Monobenzylether of hydroquinone

Of 18 severely afffected vitiligo patients who used 20% monobenzylether of hydroquinone (MBEH, Benoquin) as a depigmenting agent, 8 achieved complete depigmentation after 10 months or more of use and 3 dramatic but no complete hypopigmentation. The 3 patients with no results did not use MBEH for more than 4 months. Complications were frequent particularly among those who did well, but only 1 case of contact dermatitis limited therapy. All patients who depigmented fully were very pleased with their results. As depigmentation induced by MBEH is generally irreversible, MBEH use must be reserved for induction of complete depigmentation of severely affected vitiligo patients who cannot or do not choose to repigment and who can accept the permanence of never tanning. The history, histology and mechanism of MBEH depigmentation are discussed.     

Depigmentation therapies for normal skin in vitiligo universalis

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.     

Enhanced bleaching treatment: opportunities for immune‐assisted melanocyte suicide in vitiligo

Depigmentation in vitiligo occurs by progressive loss of melanocytes from the basal layer of the skin, and can be psychologically devastating to patients. T cell‐mediated autoimmunity explains the progressive nature of this disease. Rather than being confronted with periods of rapid depigmentation and bouts of repigmentation, patients with long‐standing, treatment‐resistant vitiligo can undergo depigmentation treatment. The objective is to remove residual pigmentation to achieve a cosmetically acceptable result – that of skin with a uniform appearance. In the United States, only the use of mono‐benzyl ether of hydroquinone (MBEH) is approved for this purpose. However, satisfactory results can take time to appear, and there is a risk of repigmentation. MBEH induces necrotic melanocyte death followed by a cytotoxic T‐cell response to remaining, distant melanocytes. As cytotoxic T‐cell responses are instrumental to depigmentation, we propose that combining MBEH with immune adjuvant therapies will accelerate immune‐mediated melanocyte destruction to achieve faster, more definitive depigmentation than with MBEH alone. As Toll‐like Receptor (TLR) agonists – imiquimod, CpG, and Heat Shock Protein 70 (HSP 70) – all support powerful Th1 responses, we propose that using MBEH in combination with these agents can achieve superior depigmentation results for vitiligo patients.     

A mouse model of vitiligo induced by monobenzone

The paucity of vitiligo animal models limits the understanding of vitiligo pathogenesis and the development of therapies for the skin disorder. In this study, we developed a new mouse model of vitiligo by topically applying the skin‐depigmenting agent monobenzone on mice. We demonstrated that monobenzone‐induced skin depigmentation on the non‐exposed sites and that the severity of lesions depended on drug dosage. The result of the histological examination of the depigmented skin indicated loss of epidermal melanocytes and perilesional accumulation of CD8⁺ T cells. Furthermore, the monobenzone‐induced depigmentation of the Rag1 gene knockout did not appear on the non‐exposed sites, supporting the involvement of infiltrating CD8⁺ T cells in melanocyte destruction. Resemblance in histological characteristics and pathogenesis between monobenzone‐induced depigmentation and active human vitiligo suggests good potential of our mouse model for use in vitiligo research.     

Depigmentation of black guinea pig skin by topical application of cysteaminylphenol, cysteinylphenol, and related compounds

Phenol and catechol were combined with sulfur to develop new melanocytotoxic agents. Among these synthetic compounds, 4-S-cysteaminylphenol (4-S-CAP) and 4-S-cysteinylphenol (4-S-CP), which showed an in vivo antimelanoma effect, were evaluated for cytotoxicity to normal epidermal melanocytes using hydroquinone (HQ) as the control. Topical application of 4-S-CAP on the skin of black guinea pigs revealed a marked depigmentation of black skin. 4-S-Cysteinylphenol also showed some depigmenting potency. 2-S-Cysteinylhydroquinone, which was made by combining cystine with HQ, on the other hand, did not show any depigmenting effect. Depigmentation of black skin by 4-S-CAP appeared to derive from: a decrease in the number of functioning melanocytes; a decrease in the number of melanosomes synthesized within the melanocytes and transferred to keratinocytes; and destruction of the membranous organelles of the melanocytes. None of these degenerative changes was observed in the keratinocytes, indicating the selective effect of 4-S-CAP on melanocytes.     

