients to chronic skin disease. A study of patients with vitiligo. GenHosp Psychiatry 1979; 1: 73–77.
observed at all sites where compounds had been injected at a con- 10 Ongenae K, Beelaert L, Van Geel N, Naeyaert JM. Psychosocial effects of vitiligo. J Eur Acad Dermatol Venereol 2006; 20: 1–8.
11 Porter J, Beuf AH, Nordlund JJ, Lerner AB. The effect of vitiligo on sexual relationships. J Am Acad Dermatol 1990; 22: 221–222.
12 Porter J, Beuf AH, Nordlund JJ, AB L. Response to cosmetic disfigure- Vitiligo is a common depigmenting disorder. Vitiligo universalis ment: patients with vitiligo. Cutis 1987; 39: 493–494.
patients wish to be depigmented rather than attempt repigmenta- 13 Njoo MD, Vodegel RM, Westerhof W. Depigmentation therapy in viti- tion therapy if vitiligo covers more than half of their bodies. There ligo universalis with topical 4-methoxyphenol and the Q-switched rubylaser. J Am Acad Dermatol 2000; 42: 760–769.
are many depigmenting therapies and agents (Table 1) described 14 AlGhamdi KM. A survey of vitiligo management among dermatologists in the literature for depigmenting the skin to obtain a more fair in Saudi Arabia. J Eur Acad Dermatol Venereol 2009; 23: 1282–1288.
colour for cosmetic purposes. However, very few therapies or 15 Gawkrodger DJ, Ormerod AD, Shaw L et al. Guideline for the diagno- agents are available to depigment the pigmented skin to achieve sis and management of vitiligo. Br J Dermatol 2008; 159: 1051–1076.
16 Kim YJ, Chung BS, Choi KC. Depigmentation therapy with uniform skin colour in patients with vitiligo universalis. To the Q-switched ruby laser after tanning in vitiligo universalis. Dermatol best of our knowledge, there is no such review about depigmenta- tion agents for vitiligo universalis that compares the advantages 17 Radmanesh M. Depigmentation of the normally pigmented patches in and disadvantages of the available agents. In this review, we com- universal vitiligo patients by cryotherapy. J Eur Acad DermatolVenereol 2000; 14: 149–152.
pared advantages, mechanisms of action, concentration, costs anddisadvantages of available depigmenting agents (Table 2). In this Journal of the European Academy of Dermatology and Venereology ª 2010 European Academy of Dermatology and Venereology 18 Oakley AM. Rapid repigmentation after depigmentation therapy: 44 Kasraee B, Handjani F, Aslani FS. Enhancement of the depigmenting vitiligo treated with monobenzyl ether of hydroquinone. Australas J effect of hydroquinone and 4-hydroxyanisole by all-trans-retinoic acid (tretinoin): the impairment of glutathione-dependent cytoprotection? 19 Falabella R. Repigmentation of stable leukoderma by autologous minigrafting. J Dermatol Surg Oncol 1986; 12: 172–179.
45 Romero C, Aberdam E, Larnier C, Ortonne JP. Retinoic acid as modu- 20 Briganti S, Camera E, Picardo M. Chemical and instrumental lator of UVB-induced melanogenic enzymes expression. J Cell Sci approaches to treat hyperpigmentation. Pigment Cell Res 2003; 16: 46 Nordlund JJ, Forget B, Kirkwood J, Lerner AB. Dermatitis produced 21 Jean L, Lapia BK, Somma S. Depigmentation therapy. Dermatol Ther, by applications of monobenzone in patients with active vitiligo. Arch 22 Kasraee B, Fallahi MR, Ardekani GS et al. Retinoic acid synergistically 47 Bandyopadhyay D. Topical treatment of melasma. Indian J Dermatol enhances the melanocytotoxic and depigmenting effects of monobenz- ylether of hydroquinone in black guinea pig skin. Experimental Derma- 48 Charlı´n R, Barcaui CB, Kac BK, Soares DB, Rabello-Fonseca R, Azulay-Abulafia L. Hydroquinone-induced exogenous ochronosis: a 23 Forman A. A note on the depigmenting properties of monobenzylether report of four cases and usefulness of dermoscopy. Int J Dermatol of hydroquinone. Br J Dermatol 1953; 65: 406–411.
