Dermatologic Therapy, Vol.

21, 2008, 110117 Printed in the United States All rights reserved

Copyright Blackwell Publishing, Inc., 2008

DERMATOLOGIC THERAPY
ISSN 1396-0296

Blackwell Publishing Inc

Vitiligo: new and emerging treatments

TORELLO LOTTI, ALESSIA GORI, FABIO ZANIERI, ROBERTA COLUCCI & SILVIA MORETTI
Department of Dermatological Sciences, University of Florence, Florence, Italy

ABSTRACT: Vitiligo is a cosmetically disguring condition, and, although there is no therapeutic full solution yet, some treatment may induce good results in most patients. The disease can be successfully treated with various medical options. Both nonfocused or focused narrowband ultraviolet B phototherapy represents the current treatment of choice, to minimize side effects and reach optimal clinical results. Topical novel approaches are also considered. Surgical methods, consisting of autologous transplantation methods, is generally recommended for focal/stable vitiligo, after medical therapy has failed. Finally, for patients with extensive vitiligo, depigmentation of the residual melanin should be taken into account. KEYWORDS: phototherapy, therapy treatment, UVB, vitiligo

Introduction
Vitiligo is an acquired pigmentation disorder, characterized by depigmented patches, as a result of the disappearance of functioning melanocytes from the epidermis. This condition, cosmetically disguring especially in dark-skinned individuals, makes the lesional skin more sensitive to sunburns and affects 0.12% of the worlds population, irrespective of gender and race (1). The histologic picture shows loss of melanocytes and melanin in the white patches, and an inconstant lympho-mononuclear inltrate in the advancing margins of vitiligo (2). Diagnostic criteria are mainly clinical, based on the ndings of acquired, well-demarcated white lesions on the skin, with no associated inammation that tend to enlarge centrifugally. A recent classication subdivides vitiligo into two clinical types: segmental (type B) and nonsegmental (type A) (3). Type B is more rare and has a dermatomal distribution; after a rapid onset and evolution usually exibits a stable course. Type A is more common, has a potential lifelong evolution,
Address correspondence and reprint requests to: Silvia Moretti, MD, Department of Dermatological Sciences, Via della Pergola 60, 50121 Florence, Italy, or email: silvia.moretti@uni.it.

and is associated with Koebner phenomenon and frequently with autoimmune diseases such as Sutton nevus, thyroid disorders, juvenile diabetes mellitus, pernicious anemia, and Addisons disease. Another clinical classication is based on the distribution and extension of lesion according to Nordlund (4) (Table 1): localized, generalized, and universal vitiligo can be differentiated. Localized vitiligo is classied 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. Generalized vitiligo can be subdivided into acrofacial (affecting face and distal extremities), vulgaris (the most common variety, with a symmetrical distribution of lesions on typical zones), and mixed (segmantalis plus vulgaris or acrofacialis) types. Universal vitiligo involves more than 80% of the body. The natural course of the disease is generally unpredictable, but is often progressive; some degree of spontaneous repigmentation occours in 10 20% of patients, but rarely is it cosmetically acceptable (5), often occurring in a perifollicular pattern. The pathogenic basis of the disease is melanocyte disappearance from the achromic patches. Regarding this mechanism, three possible pathways could occur and are supported by experimental

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Table 1. Clinical classication of vitiligo according to Nordlund

Localized: a. Focal b. Unilateral One or more macules with casual distribution One or more macules are localized in a unilateral body region, with a dermatomeric distribution; a typical feature is an abrupt stop of the lesions at the midline Unique involvement of mucous membranes Presence of scattered stains extensively disseminated Patches are localized on distal extremities and face Co-existence of acrofacialis and vulgaris forms Depigmented lesions interest completely or almost completely the skin surface

c. Mucosal Generalized: a. Vulgaris b. Acrofacialis c. Mixed Universalis:

evidence: an apoptotic process (6), a necrotic event (associated with the inammatory process), (7) and a melanocythorragy, or detachment, following trauma or friction, as a result of an impaired function of cell-cell or cell-matrix adhesion (8,9). A crucial point is whether in vitiligo depigmented skin melanocytes completely disappear. Specic stainings such as the Masson Fontana method for melanin or dihydroxyphenylalanine technique for tyrosinase generally show absence of melanocytes from vitiligo lesions (10). Accordingly, specic autoantibodies for melanocytic lineage give no evidence of melanocytes in completely vitiliginous skin (11,12). These histologic data are also supported by electron microscopy, which fail to identify melanocytic cells in vitiligo achromic patches (13). In addition, cultured melanocytes can be obtained from pigmented (nonlesional) skin of vitiligo patients (14), and occasionally from depigmented (lesional) skin of vitiligo patients (15). As a subpopulation of residual epidermal melanocytes persist apart from the duration of the disease, repigmentation could occur after specic stimulation (16). Because of the growing importance of the aesthetic aspect in our modern society, many methods have been introduced to treat vitiligo, often with poor or disappointing results because repigmentation does not always occur, and this process often requires a lot of time to start and can be extremely slow. A rational approach to the treatment of vitiligo needs a careful differential diagnosis of hypomelanoses (17). At rst the present authors should classify the patient according to the age of beginning of the disease. Among these classications the present authors can distinguish three major groups: birth/infancy, childhood, and adulthood

vitiligo. In birth/infancy and in childhood, the differential diagnosis includes achromic nevus, piebaldism, and rare diseases like Angelman and Prader-Willy syndrome, Hermansky-Pudlak syndrome, oculocutaneous albinism, and other syndromes that require a wide systemic evaluation by a geneticist, because of their association with metabolic disorders and mental retardation. Childhood vitiligo must also be differentiated from postinammatory diseases like atopic dermatitis (in the antecubital and popliteal fossae), contact dermatitis, lichen striatus, chronic lichenoid pityriasis, lichen sclerosus, and postinfectious hypopigmentation that often follows viral exanthems like varicella, pytiriasis versicolor. Leprosy and treponemal infections such as pinta and jaws in endemical areas can interest childhood and adulthood. Moreover, in adults vitiligo should be differentiated versus VogtKoyanagi-Harada syndrome, melanoma associated leukoderma, scleroderma, sarcoidosis, mycosis fungoides, follicular mucinosis and secondary hypomelanoses that can be associated with lupus erythematosus (18).

Vitiligo treatments
Nowadays, vitiligo can be managed using a wide range of traditional, new, and experimental therapeutic methods, each of which has different indications, efcacy and side effects (summarized in Table 2). Narrowband ultraviolet B The mechanism explaining how narrowband ultraviolet B (NB-UVB) light (311 +/ 2) causes the repigmentation of vitiligo stain is at least

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Table 2. Summary of classical and recent experimental therapies

Classical treatements Forms of vitiligo where they can be used: Localized vitiligo, but only for 3 months of continued use Localized vitiligo (face, trunk, proximal extremities) Possible problems related to the use: Acne and acneiform eruptions, rosacea, skin atrophy, itch, erythema, teleangectasias, striae distensae, hypertricosis, blistering and vesciculation, edema, burns and sunburns like reactions, photoaging, increased risk of development of nonmelanoma skin cancer (NMSC) Nausea, vomiting, dizziness, seizure, headache, cataracts, risk of NMSC Contact dermatitis, conjunctival melanosis, leukoderma in nontreated areas; increases the risk of sunburns, premature aging and cutaneous neoplasms. Successive repigmentation treatment can be uneffective Itch, erythema, xerosis: long-term side effects are unknown Transient erythema, with rare desquamation

Topical corticosteroids Topical phototherapy (TUVA) with topical furocoumarin psoralens photosensitizers and recently with furanochromone

PUVA

Localized vitiligo

Depigmentation

Generalized or universalis vitiligo that involves more than 50% of their body surface area

Broadband UVB (280 320 nm)

Localized vitiligo Recent and experimental therapies Localized vitiligo, also in pregnant women and children

NB-UVB treatments: 1) Nonfocused NB-UVB 2) Microphototherapy 3) NB excimer light Recent topical treatments: 1) Tacrolimus and Pimecrolimus ointments 2) Vit. D derivates 3) PGE2 4) Antioxidants Surgical therapies: consisting in the transfer of melanocytes, melanocytes and keratinocytes or full-thickness skin from normally pigmented areas to hypomelanotic patches

Localized vitiligo

Tacrolimus and pimecrolimus: possibility of unexpected sunburns when associated with excimer laser 308 nm PGE2: episodes of mild irritation after exposure to sunlight Failure of the graft when performed on receiving areas in active phase. Koebner phenomenon, keloids, hyperpigmentation, especially in darker phototypes, scarring and infections