Vitiligo and idiopathic guttate hypomelanosis. Repigmentation of skin following engraftment onto nude mice

Several diseases are included in the category of hypomelanosis. Their clinical course as well as the pathogenesis are diverse and in many cases poorly understood. The aim of the present study is to use the nude mice model to determine whether the primary defect in various pigmentary skin disorders is inherent to the tissue itself or is secondary to systemic factors. Split-thickness skin grafts obtained from patients with vitiligo, acquired hypomelanosis guttata, and tyrosinase-negative albinism were grafted onto nude mice. Histologic examination and dopa staining were performed prior to and following the engraftment. The dopa staining was performed on the epidermal sheet following separation from the dermis. The depigmented area of the vitiligo became completely pigmented 6 to 10 weeks after skin transplantation. The dopa reaction that was negative prior to skin engraftment became completely positive after the transplantation. The number of melanocytes (expressed per square millimeter of skin surface) 8 weeks after transplantation was 197 +/- 73 mm2. Dopa reaction in acquired hypomelanosis guttata showed reduction of the number of melanocytes in the depigmented macula as compared with the surrounding area (55.25 +/- 18.00 mm2 vs 220 +/- 28.28 mm2. Twenty days after skin transplantation, repigmentation of the area was observed. The number of melanocytes increased significantly (388.75 +/- 213 mm2). The grafted skin obtained from patients with tyrosinase-negative albinism showed persistence of the depigmentation after skin transplantation. Dopa reaction was negative prior to and 8 weeks after transplantation. The results of the present study suggest that systemic factors may play a role in the pathogenesis of vitiligo and acquired hypomelanosis guttata.     

The depigmenting effect of RALGA in C57BL/6 mice

BACKGROUND: It has been known for a long time that the topical use of retinoic acid (RA) produces mild depigmentation of human skin. However, RA has two major disadvantages for its utilisation as a topical depigmenting compound. First, RA can act as an irritant and can produce considerable erythema and exfoliation of skin. Second, RA has a relatively weak depigmenting ability compared to other known depigmenting chemicals. OBJECTIVE: In this study, we show that RALGA, a combination of the less irritant retinoid retinaldehyde (RAL; 0.1%) and glycolic acid (6.4%), has a higher skin-depigmenting potential than RA 0.05% in the tail skin of C57BL/6 mice. This effect was observed in reducing the number of functioning melanocytes and/or in inhibiting their ability to synthesise melanin. In addition, the visually recognisable depigmenting effect of RALGA was evident earlier than that of RA, i.e. only after 1 week of application. RALGA may therefore serve as a depigmenting product for the treatment of skin hyperpigmentary disorders. Postacne hyperpigmented lesions represent a very common pigmentary problem among acne patients. RALGA may thus act as an anti-acne product, due to the presence of RAL--an RA precursor--which could simultaneously remove the postacne hyperpigmented lesions in such patients.     

Alterations in cutaneous immune reactivity to dinitrofluorobenzene in graying C57BL/vi.vi mice

The fur of the C57BL/vi.vi mouse is black at 6 weeks of age. By 6 months of age the animals are white and there are no identifiable pigment cells within the epidermis or hair bulbs. Human subjects with vitiligo exhibit loss of epidermal pigment cells. The loss of pigment cells in human subjects with vitiligo has been associated with loss of cutaneous immune reactivity to contact allergens. Therefore, studies were performed to determine whether loss of pigment cells in these depigmenting mice also was associated with loss of the cutaneous immune response. The number of Ia-positive (Ia +) Langerhans cells (LC)/mm2 on the back and the ear, the sites of sensitization and challenge with dinitrofluorobenzene (DNFB), was quantified before, during, and after depigmentation. We observed that there were fewer LC/mm2 on the back and the ear before and after pigment loss in the graying mice than in the normal control C57BL/6 mice. The young pigmented C57BL/vi.vi mice were capable of developing moderate contact hypersensitivity; the older depigmented mice did not sensitize to DNFB. We conclude that the depigmented mice, like human subjects with vitiligo, have a loss of contact hypersensitivity associated with a loss of pigment cells within the epidermis. In the mouse, loss of melanocytes is associated with a decrease in the population density of Ia + cells.     

Depigmentation therapies in vitiligo

Depigmentation therapy in vitiligo is an option in those with extensive vitiligo who have failed to respond to medical therapy and have obvious cosmetic disfigurement due to intervening patchy pigmented areas. Various aspects of this therapy such as the cost, treatment time, course, permanency of depigmentation, side effects, and the possibility of repigmentation should first be discussed with the patient. At present, there is no ideal depigmenting therapy available, but many agents in the market have been in use for many years. Monobenzyl ether of hydroquinone (MBEH) is the mainstay and Food and Drug Administration (FDA) approved in USA but takes many months to depigment and is associated with local side effects and risk of repigmentation. Other agents which are also used are 4-methoxy phenol and 88% phenol. Physical therapies for depigmentation include Q-switched ruby and alexandrite lasers and cryotherapy. Second-line agents which can be explored for depigmentation include imatinib mesylate, imiquimod, and diphencyprone. Many possible experimental agents are being explored like various phenol derivatives, melanoma vaccines, interferon gamma, busulfan, etc. A major lacuna still exists in this area and a lot more research is desirable to give satisfactory cosmesis to these patients with extensive vitiligo.     