24 Lerner AB, Fitzpatrick TB. Treatment of melanin hyperpigmentation.
49 Ortonne JP, Passeron T. Melanin pigmentary disorders: treatment J Am Med Assoc 1953; 152: 577–582.
update. Dermatol Clin 2005; 23: 209–226.
25 Arndt KA, Fitzpatrick TB. Topical use of hydroquinone as a depig- 50 Bolognia JL, Lapia K, Somma S. Depigmentation therapy. Dermatol menting agent. J Am Med Assoc 1965; 194: 965–967.
26 Mosher DB, Parrish JA, Fitzpatrick TB. Monobenzylether of hydroqui- 51 Levitt J. The safety of hydroquinone: a dermatologist’s response to the none: a retrospective study of treatment of 18 vitiligo patients and a 2006 Federal Register. J Am Acad Dermatol 2007; 57: 854–872.
review of literature. Br J Dermatol 1977; 97: 669–679.
52 Reynolds JEF. Dermatological agents: mequinol. In Reynolds JEF, ed.
27 Freedberg IM, Eisen AZ, Wolff K et al. Hypomelanosis and hypermela- The Extra Pharmacopoeia. Martindale, 29th edn. The Pharmaceutical noses. In Mosher DB, Fitzpatrick TB, Ortonne JP, Hori Y, eds. Fitzpa- trick’s Dermatology in General Medicine, 5th edn. McGraw-Hill, New 53 Fleischer AB, Schwartzel EH, Colby SI, Altman DJ. Thecombination of 2% 4-hydroxyanisole (Mequinol) and0.01% tretinoin is effective in 28 Peck SM, Sabotka H. Effect of monobenzyl hydroquinone on oxidase improving the appearance of solar lentigines and related hyperpig- systems in vivo and in vitro. J Invest Dermatol 1941; 4: 325–332.
mented lesions in two phase double-blind multicenter clinical studies.
29 Denton CR, Lerner AB, Fitzpatrick TB. Inhibition of melanin forma- J Am Acad Dermatol 2000; 42: 459–467.
tion by chemical agents. J Invest Dermatol 1952; 18: 119–135.
54 Boyle J, Kennedy CTC. Leucoderma induced by monomethylether of 30 Hariharan V, Klarquist J, Reust MJ et al. Monobenzyl ether of hydroquinone. Clin Exp Dermatol 1985; 10: 154–158.
hydroquinone and 4-tertiary butyl phenol activate markedly different 55 Brody HJ. Chemical Peeling and Resurfacing, 2nd edn. Mosby, Mis- physiological responses in melanocytes: relevance to skin depigmen- tation. J Invest Dermatol 2010; 130: 211–220.
56 Moy LS, Kotler R, Lesser T. The histologic evaluation of pulsed carbon 31 Riley PA. Mechanism of pigment cell toxicity produced by hydroxy- dioxide laser resurfacing versus phenol chemical peels in vivo. Derma- anisole. J Pathol 1970; 101: 163–169.
32 Riley PA. Hydroxyanisole depigmentation: in vivo studies. J Pathol 57 Stuzin JM, Baker TJ, Gordon HL. Treatment of photoaging: facial chemical peeling (phenol and trichloroaceticacid) and dermabrasion.
33 Grojean MF, Thivolet J, Perrot H. Acquired leukomelanoderma caused by topical depigmenting agents. Ann Dermatol Venereol 1982; 109: 58 Parvez S, Kang M, Chung HS et al. Survey and mechanism of skin depigmenting and lightening agents. Phytother Res 2006; 20: 921–934.