Vitiligo patches stable at least from 2 years and refractory to medical treatments: areas of skin involvment more than 23 cm that contain depigmented hairs; Piebaldism, halo nevi, thermal burns, trauma, inammation

TREATMENT with TISSUEENGINEERED SKIN

twofold (19): (a) immunosuppression to stop melanocyte killing, and (b) restoring pigmentation via increasing the numbers of melanocytes. According to numerous laboratory models and some human data, there is increasing evidence that UVB irradiation can induce T-regulatory (suppressor) cell activity. IL-10, produced in the

epidermis following UVR irradiation, may be important for the differentiation and the activity of populations of T-regulatory cells in the periphery. By suppressing autoreactive cells, regulatory T-cell populations may prevent autoimmune disease (20). NB-UVB has relatively more suppressive effects than narrowband UVB on systemic immune

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responses as judged by natural killer cell activity, lymphoproliferation, and cytokine responses (21). UV radiation stimulates melanocyte number in residual places, e.g., hair follicles and borders of lesional skin. The increase in melanocytes may be because of a UV-mediated increase in melanocyte growth factors such as bFGF and endothelin (22), which are lower in lesional compared to perilesional, nonlesional, and healthy skin (23). An alternative possibility to account for the therapeutic action of UV on lesional skin is that rather than to activate differentiated melanocytes, UV would activate the melanocyte stem cell population resident in the hair follicle and possibly also in the interfollicular epidermis. Melanocyte stem cells would escape any antimelanocyte immune response as they do not express melanocyte differentiation markers (24). Ultraviolet treatment is sometimes combined with other immunosuppressants, such as corticosteroids and calcineurine antagonists (25). Many therapeutic protocols are available, but usually the rst dose of irradiation is variable between 0.075 J/cm2 and 0.25 J/cm2, and then the successive applications require a 20% increase of the initial dose until the formation of a mild erythema (17). NB-UVB shows a comparable efcacy toward psoralen plus UVA (PUVA). The major advantages of NB-UVB are to avoid psoralen side effects and to reduce the cumulative dose of radiation. Current evidence-based guidelines indicate that NB-UVB phototherapy is recommended for generalized vitiligo (26). Phototherapy cannot be used in patients previously treated with photosensitizing agents or with anamnesis of diseases like xeroderma pigmentosum, systemic lupus erythematosus, porphyrias, and skin viral infections (27). An advantage of NB-UVB is the possibility of a therapeutic use in pregnant women and children without phototoxic effects or epidermal atrophy, with less erythema compared to other phototherapic treatments. NB-UVB microphototherapy The microphototherapy (28), named BIOSKIN, was developed in order to avoid side effects of longtime UV absorption, which can cause photoaging, teleangetasias, excessive tanning, and consequent risk. An advantage of BIOSKIN is its capacity to irradiate only the hypopigmentated areas using a narrowband UVB light (Philips TL-10) with a wavelength peak at 311 nm, sorting the effect that the total radiation dose and side effects of UV

therapy are both reduced (27). This is also a useful method because the present authors can administer different UV doses in different areas, for example major doses in zones more reluctant to repigmentation such as hands, distal digits, and lips, lesser in intermediate resistant zones like trunk and proximal extremities and minor on the face (17). Three days before the rst onset of treatment the minimum erythema dose is evaluated through the irradiation of lesional and nonlesional skin with increasing (from 80 to 400 mW/cm2) UVB doses: the starting UVB dose is usually 20% less than the minimal erythema dose, whereas sensitive areas, e.g., eyelids, are irradiated with 80% of the minimal erythema dose. The radiation dose is increased by 20% at each consecutive session (28), and reduced by 20% when erythema occurs. The entire treatment can last from 2 months to 2 years until the repigmentation is obtained. Usually, rst signs of repigmentation come up in three to six sessions, appearing as pigmented spots around follicular ostium or sometimes as interfollicular repigmentation. In 2003 Menchini (29) studied 734 patients treated with the previously described protocol every 2 weeks. After 1 year, 510 patients (69.8%) had more then 75% of repigmentation in affected areas exposed to BIOSKIN light, 155 (21.12%) obtained from 50% to 75% of repigmentation, 69 patients (9.4%) less then 50% of repigmentation, and only in 5 patients did vitiligo become more severe. Microphototherapy is particularly useful in the treatment of localized, segmental vitiligo, and bilateral symmetrical vitiligo, with an involvement less than 20% of the total body surface, and has the important advantage of lower side effects (such as a transient erythema, with rare desquamation) (30). NB-UVB narrow band excimer laser and monochromatic excimer light Ultraviolet B excimer laser (XeCl) and monochromatic excimer light use UV light at 308 nm and are similar to the classical narrowband treatment, but are more selective in treating the vitiligo patches with the advantage of lower side effects. A recent study performed to evaluate results in 24 patients treated for 1757 months with excimer laser, showed a total repigmentation in seven subjects (29.2%), a repigmentation of 25% to 75% of treated areas in six patients (25%), of less than 25% in other six patients, and no response in ve patients (20.8%) (31). The use of monochromatic excimer light has similar characteristics and results (32). These methods seem to be particularly

