Author: Doctor Silvia Moretti1 Creation date: October 2003 Scientific editor: Professor Benvenuto Giannotti
University of Florence, 2nd Dermatology Clinic, Department of Dermatological Sciences, Via della Pergola 60, 50121 Firenze, Italy.

Abstract Keywords Definition Diagnostic criteria Differential diagnosis Frequency Clinical description Management and treatment Etiology and pathogenesis Diagnostic methods Unresolved questions References

Abstract Vitiligo is an acquired skin disorder characterized by white and depigmented patches enlarging and becoming more numerous with time. It is due to a disappearance of functioning melanocytes and loss of melanin in the epidermis. The condition can be cosmetically disfiguring and the lesional skin is thus more sensitive to sunburns. It affects 0.1-2% of the world’s population, irrespective of gender and race. Etiology is unknown and the several pathogenetic hypotheses do not account for the entire spectrum of the disease. Although no full therapeutic solution for vitiligo is available, many options may lead to acceptable results in most patients. Management includes sun protection, as well as medical and surgical repigmentation therapy. Medical treatments consist of narrowband ultraviolet B (UVB), broadband UVB, psoralen plus UVA, corticosteroids and other novel approaches. Surgical treatment, consisting of autologous transplantation methods, is generally recommended for stable/focal vitiligo, after medical therapy has failed. Finally, for patients with extensive areas of vitiligo, depigmentation of the residual melanin should be taken into account. Keywords: vitiligo, melanocytes, immune response, neural mediators, oxidative stress, epidermal microenvironment, repigmentation therapy.

Definition Vitiligo is a non contagious acquired pigmentation disorder characterized by sharplydefined white patches of variable shape and dimensions, increasing in size and number with time. The histological picture shows loss of melanocytes and melanin in the white patches and an inconstant lympho-mononuclear infiltrate in the advancing margins of vitiligo (1).

Diagnostic criteria Diagnostic criteria are based on the findings of acquired, well-demarcated white lesions on the skin, with no associated inflammation. These lesions tend to enlarge centrifugally. Differential diagnosis Differential diagnosis is made versus: 1) piebaldism, which is a rare depigmentation disorder due to a mutation of c-kit

Moretti S. Vitiligo. Orphanet Encyclopedia. October 2003.


Frequency Vitiligo is the most common pigmentary disorder affecting 0. has a potential lifelong evolution and is associated with Koebner phenomenon and frequently with autoimmune diseases. Oral PUVA may induce shortterm systemic adverse effects. Vitiligo classification by Koga This is a more recent classification subdividing vitiligo into two clinical types: vitiligo non segmentalis (type A) and vitiligo segmentalis (type B) and (4). The natural course of the disease is generally unpredictable. Type A Type A is more common. headaches. often occurring in a perifollicular pattern. hypopigmented areas sometimes occur together with the depigmented lesions and the normally pigmented skin (trichrome vitiligo). 5) depigmented lesions in leprosy. Medical and surgical repigmentation therapies can be carried out (6). actinic elastosis. Efficacy has been noted in a proportion of cases. irrespective of race and gender (2). Vitiligo. Universal vitiligo Universal vitiligo involves more than 80% of the body. knees and elbows. such as Sutton nevus. skin malignancies. generalized and universal vitiligo. can be observed. affecting the face (especially the central area with localized poliosis). external genitalia. Management and treatment Treatment of vitiligo includes cosmetic camouflage for the lesions on sun-exposed skin and mandatory prescription of sunscreens in sunny climates. They are asymptomatic generally. sternal and abdominal zones. Localized vitiligo Localized vitiligo is classified into focalis (one or more patches in one area but not in a segmental pattern) and segmental (one or more maculae in dermatomal distribution) forms.8-trimethylpsoralen is administered per os 2h before radiation exposure. It is characterized by stable and circumscribed white patches (with absence of melanocytes) present at birth. However. pregnant or lactating women and children aged Moretti S. some degree of spontaneous repigmentation occurs in 10-20% of patients.g. Contraindications for PUVA therapy are skin type I (i. which is a well-limited depigmented area. as well as canities and premature graying. Medical treatments Photochemotherapy It consists of photosensitizing psoralen plus ultraviolet A (PUVA) or natural UV (PUVASOL). pruritus and xerosis may represent the shortterm cutaneous adverse effects of PUVA. Poliosis circumscripta. elevation in liver function tests. Generalized vitiligo Generalized vitiligo can be subdivided into acrofacial (affecting face and distal extremities).e. vulgaris (the most common variety. in which melanocytes are either normal or reduced. juvenile diabetes mellitus. 3) post-inflammatory leukoderma (e. The UV dosage is gradually increased until minimal erythema of vitiligo lesions occurs. UV blocking sunglasses should be used. mucosae are rarely involved. with a symmetrical distribution of lesions in typical zones) and mixed (segmental plus vulgaris or acrofacial) types. Type B Type B is rarer and has a dermatomal distribution. Patients go through this treatment twice a week for at least 6 months. skin that will never tan and always burn). Topical applications of psoralen may be hazardous and can result in skin blistering. Rarely an inflammatory border may be found around the vitiligo patch resulting in a raised and erythematous edge (inflammatory vitiligo). Three types have been delineated: localized. stable and evident at birth. dorsum of hands and fingers. but it is rarely cosmetically acceptable (5). The lesions usually appear on sunexposed or constitutionally hyperpigmented areas or on sites of stretch and pressure (face. while skin disorders (such as lichenification. 2) achromic nevus. knees and elbows). where mycologic examination reveals hyphae and spores. 8-methoxypsoralen or 5methoxypsoralen or 4. 4) pytiriasis versicolor.protooncogene affecting the differentiation and migration of melanocytes. Orphanet Encyclopedia. such as nausea.5. Clinical description The clinical picture consists of one or more welldemarcated and white maculae. progressing in size and number. after psoriasis or syphilis) in which patients have a history of pre-existing dermatosis. gastric disturbance. thyroid pernicious anemia and Addison’s disease. In systemic treatment.1-2% of the world’s population. but it is often progressive.pdf 2 . Cataract has also been described as related to oral PUVA (7). Vitiligo classification by Nordlund Nordlund established a clinical classification based on distribution and extension of lesions (3). October 2003. phototoxic reactions. after rapid onset and evolution it usually exhibits a stable course..orpha. The margins of the patches are often hyperpigmented. actinic keratosis and cutaneous malignancies) may be the long-term cutaneous adverse reactions. http://www. which shows anesthetic disturbance of sensibility.