34 Snell RS. Monobenzylether of hydroquinone. Arch Dermatol 1964; 90: 59 Lyon CC, Beck MH. Contact hypersensitivity to monobenzyl ether of hydroquinone used to treat vitiligo. Contact Derm 1998; 39: 132–133.
35 Frenk E. Depigmentation par agents chimiques. Bull Soc Fr Dermatol 60 Coleman KM, Coleman WP. Complication. In Rubin MG, Dover JS, Alam M, eds. Chemical Peels, 1st edn. Elsevier & Saunders, Philadel- 36 Antoniou C, Katsambas A. A guidelines for the treatment of vitiligo.
61 Agency for Toxic Substances and Disease Registry (ATSDR). Toxicolog- 37 Grimes PE. Vitiligo: an overview of therapeutic approaches. Dermatol ical Profile for Phenol. US Department of Health and Human Services, 38 Drake LA, Dinehart SM, Farmer ER et al. Guidelines of care for viti- 62 Zanini M. Depigmentation therapy for generalized vitiligo with topical ligo. J Am Acad Dermatol 1996; 35: 620–626.
88% phenol solution. An Bras Dermatol 2005; 80: 415–416.
39 Dorsey CS. Dermatitic and pigmentary reactions to monobenzylether 63 Thissen M, Westerhof W. Laser treatment for further depigmentation of hydroquinone: report of cases. Arch Dermatol 1960; 81: 245–248.
in vitiligo. Int J Dermatol 1997; 36: 386–388.
40 Hedges TR III, Kenyon KR, Hanninen LA, Mosher DB. Corneal and 64 Nelson JS, Applebaum J. Treatment of superficial cutaneous pigmented conjunctival effects of monobenzone in patients with vitiligo. Arch lesions by melanin-specific selective photothermolysis using the Q-switched ruby laser. Ann Plast Surg 1992; 29: 231–237.
41 Kligman AM, Willis I. A new formula for depigmenting human skin.
65 Leuenberger ML, Mulas MW, Hata TR. Comparison of the Q-switched alexandrite, Nd:YAG and ruby lasers in treating blue-black tattoos.
42 Njoo M, Menke H, Pavel S et al. N-acetylcysteine as a bleaching agent in the treatment of melasma. J Eur Acad Dermatol Venereol 1997; 9: 66 Anderson R, Parrish J. Selective photothermolysis: precise microsur- gery by selective absorption of pulsed irradiation. Science 1983; 220: 43 Nair X, Parab P, Suhr L, Tramposch KM. Combination of 4-hydroxy- anisole and all-trans retinoic acid produces synergistic skin depigmen- 67 Spicer MS, Goldberg DJ. Lasers in dermatology. J Am Acad Dermatol tation in swine. J Invest Dermatol 1993; 101: 145–149.
Journal of the European Academy of Dermatology and Venereology ª 2010 European Academy of Dermatology and Venereology Depigmentation therapies for vitiligo universalis 68 Alster TS. Q-switched alexandrite laser treatment (755 nm) of profes- 92 Zirvi TBM, Costarelis G, Gelfand JM. Vitiligo-like hypopigmentation sional and amateur tattoos. J Am Acad Dermatol 1995; 33: 69–73.
associated with imiquimod treatment of genital warts. J Am Acad 69 Reda AM, Taha IR, Riad HA. Clinical and histological effect of a single treatment of normal mode alexandrite (755 nm) laser on small melan- 93 Skinner RB Jr. Imiquimod. Dermatol Clin 2003; 21: 291–300.
ocytic nevi. J Cutan Laser Ther 1999; 1: 209–215.
94 Ongenae K, Van Geel N, Naeyaert JM. Evidence for an autoimmune 70 Lam AY, Wong DS, Lam L et al. A retrospective study on the efficacy pathogenesis of vitiligo. Pigment Cell Res 2003; 16: 90–100.
and complications of Q-switched alexandrite laser in the treatment of 95 Dahl MV. Imiquimod: a cytokine inducer. J Am Acad Dermatol 2002; acquired bilateral nevus of Ota-like macules. Dermatol Surg 2001; 27: 96 Gupta AK, Browne M, Bluhm R. Imiquimod: a review. J Cutan Med 71 Rao J, Fitzpatrick RE. Use of the Q-switched 755 nm alexandrite laser to treat recalcitrant pigment after depigmentation therapy for vitiligo.