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helpful in localized and segmental vitiligo, especially in young patients (28). New topical treatments and antioxidants Some positive results are reported with topical immunosuppressive calcineurine inhibitors such as tacrolimus and pimecrolimus. The application of tacrolimus ointment 0.1% on hypopigmented patches inhibits T-lymphocyte activation and reduces the delivery of proinammatory cytokines such as TNF in affected skin on sun-exposed body areas (33,34). The association of topical tacrolimus and the 308-nm excimer laser has been suggested (35) to improve the response rate, but it has been reported the possibility of unexpected burns. Another innovative topical treatment is represented by the application of prostaglandin E (PGE2) and it is based on the consideration that UV rays also induce melanogenesis through an impaired turnover of membrane phospholipids with consequent increased production of prostaglandins, which could have a primary role in activating the process of repigmentation (36). In a recent study, 24 vitiligo patients with less than 5% skin involvement were treated with a gel containing 166.6 g/g PGE2 applied to depigmented patches one time per day for 6 months. At the end of this trial, 15 (5075%) patients reported a complete repigmentation, whereas six patients showed 2550% improvement, and six patients reported minimal or no improvement (36). Defective calcium uptake is reported in vitiliginous keratinocytes and melanocytes and related to high thioredoxin levels, which could inhibit melanogenesis through down-regulation of tyrosinase activity (37). The expression of 1,25dihydrossi-vitamin D3 receptor has also been reported in human melanocytes (38). These receptors could be stimulated by synthetic vitamin D derivates, such as calcipotriol, possibly adjusting the impaired calcium homeostasis. However, topical calcipotriol alone does not seem to be effective (39). Topical calcipotriol and PUVA therapy can act in synergy in treating vitiligo (40,41) but the efcacy of this treatment is not conrmed in all studies (42). A signicant depletion of enzymatic and nonenzymatic antioxidants characterizes the epidermis of patients with active vitiligo, and represents a ngerprint of an abnormal oxidative stress leading to impaired cofactor 6-tetrahydrobiopterin (6-BH4) levels, which inhibit melanogenesis interfering with the conversion of 1-phenylanine

to tyrosine (43,44). For this reason in the latest years the application of creams containing pseudocatalases alone or in combination with narrowband UVB exposure has been proposed for vitiligo treatment with uncertain results (45,46). A vegetal extract, obtained from Cucumis melo, has shown antioxidant (in particular, super-oxide dismutase and catalase-like activities) properties in association with focused NB-UVB treatment (47). More recently, NB-UVB phototherapy has been combined with an antioxidant pool containing alpha-lipoic acid, vitamins C, and E, and polyunsaturated fatty acids, or Polypodium leucotomos, an antioxidative and immunomodulatory plant extract, with an objective response improvement (48,49). Surgical therapies In the last years, surgical therapies consist the use of autologous skin grafts have been proposed. These methods can be used in vitiligo that are refractory to medical treatment, in patients with piebaldism, or to obtain repigmentation in case of thermal burns, trauma, and inammation. It is mandatory to treat only patients showing stability in their vitiligo lesions: hypopigmented patches should be stable from at least 2 years before surgical therapy and is warmly recommended to subject the patient to a minigrafting test before performing the denitive graft, in order to evaluate the positive response and the inauspicious occurrence of Koebners phenomenon at the donor site after 23 months follow-up (50). All these pieces of advice are really important because the graft failure is recurrent if the candidates have an active vitiligo. The surgical response is higher in segmental or focal vitiligo than in generalized vitiligo. Moreover, better surgical results are obtained in patients younger than 20 years, but skin graft is not recommended for patients with a tendency to form keloids or develop hyperpigmentation after minimal trauma (51). The present authors can distinguish three major forms of autologous skin grafts: normal skin (epidermis with or without dermis) containing melanocytes; a noncultured epidermal or hair follicle suspension that contains melanocytes; and nally cultured melanocytes, in suspension or as sheets, with or without keratinocytes (52). Thin dermal and epidermal sheets must be taken from the donor site with a dermatome at a depth of 0.10.3 mm to avoid scarring. The receiving site is prepared to the graft through a supercial dermabrasion (52). The possibility of