Site‐oriented depigmentation in vitiligo patients using Q‐switched Nd:YAG laser (1,064/532 nm), cryotherapy and chemical peels: A comparative study

Depigmentation emerges as a feasible solution for vitiligo universalis and refractory cases of vitiligo vulgaris that hinder patients' quality of life. A range of depigmenting modalities has previously been developed. However, each has its own limitations. Based on skin sensitivity, this study sets out to compare the efficacy and tolerability of “trichloroacetic acid (TCA) peels 25% and 50% and Qs Nd:YAG laser (1,064/532 nm)” for facial depigmentation and “cryotherapy, phenol 88% and Qs Nd:YAG (1,064/532 nm)” for extrafacial skin depigmentation. Forty vitiligo patients were examined and equally divided into facial & extrafacial groups. Regular sessions were performed. Patients' responses were assessed after 3 months or when excellent/complete depigmentation was attained through assessing “depigmentation grade”, “extent of depigmented skin”, “patient satisfaction” and “overall response”. Patients were observed for a six‐month follow‐up period. In facial depigmentation, Qs Nd:YAG showed the highest significant response followed by TCA 50% and 25%. In extrafacial depigmentation cryotherapy, phenol 88% and Qs Nd:YAG laser displayed positive outcomes without significant difference. Among the modalities tested Qs Nd:YAG yielded superior results in facial residual pigmentation in vitiligo when compared to TCA 50% and 25%, whereas in extrafacial sites Qs Nd:YAG, cryotherapy and phenol were equally effective.     

自体黑素细胞体外培养移植治疗白癜风

目的 探讨自体黑素细胞体外培养扩增和移植治疗白癜风的疗效.方法 用负压吸疱法在白癜风患者正常皮肤区吸疱取皮,用胰蛋白酶消化皮肤制成细胞悬液,在M2黑素细胞选择性培养基中培养,每周传代1次,经4～5次传代,以免疫荧光和多巴胺染色检测培养细胞的纯度和生物学特性.观察培养的自体黑素细胞移植到白癜风患者皮损区后色素生成效果.结果 黑素细胞能在培养基中选择性生长,经4～5周培养,获得纯的黑素细胞,无成纤维细胞和角质形成细胞污染.16例患者28个皮损区接受了移植治疗,病变皮肤面积从2cm²到200 cm²,1个月后移植区出现部分色素,呈淡红色.所有皮损区在移植后3～5个月均有色素再生,色素水平较周围正常皮肤略深或稍浅,6～8个月时色素恢复稳定,颜色与临近正常皮肤接近.87.5%皮损区色素再生面积超过50%.未见瘢痕和其他不良反应.结论 自体黑素细胞体外培养移植治疗白癜风具有效果好、安全、取较小表皮可以治疗较大面积皮损区的优点.     

Depigmentation therapy for vitiligo in patients with Fitzpatrick skin type VI

Vitiligo is a depigmenting disorder characterized by the progressive loss of melanocytes. In cases of extensive vitiligo that is unresponsive to treatment and involves noticeable areas, such as the face and hands, total depigmentation is a clinical option. The choice to depigment is a difficult one for the patient given the irreversible nature of treatment and the psychosocial implications of skin color change. This issue can be particularly complex for black patients. Depigmentation has been practiced for decades and documented in the literature, but the practice in Fitzpatrick skin type VI is not well-documented. We present a case of depigmentation in a patient with Fitzpatrick skin type VI, as well as technical options for depigmentation, the clinical approach, patient preparation, and psychosocial issues involved with this treatment option.     

The use of Janus kinase inhibitors and narrowband ultraviolet B combination therapy in non-segmental vitiligo

Vitiligo is a depigmentation disorder of the skin that occurs secondary to the destruction of melanocytes by an immune-mediated process. Vitiligo clinically presents with depigmented macules and patches, most commonly on the face, acral sites, and genitalia. It can be characterized as generalized or localized based on distribution. The localized form can be further divided into segmental (linear, band-like, or Blaschkoid) and non-segmental vitiligo. The classical treatment of vitiligo includes topical steroids, pulsed oral steroids in unstable vitiligo, phototherapy, a combination of steroid therapy and phototherapy, surgical grafting, as well as intentional depigmentation therapy in severe cases. However, recent advances in understanding the immune mechanisms implicated in the pathogenesis of vitiligo have led to the use of an FDA-approved topical Janus kinase (JAK) inhibitors for vitiligo. Despite this novel therapy advancement, we recommend the addition of narrowband ultraviolet B (NB-UVB) to JAK inhibitors in patients with extensive and progressive lesions, or those not fully responsive to JAK inhibitor monotherapy.     