Vitiligo. PUVA therapy seems to act via stimulation of melanocytes of hair follicles or of the edge of achromic lesions. Another approach uses the roof of a suction blister produced in normally pigmented skin to cover the denuded areas obtained in lesional skin where a blister formation has been induced and the depigmented epidermis has been removed. carefully trying to avoid local adverse effects. so that after therapy they will be at lifelong risk of sunburns. this treatment uses a narrow band UVBactivated pseudocatalase complex in combination with calcium. http://www. The advantages of this therapy over PUVA regimen are represented by shorter time of treatment. with a non-Mendelian pattern suggestive of multifactorial. Novel therapies Microphototherapy In this approach. polygenic inheritance (14). October 2003. no contraindications in children or lactating The substance commonly used is topic monobenzylether of hydroquinone. Generally low or mid potency preparations are utilized. Several genes and chromosomal regions have been implicated in susceptibility to vitiligo. several HLA abnormalities have been associated with vitiligo. no oral drug administration.orpha. Treatment is administered twice a week. including association with Dr4. B13. Corticosteroids Corticosteroids can be used topically and orally. These treatments include the use of minigrafting.pdf 3 . using either melanocytes or melanocytes mixed with keratinocytes. or of thin splitthickness skin grafting obtained from a normally pigmented site and transplanted onto a dermabraded depigmented area. The mechanism of action is unknown. Narrowband UVB leads to erythematous reactions less frequently than broadband UVB. methionine and others. Depigmentation therapies should be considered for patients with more than 80% of skin affected by vitiligo. a potent melanocytoxic agent capable of inducing depigmentation at distant sites also (10). Transplantation onto a previously denuded achromic area can be done also with cultured autologous melanocytes. This therapy requires expensive equipment and trained personnel (11). a narrowband UVB is focused only onto the depigmented skin. in this case no scarring occurs at the donor site. A 2-mm full thickness punch graft is collected from normally pigmented sites and transplanted onto a depigmented area where similar punched out skin has been extracted. BW35. indicated generally in vitiligo patients unresponsive to medical therapy and with stable (commonly segmental) vitiligo (6). Scarring at the donor site and infections at the recipient site are possible. the oral administration of antioxidant agents such as selenium. segregation analyses suggest the involvement of multiple interacting genes in different populations (15). possibly due to a suppression of inflammation. Shortterm cutaneous adverse effects include pruritus. Systemic antioxidant therapy Based on the demonstration of an abnormal oxidative stress in vitiligo epidermis (13). is given for long periods. since about 20% of patients have at least one affected first-degree relative. a worldwide open clinical trial is currently underway. family clustering of cases is not uncommon. Narrowband UVB In this phototherapy an emission spectrum of 310 to 315 nm is used (9). In addition.less than 12 years. The UV dose is gradually increased until reaching minimal erythema of white lesions. less side effects. and possibly through a suppression of immunological activity. Etiology and pathogenesis Etiology is still unknown. and A30 (17). Pseudocatalase plus UVB therapy Based on the evidence of epidermal H2O2 accumulation and reduced catalase activity in vitiligo. Actually. A very recent and large epidemiological study supports the involvement of both genetic and non genetic factors in the pathogenesis of the disease and Moretti S. The mechanism of action is still unclear. Adverse effects include contact dermatitis and acquired ochronosis. Broadband UVB This phototherapy uses an emission spectrum of 290 to 320 nm (8). which is applied topically and seems to be able to remove epidermal H2O2 in association with a recovery of functioning melanocytes (12). Genetic hypothesis A positive family history for vitiligo is reported. Creams are applied once or twice per day in localized lesions. xerosis. These patients should be informed that depigmentation of residual melanin is a permanent process. erythema. so that unaffected skin areas are not exposed to UV irradiation. but none has been confirmed so far (16). later the grafted area is irradiated with UVA. tocopherol. but some evidencebased pathogenetic hypotheses have been proposed to explain the loss of melanocytes in epidermis. such techniques require specialized laboratories and are expensive. Surgical treatments They consist in autologous transplantation methods. Orphanet Encyclopedia. Patients are treated twice to three times a week for long periods. Caution is needed during the UVB dose increments.