97 Burns CA, Brown MD. Imiquimod for the treatment of skin cancer.
Dermatol Surg 2004; 30: 1043–1045.
Dermatol Clin 2005; 23: 151–164. vii.
72 Lask GP, Glassberg E. Neodymium:yttrium-aluminum-garnet laser for 98 Woodmansee C, Pillow J, Skinner RB Jr. The role of topical immune the treatment of cutaneous lesions. Clin Dermatol 1995; 13: 81–86.
response modifiers in skin cancer. Drugs 2006; 66: 1657–1664.
73 Lee MW. Combination visible and infrared lasers for skin rejuvena- 99 Berman B, Sullivan T, De Araujo T et al. Expression of Fas receptor tion. Semin Cutan Med Surg 2002; 21: 288–300.
on basal cell carcinomas after treatment with imiquimod 5% cream or 74 Taylor CR, Anderson RR. Ineffective treatment of refractory melasma vehicle. Br J Dermatol 2003; 149(Suppl. 66): 59.
and post-inflammatory hyperpigmentation by Q-switched ruby laser.
100 Urosevic M, Maier T, Benninghoff B et al. Mechanisms underlying J Dermatol Surg Oncol 1994; 20: 592–597.
imiquimod-induced regression of basal cell carcinoma in vivo. Arch 75 Kuflik GE. Cryosurgery updated. J Am Acad Dermatol 1994; 31: 925– 101 Sullivan TP, Dearaujo T, Vincek V, Berman B. Evaluation of superfi- 76 Andrews MD. Cryosurgery for common skin conditions. Am Fam cial basal cell carcinomas after treatment with imiquimod 5% cream or vehicle for apoptosis and lymphocyte phenotyping. Dermatol Sur 77 Guidelines of care for cryosurgery. American Academy of Dermatology Committee on guidelines of care. J Am Acad Dermatol 1994; 31: 102 Vidal D, Matias-Guiu X, Alomar A. Efficacy of imiquimod for the expression of Bcl-2, Ki67, p53 and basal cell carcinoma apoptosis. Br J 78 Mirshams M, Daneshpazhooh M, Mirshekari A et al. Cryotherapy in the treatment of pyogenic granuloma. JEADV 2006; 20: 788–790.
103 Schon M, Bong AB, Drewniok C et al. Tumor-selective induction of 79 Elton RF. Complications of cutaneous cryosurgery. J Am Acad Derma- apoptosis and the small-molecule immune response modifier imiqui- mod. J Natl Cancer Inst 2003; 95: 1138–1149.
80 Cerchione C, Fabbricini R, Pane F, Luciano L. Vitiligo-like lesions in 104 Kim CH, Ahn JH, Kang SU et al. Imiquimod induces apoptosis of an adult patient treated with Imatinib mesylate. Leuk Res 2009; 33: human melanocytes. Arch Dermatol Res 2010; 302: 301–306.
105 Ortonne JP. Vitiligo and other disorders of hypopigmentation. In 81 Leong KW, Lee TC, Goh AS. Imatinib mesylate causes hypopigmenta- Bolognia JL, Jorizzo J, Rapini R, eds. Dermatology. CV Mosby, tion in the skin. Cancer 2004; 100: 2486–2487.