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performing this method mincing epidermal skin into fragments smaller than 1 mm2 and localizing them on vitiligo lesions, the so-called seed grafting technique also exists. The full-thickness minigrafts (12 mm), which are preferentially taken on the medial upper arms, thighs, or buttocks, give good esthetic results, permitting repigmentation in 13 months in 70% to 100% of cases by melanocytes spread from minigrafts. The technique of transplantation of noncultured keratinocyte/ melanocyte suspensions is performed using melanocytes achieved after having digested a biopsy of the buttocks or full-thickness biopsy of the scalp with trypsin and in the latter case collagenase. The so-obtained cells are put into a suspension without cellular expansion by culture and directly applied to the depigmented receiving site. This method is simpler, more rapid than cell cultured techniques, and gives the opportunity to treat small areas. Unfortunately, the possibility of a successful result are lower (3070%) in comparison with other surgical methods (53). Finally, there are culture methods that present many advantages: the most important is that they allow to use small donor sites to cover large hypopigmented areas and to achieve a relatively uniform repigmentation; moreover tissue textural changes are minimal. Unfortunately, there are some disadvantages such as higher costs, need for specic laboratory tests, a 25-week period for cell culture, and the need to use mitogens frequently in enhancing cell growth (36,54). The side effects of surgical therapies are Koebner phenomenon, keloids, hyperpigmentation, especially in darker phototypes, cobblestoning, scarring, and infections. Today, grafts with tissue-engineered skin are under study and seem to give good results with minimal side effects. Depigmentation therapy In the case of a widespread and extensive hypopigmentation, which involves more than 50% of the body surface area, it is advisable to consider the possibility of the depigmentation of the residual pigmented areas (55). This depigmentation is permanent and irreversible and increases the risk of sunburns, premature aging, and skin cancer. The most common technique is based on the topical application of 20% monobenzyl ether of hydroquinone (MBEH) cream, approved by the Food and Drug Administration (FDA) for patients who have vitiligo that involves more than 50% of their body surface area. This compound produces an increased delivery of oxygen radicals, which

induce a gradual and progressive destruction of epidermal melanocytes. The results are visible after 412 months of therapy and the potential side-effects, such as contact dermatitis, conjunctival melanosis, leuko-melanoderma, can occur in sites far from those of MBEH application. 4-Methoxyphenol is a phenol derivative that has melanocytotoxic properties similar to those of MBEH and has similar results to those obtained with MBEH (56); it can be combined with Q-switched ruby laser (56) and cryotherapy (57), obtaining a synergic therapeutic effect. Recently, the use of Q-switched ruby laser has been successfully introduced thanks to its capacity to destroy selectively melanin at its a 694-nm wavelength. This technique, which allows a depigmentation occurring in 714 days, gives better results in comparison to bleaching agents (which require 112 months), with a reduced risk of scarring; this method could be painful, so that the application of an anesthetic cream before the laser procedure is required (58). Another possibility of depigmentation is given by cryotherapy: this approach seems to have no side effects (57); however, the patient must be aware of the possibility of an unwanted repigmentation starting from follicular melanocytes with bad esthetic results. Alternative treatments In the last decade a lot of alternative therapies have been proposed to treat vitiligo: among these the present authors can mention topical treatments such as khellin, melagenina I and II, minoxidil, and the oral assumption of L-phenylalanine associated with light exposure. Some studies have also suggested the possibility to use homeopathy, ayurvedic medicine, climatologic, and balneologic therapies (59).