Chronic actinic dermatitis with vitiligo-like depigmentation

This report describes two patients suffering from severe chronic actinic dermatitis. Unusual widespread vitiligo-like depigmentation occurred during the course of the disease. The progression of these lesions was triggered by the chronic actinic dermatitis. Loss of pigment and complete absence of tyrosinase positive melanocytes were found in depigmented skin of both cases. Immunohistological investigation of the inflammatory infiltrate in case 2 revealed a predominance of CD-8 positive cytotoxic/-suppressor lymphocytes. Analysing the adjacent pigmented epidermis of progressive depigmenting lesions a dense exocytosis of CD-8 T-cells was notable. This distribution suggests cytotoxic destruction of melanocytes as the cause for the vitiligo-like depigmentation.     

Clinical and histopathologic characteristics of trichrome vitiligo

BACKGROUND: The term trichrome vitiligo describes lesions that have a tan zone of varying width between normal and totally depigmented skin, which exhibits an intermediate hue. However, the pathogenesis and the histopathologic characteristics of trichrome vitiligo are unknown. OBJECTIVE: Our purpose was to investigate the clinical and histopathologic characteristics and the pathogenesis of trichrome vitiligo. METHODS: Four punch biopsy specimens were taken from 21 patients with trichrome vitiligo; they were from vitiliginous skin, light brown skin, perilesional normal skin, and normal skin as far as 5 cm from the nearest vitiligo spot. The sections were stained with hematoxylin-eosin; in selected cases, we performed immunohistochemical staining with S-100 protein and CD1a. RESULTS: Trichrome vitiligo occurred most frequently on the trunk in active vitiligo vulgaris. Focal vacuolar degeneration of the basal cell layer and mild inflammatory cell infiltration of the epidermis and dermis were more prominent in light brown skin and perilesional normal skin than in vitiliginous skin and normal skin. The number of melanocytes was decreased in light brown skin compared with perilesional normal skin (P <.05) and in vitiliginous skin compared with light brown skin (P <.05); a few melanocytes were observed even in skin affected by trichrome vitiligo. The number of Langerhans cells was increased in the epidermis of light brown skin and perilesional normal skin compared with vitiliginous and normal skin (P <.05). PUVA therapy yielded excellent repigmentation. CONCLUSION: Trichrome vitiligo is a variant of active vitiligo. The changes of melanocytes, keratinocytes, and Langerhans cells may be involved in the pathogenesis of depigmentation in trichrome vitiligo.     

Melanocyte detachment after skin friction in non lesional skin of patients with generalized vitiligo

BACKGROUND: In vitiligo, melanocytes are gradually lost in depigmented macules of the skin. The disappearance of melanocytes has, however, not been clearly observed and consequently the aetiology of the disease (autoimmune, neural, cytotoxic) is still elusive. The starting point of vitiligo macules is frequently determined by local conditions such as wounds and excoriations, but may also follow minor traumas such as pressure or repeated friction. This prominent feature is often neglected. OBJECTIVES: To clarify the biological consequences of repeated friction on the attachment and survival of melanocytes in non lesional vitiligo skin. METHODS: Light reproducible skin friction was performed for 4 min on the volar forearm of 18 patients with extensive vitiligo and five controls with normal healthy skin. Biopsies from the test area and control skin were taken at 1, 4, 24 and 48 h following friction. Serial sections were examined with standard light microscopy, transmission electron microscopy, histochemistry and immunohistochemistry (dihydroxyphenylalanine, HMB-45, E-cadherin and an early apoptosis marker, M30 cytoDEATH antibody). RESULTS: The observation of sections at 1 and 48 h after friction on vitiligo skin and at all time points in controls revealed no changes. In contrast, in vitiligo skin at 4 and 24 h after friction, several melanocytes had undergone detachment and were found in various suprabasal positions, including the stratum spinosum, granular layer, and within and outside the stratum corneum. CONCLUSIONS: Detachment and transepidermal elimination of melanocytes following minor mechanical trauma in non lesional vitiligo skin is probably the cause of depigmentation occurring in the isomorphic response (Koebner phenomenon). We propose that transepidermal elimination of melanocytes in vitiligo should be regarded as a possible mechanism of chronic loss of pigment cells, perhaps previously damaged by another process.     