pernicious anemia and Addison’s disease) are associated with vitiligo. Concerning cellular immunity. a decrease in cytokines stimulating melanocytes and an increase in cytokines inhibiting melanocytes (in particular. suggesting a role of catecholamines in the depigmentation process (26). Melan-A/Mart1 specific CD8 positive T lymphocytes were identified in inflammatory lesions of melanocyte destruction following infusion of Melan-A/Mart1 specific CD8 positive T-cell clones in melanoma patients (22): this finding gives direct evidence of T-cellmediated vitiligo. and by the onset of disease in patients with neurological disorders or with peripheral nerve injury (23. where CD4 and CD8 positive T cells were detected. In addition. by the occurrence of vitiligo after a period of severe emotional stress. high frequencies of Melan-A/Mart1 (a melanosomal antigen) specific CD8 positive T cells were detected in peripheral blood (1). possibly secreted from contiguous nerve endings. Sutton nevi. a central role is assigned to cutaneous microenvironment. antibodies to surface and cytoplasmic antigens of melanocytes have been found in vitiligo patients. the antioxidant imbalance has been confirmed also in peripheral blood mononuclear cells of active vitiligo patients. tyrosinase-related protein (TRP)-1 and TRP-2 (the last three are melanocytespecific antigens) (19). Autoimmune hypothesis This hypothesis proposes that an immune system disorder results in destruction of melanocytes. the pathogenetic role of antimelanocyte antibodies remains unclear. Interestingly. tyrosinase. mycological examination is Moretti S. It is first supported by the frequent observation that several autoimmune disorders (thyroid diseases. and to decrease in vitiligo patients responding to therapy (19). has been demonstrated in both lesional and non lesional epidermis of patients (30). mutations.pdf 4 . Diagnostic methods The diagnosis is mainly based on clinical evaluation. However. Defective recycling of tetrahydrobiopterin has been reported in vitiligo epidermis. Autocytotoxic/metabolic hypothesis Oxidative stress has been suggested to be the initial pathogenetic event in melanocyte degeneration (28. These findings support the concept of a possible systemic oxidative stress in vitiligo. 12). Vitiligo. A significant association of vitiligo was demonstrated with thyroid dysfuntion and/or thyroid antibodies in particular (18). A substantial number of infiltrating T cells express the cutaneous lymphocyte antigen (CLA) typical of skin homing T cells (20). Neural hypothesis This hypothesis suggests that some neurochemical mediators. as well as in melanocytes (29). Evolution of the disease allows differential diagnosis versus piebaldism and achromic nevus. In addition. According to this hypothesis. are cytotoxic for pigment cells. Concerning humoral immunity. http://www.suggests that some genetic factors may be shared with other autoimmune diseases (16). mainly belonging to the IgG class. This could impair normal life and activity of melanocytes. Genetic factors. altered cellular environment can all contribute to the disease (33). tumor necrosis factorα) were detected in depigmented lesions (32). oxidative stress. increased catecholamine discharge or synthesis has been associated with disease activity. Orphanet Encyclopedia. In vitiligo patients. 24). in which different causal elements may act synergistically or independently to provoke disappearance of melanocytes. associated to the intracellular production of H2O2 (28. Novel microenvironment-related hypothesis Cytokine imbalance in the epidermal microenvironment has been demonstrated in lesional skin in active vitiligo. and a recent study localized CLA positive cytotoxic T cells in apposition to disappearing melanocytes in the perilesional skin (21). It is likely that both humoral and cellular immunity co-operate in the destruction of melanocytes. an alteration in the antioxidant pattern. This theory is supported by the existence of segmental variant of vitiligo that affects a dermatome. juvenile diabetes mellitus. The autoantigens most frequently identified are antigens related to HLA class I molecules. Abnormalities of neuropeptides have been observed in perilesional skin and in blood of vitiligo patients (25). with a significant reduction of catalase activity. October 2003. autoimmunity. also expressing activation molecules (20). Important support to this theory has been given by the demonstration of morphological and functional communication between epidermal melanocytes and nervous system (27). it was correlated to an increased intracellular production of reactive oxygen species and appeared to be due to a mitochondrial impairment (31). Convergence theory The description of many credible contributory factors to the pathogenesis of vitiligo led to this theory. The serum levels of antibodies to melanocyte antigens seem to correlate with activity and extent of the disease and with the presence of other immune disorders. 29) with H2O2 accumulation in the epidermis of patients with active disease (12).orpha. an important role has been given to the infiltrate underlying the pigmented lesional skin.

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