Conclusion
Vitiligo can be treated successfully with medical, physical, and surgical techniques. Nowadays, minimizing the side effects of treatments and therapies is the true priority at all ages, with special regards to childhood. Optimal clinical results in terms of repigmentation in the full respect of safety are reached with irradiation of the depigmented skin with narrow band UVB-focused treatments. Narrow-band UVB nonfocused irradiation, excimer laser, and monochromatic excimer light associated or not with topical corticosteroids

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cream, derivatives of vitamin D topicals, and calcineurine inhibitors ointment and cream may give excellent results. Surgical therapies and depigmentation treatments can be considered if previous treatments have failed.

References
1. Moretti S, Amato L, Bellandi S, Fabbri P . Focus on vitiligo: a generalized skin disorder. Eur J Inamm 2006: 4: 2130. 2. Ogg GS, Dunbat PR, Romero P, Chen JL, Cerundulo V. High frequency of skin homing melanocyte-specic cytotoxic T lymphocytes in autoimmune vitiligo. J Exp Med 1998: 188: 1203 1208. 3. Koga M, Tango T. Clinical features and course of type A and type B vitiligo. Br J Dermatol 1988: 118: 223228. 4. Nordlund JJ, Lerner AB. Vitiligo. It is important. Arch Dermatol 1982: 118: 5 8. 5. Castanet J, Ortonne JP. Pathophysiology of vitiligo. Clin Dermatol 1997: 15: 845 851. 6. Van der Wijngaard RM, Aten J, Sheepmaker A, et al. Expression and modulation of apoptosis regulatory molecules in human melanocytes: signicance in vitiligo. Br J Dermatol 2000: 143: 573581. 7. Le Poole IC, Wankowicz-Kalinska A, Van der Wijngard RM, Nickoloff BJ, Das PK. Autoimmune aspects of depigmentation in vitiligo. J Invest Dermatol Symp Proc 2004: 9: 68. 8. Gauthier Y, Cario-Andre M, Lepreux M, Pain C, Taieb A. Melanocytes detachment after skin friction in non lesional skin of patients with generalized vitiligo. Br J Dermatol 2003: 148: 95101. 9. Gauthier Y, Cario-Andre M, Taieb A. A critical appraisal of vitiligo etiologic theories. Is melanocyte loss a melanocitorragy? Pigment Cell Res 2003: 16: 322332. 10. Birbeck MS, Breathnach AS, Everall JD. An electron microscope study of basal melanocyes and high level-clear cells (Langerhans cells) in vitiligo. J Invest Dermatol 1961: 37: 5154. 11. Le Poole IC, Das PK, Van der Wijngard RM, Westerhof W, Dutrieux RP, Das PK. Presence or absence of melanocytes in vitiligo lesions: an immunohistochemical investigation. J Invest Dermatol 1993: 100: 816822. 12. Dippel E, Haas N, Grabbe J, Schadendorf D, Hamann K, Czarnetzki BM. Expression of the c-kit receptor in hypomelanosis: a comparative study between piebaldism, naevus depigmentosus and vitiligo. Br J Dermatol 1995: 132: 182189. 13. Morohashi M, Hashimoto K, Goodman TF Jr, Newton DE, Rist T. Ultrastructural studies of vitiligo, Vogt Koyanagi syndrome and incontinentia pigmentis achromians. Arch Dermatol 1997: 13: 755766. 14. Medrano EE, Nordlund JJ. Successful culture of adult human melanocytes obtained from normal and vitiligo donors. J Invest Dermatol 1990: 95: 441445. 15. Tobin DJ, Swanson NN, Pittelkow MR, Peters EM, Schallreuter KU. Melanocytes are not absent in lesional skin of long duration vitiligo. J Pathol 2000: 191: 407 416. 16. Menchini G, Lotti T, Tsoureli-Nikita E, Hercogova J. UV-B Narrowband microphototherapy: a new treatment for vitiligo. In: Lotti T, Hercogov J, eds. Vitiligo, problems and solutions, 1st ed. New York-Basel: Marcel Dekker, Inc., 2004: 323334.