Depigmentation therapy

ABSTRACT: Depigmentation therapy is a treatment option for patients with widespread, treatment-resistant vitiligo. The most commonly employed technique is the application of monobenzylether of hydroquinone (MBEH), also known as monobenzone, to areas with residual pigment. Prior to instituting therapy, the patient must be aware of the cost, treatment time course, risk of distant sites of depigmentation, probable permanency of depigmentation, side effects such as contact dermatitis, and the potential for repigmentation via follicular melanocytes. The social ramifications of depigmentation therapy also must be discussed, especially for patients with skin types IV and V. The sequential use of 4-methoxyphenol and Q-switched ruby laser also has been reported as a successful form of depigmentation therapy.     

Enhancement of the depigmenting effect of hydroquinone and 4-hydroxyanisole by all-trans-retinoic acid (tretinoin): the impairment of glutathione-dependent cytoprotection?

Many of the well-known depigmenting agents such as hydroquinone and 4-hydroxyanisole are, in fact, melanocytotoxic chemicals which are oxidized in melanocytes to produce highly toxic compounds such as quinones. These cytotoxic compounds are responsible for the destruction of pigment cells, which results in skin depigmentation. However, cells are capable of protecting themselves against cytotoxic agents by intracellular glutathione (GSH). This protection takes place under the enzymatic action of the detoxification enzyme glutathione S-transferase (GST), which is responsible for the conjugation of toxic species to GSH. The depigmenting effect of hydroquinone is shown to be potentiated by buthionine sulfoximine (BSO) and cystamine as the result of the reduction of intracellular levels of GSH by these two agents. Additionally, BSO and cystamine are shown to inhibit the activity of GST. The combination of all-trans-retinoic acid (tretinoin, TRA) with hydroquinone or 4-hydroxyanisole is also known to produce synergetic skin depigmentation. TRA serves as a potent inhibitor of mammalian GSTs and is known to make cells more susceptible to the cytotoxic effect of chemicals by inhibiting the activity of this enzyme. This agent is also shown to reduce the level of intracellular GSH in certain cells. We have proposed that the mechanism of action of TRA to synergistically enhance the melanocytotoxic effect of chemicals involves the inhibition of GST and the impairment of glutathione-dependent cytoprotection against melanocytotoxic agents.     

Basic research confirms coexistence of acquired Blaschkolinear Vitiligo and acrofacial Vitiligo

We report about a female patient with bilateral and unilateral blaschkolinear depigmentation on the extremities and coexistence of acrofacial vitiligo, who initially presented her first signs of depigmentation at the age of 32 years. The patient was otherwise healthy. The correct diagnosis was based on the latest up to date technology utilizing in vivo FT-Raman and Fluorescence spectroscopy, Wood's light examination of the depigmented skin and immunoreactivity of epidermal catalase expression in 3 mm punch biopsies from the linear depigmented area. The results yielded decreased catalase protein expression compared to healthy controls as well as complete absence of melanocytes. FT-Raman spectroscopy identified the presence of hydrogen peroxide (H(2)O(2)) in the mM range and Fluorescence spectroscopy demonstrated H(2)O(2)-mediated oxidation of tryptophan residues in the depigmented area. The results were in agreement with vitiligo. Repigmentation of the linear lesion was initiated after reduction/removal of epidermal H(2)O(2) with pseudocatalase PC-KUS further supporting the correct diagnosis. To the best of our knowledge this is the first case documented with vitiligo following Blaschko lines in coexistence with classical acrofacial vitiligo. This observation raises the question whether besides H(2)O(2)-mediated stress in association with genomic mosaicism could play a role in some cases with vitiligo.     

BRASSIERE DEPIGMENTATION: LIGHT AND ELECTRON MICROSCOPE STUDIES

SUMMARY.— A case is described where marked depigmentation of the skin developed in areas in direct contact with an elasticated brassiere containing Spandex yarn. Patch tests to the constituents of the brassiere and other chemicals were negative. Histological studies with the light and electron microscope were carried out on biopsies from the depigmented skin and from an adjacent control pigmented area. In the depigmented skin there was an almost complete absence of functional melanocytes and melanized melanosomes in the epidermis.
The differential diagnosis of this case is discussed and it is suggested that the persistent depigmentation of the skin that occurred in this case is an isomorphic phenomenon due to friction and pressure from the brassiere in a patient with vitiligo.