82 Tsao AS, Kantarjian H, Cortes J et al. Imatinib mesylate causes hypo- 106 Schuttlaar ML, Hamstra JJ, Plinck EPB et al. Alopecia areata in pigmentation in the skin. Cancer 2003; 98: 2483–2487.
children: treatment with diphencyprone. Br J Dermatol 1996; 135: 83 Alexandrescu DT, Dasanu CA, Farzanmehr H, Kauffman L. Persistent cutaneous hyperpigmentation after tyrosine kinase inhibition with 107 Hatzis J, Gourgiotou K, Tosca A, Stratigos J. Vitiligo as a reaction to imatinib for GIST. Dermatol Online J 2008; 14: 7.
topical treatment with diphencyprone. Dermatologica 1988; 177: 84 US Food and Drug Administration. Aldara (imiquimod) 5% cream (online 14 July 2004). [WWW document]. URL http://www.fda.gov/ 108 Duhra P, Foulds IS. Persistent vitiligo induced by diphencyprone. Br J cder/foi/label/2004/20723s016lbl.pdf (last accessed 1 December 2006).
85 Zhu KJ, Cen JP, Lou JX, Wang Q, Zhang X, Xu Y. Imiquimod inhibits 109 Pan JY, Theng C, Lee J, Goh BK. Vitiligo as an adverse reaction to the differentiation but enhances the maturation of human monocyte- topical diphencyprone. Ann Acad Med 2009; 38: 276–277.
derived dendritic cells. Int Immunopharmacol 2009; 9: 412–417.
110 Gellin GA, Manibach HI. Detection of environmental depigmenting 86 Miller RL, Gerster JF, Owens ML et al. Imiquimod applied topically: a chemicals. In Marzulli F, Manibach H, eds. Dermatotoxicology and novel immune response modifier and new class of drug. Int J Immuno- Pharmacology. Hemisphere Publishing, New York, 1983: 443.
111 Schwartzkopf KS, Stookey JM, Hull PR, Clark EG. Screening of depig- 87 Gollnick H, Guillen Barona C, Frank RGP et al. Efficacy by clinical menting compounds for the development of an alternative method of evaluation of imiquimod 5% cream in the treatment of superficial branding beef cattle. J Anim Sci 1994; 72: 1393–1398.
basal cell carcinoma: initial results from an ongoing, long-term follow- 112 Bangham AD, Hill AW, Miller AG. Preparation and use of liposomes up study in Europe. J Am Acad Dermatol 2004; 50: 124. Abstract.
as models of biological membrane. In Korn ED, ed. Methods in Mem- 88 Dummer R, Urosevic M, Kempf W, Hoek K, Hafner J, Burg G.
brane Biology, Vol. 1. Plenum Press, New York, 1974: 1.
Imiquimod in basal cell carcinoma: how does it work? Br J Dermatol 113 Schafer-Korting M, Korting HC, Braun-Falco O. Liposome prepara- tions: a step forward in topical drug therapy for skin disease. J Am 89 Geisse JK, Rich P, Pandya A et al. Imiquimod 5% cream for the treat- Acad Dermatol 1989; 21: 1271–1275.
ment of superficial basal cell carcinoma: a double-blind, randomized, 114 Senel E, Seckin D. Imiquimod-induced vitiligo-like depigmentation.
vehicle-controlled study. J Am Acad Dermatol 2002; 47: 390–398.
Indian J Dermatol Venereol Leprol 2007; 73: 423.
90 Marks R, Gebauer K, Shumack S, Amies M, Bryden J, Fox TL, Owens 115 Sriprakash K, Godbolt A. Vitiligo-like depigmentation induced by ML, Australasian Multicentre Trial Group. Imiquimod 5% cream in imiquimod treatment of superficial basal cell carcinoma. Australas J the treatment of superficial basal cell carcinoma: results of a multicen- ter 6-week dose-response trial. J Am Acad Dermatol 2001; 44: 807–813.
116 Nuzzo SD, Masotti A. Depigmentation therapy in vitiligo universalis 91 Neville JA, Welch E, Leffell DJ. Management of nonmelanoma skin with cryotherapy and 4-hydroxyanisole. Clin Exp Dermatol 2010; 35: cancer in 2007. Nat Clin Pract Oncol 2007; 4: 462–469.
Journal of the European Academy of Dermatology and Venereology ª 2010 European Academy of Dermatology and Venereology

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