17. Hercogov J, Buggiani G, Prignano F, Lotti T. A rational approach to the treatment of vitiligo and other hypomelanoses. In: Lotti T, Thiers BH, eds. Pigmentary disorders. Ed Elsevier Saunders. Dermatol Clin 2007: 25: 383392. 18. Fitzpatrick TB, Allen Johnson R, Wolff K, Suurmond D. Vitiligo. In: Color atlas and synopsis of clinical dermatology. Common and serious disease. New York: Mcgraw-Hill Companies, 1997. 19. Westerhof W, DIschia M. Vitiligo puzzle: the pieces fall in place. Pigment Cell Res 2007: 20: 345359. 20. Posonsby AL, Lucas RM, Van Der Mei IA. UVR, vitamin D and three autoimmune diseases-multiple sclerosis, type-1 diabetes, rheumatoid arthritis. Photochem Photobiol 2005: 81: 12671275. 21. El Ghorr AA, Norval M. Biological effects of narrow band (301 nn TL01) UVB irradiation: a review. J Photochem Photobiol B 1997: 38: 99106. 22. Hirobe T. The role of keratinocyes derived factors involved in the proliferation and differentiation of mammalian epidermal melanocytes. Pigment Cell Res 2005: 18: 212. 23. Moretti S, Spallanzani A, Amato L, et al. New insights into the pathogenesis of vitiligo: imbalance of epidermal cytokines at sites of lesions. Pigment Cell Res 2002: 15: 87 92. 24. Osawa M, Egawa G, Mak SS, et al. Molecular characterization of melanocyte stem cells in their niche. Development 2005: 132: 55895599. 25. Westerhof W, Nieuweboer-Krobotova L. Treatment of vitiligo with UV-B radiation vs. topical psoralen plus UV-A. Arch Dermatol 1997: 133: 15251528. 26. Lecha M. Use of UVB in vitiligo. In: Lotti T, Hercogov J, eds. Vitiligo, problems and solutions, 1st ed. New York-Basel: Marcel Dekker, Inc, 2004: 341347. 27. Lotti T, Prignano F, Buggiani G. New and experimental treatment of vitiligo and other hypomelanoses. In: Lotti T, Thiers BH, eds. Pigmentary disorders. Ed Elsevies Saunders. Dermatol Clin 2007: 25: 393400. 28. Lotti T, Menchini G, Andreassi L. UV-B radiation microphototherapy: an elective treatment for segmental vitiligo. J Eur Acad Dermatol Venereol 1999: 13: 102108. 29. Menchini G, Tsoureli-Nikita E, Hercogov J. Narrowband UV-B radiation microphototherapy: a new treatment for vitiligo. J Eur Acad Dermatol Venereol 2003: 17: 171177. 30. Lotti T, Rossi R, Campolmi P. Targeted UVB therapy: when and why to start. Arch Dermatol 2006: 142: 933934. 31. Esposito M, Soda R, Costanzo A, Chimenti S. Treatment of vitiligo with the 308-nm excimer laser. Clin Exp Dermatol 2004: 29: 133137. 32. Leone G, Iacovelli P, Paro Vidolin A, Picardo M. Monochromatic excimer light in the treatment of vitiligo: a pilot study. J Eur Acad Dermatol Venereol 2003: 17: 531537. 33. Grimes PE, Soriano T, Dytoc M. Topical tacrolimus for repigmentation of vitiligo. J Am Acad Dermatol 2002: 47: 789791. 34. Grimes PE, Morris R, Avaniss-Aghajani E, Soriano T, Meraz M, Metzger A. Topical tacrolimus therapy for vitiligo: therapeutic responses and skin messenger RNA expression of proinammatory cytokines. J Am Acad Dermatol 2004: 51: 5261. 35. Passeron T, Ostovari N, Zakaria W, et al. Topical tacrolimus and the 308 nm excimer laser: a synergistic combiantion for treatment of vitiligo. Arch Dermatol 2004: 140: 1065 1069. 36. Parsad D, Pandhi R, Dogra S, Kumar B. Topical prostaglandin analog (PGE2) in vitiligo: preliminary study. Int J Dermatol 2002: 41: 942945.

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37. Schallreuter KU, Pittelkow MR, Swanson NN. Defective calcium transport in vitiliginous melanocytes. Arch Dermatol Res 1996: 288: 1113. 38. Milde P, Huser U, Simon T, et al. Expression of 1,25 dihydroxivitamin D3 receptors in normal and psoriatic skin. J Invest Dermatol 1991: 97: 230239. 39. Chiaverini C, Passeron T, Ortonne JP. Treatment of vitiligo by topical calcipotriol. J Eur Acad Dermatol 2002: 16: 137 138. 40. Ermis O, Alpsov E, Cetin L, Yilmaz E. Is the efcacy of psoralen plus ultarviolet a therapy for vitiligo enhanced by concurrent topical calcipotriol? A placebo controlled double blind study. Br J Dermatol 2001: 145: 472475. 41. Parsad D, Phandi R, Dogra S, Kumar B. Clinical study of repigmenattion patterns with different treatment modalities and their correlation with speed and stability of repigmentation in 352 vitiliginous patches. J Am Acad Dermatol 2004: 50: 63 67. 42. Baysal W, Yildirim M, Erel A, Kesici D. Is the combination of calcipotriol and PUVA effective in vitiligo? J Acad Dermatol Venereol 2003: 17: 299302. 43. Hasse S, Gibbons NC, Rokos H, Marles LK, Schallreuter KU. Perturbed 6-tetrahydrobiopterin recycling via decreased dihydrobiopteridine reductase in vitiligo: more evidence for H2O2 stress. J Invest Dermatol 2004: 122: 307313. 44. Koca R, Armutcu F, Altinyazar HC, Grel A. Oxidantantioxidant enzymes and lipid peroxidation in generalized vitiligo. Clin Exp Dermatol 2004: 29: 406 409. 45. Schallreuter KU, Moore J, Behrens-Williams S, Panske A, Harari M. Rapid initation of repigmentation in vitiligo with Dead Sea climatotherapy in combination with pseudocatalase (PC-KUS). Int J Dermatol 2002: 41: 482 487. 46. Schallreuter KU, Wood JM, Lemke KR, Levenig C. Treatment of vitiligo with a topical application of pseudocatalase and calcium in combination with short-term UVB exposure: a case study on 33 patients. Dermatology 1995: 190: 223229. 47. Khemis A, Ortonne JP. Etude comparative dun extrait vegetal possedant une activit superoxide dismutase (VITIX) plus phototherapie UVB selective versus son excipient plus phototherapie selective dans le traitement du vitiligo vulgaire. Nouvelle Dermatologique 2004: 23: 711. 48. DellAnna ML, Mastrofrancesco A, Sala R, et al. Antioxidants and narrow band UVB in the treatmant of vitiligo: a double blind placebo controlled trial. Clin Exp Dermatol 2007: 32: 631636. 49. Middelkamp-Hup MA, Bos JD, Rius-Diaz F, Gonzales S, Westerhof W. Treatment of vitiligo vulgaris with narrowband UVB and oral Polypodium leucotomos extract: a randomized trial double-bind placebo-controlled study. J Eur Acad Dermatol 2007: 21: 942950. 50. Chen YF, Yang PY, Hu DN, Kuo FS, Hung CS, Hung CM. Treatment of vitiligo by transplantation of cultured pure melanocytes suspension: analysis of 120 cases. J Am Acad Dermatol 2004: 51: 6874. 51. Gupta S, Kumar B. Epidermal grafting in vitiligo: inuence of age, site of lesion and type of disease on outcome. J Am Acad Dermatol 2003: 49: 99104. 52. Andreassi A, Pianigiani E, Taddeucci P, et al. Tissueengineered skin in the treatment of vitiligo lesions. In: Lotti T, Hercogov J, eds. Vitiligo: problems and solutions. New York: Marcel Dekker, Inc., 2004: 313321. 53. Leachman S. Surgical therapies. Part III. Melanocyte transplants. Dermatol Ther 2001: 14: 2028. 54. Andreassi L, Pianigiani E, Andreassi A, Taddeucci P, Biagioli M. A new model of epidermal culture for the surgical treatment of vitiligo. Int J Dermatol 1998: 37: 595598. 55. Antoniou C, Nicolaidou E. Depigmentation and vitiligo. In: Lotti T, Hercogov J, eds. Vitiligo: problems and solutions. New York: Marcel Dekker, Inc., 2004: 359364. 56. Njoo MD, Vodegel RM, Westerhof W. Depigmentation therapy in vitiligo universalis with topical 4-methoxyphenol and Q-switched ruby laser. J Am Acad Dermatol 2000: 42: 760769. 57. Radmanesh M. Depigmentation of the normally pigmented patches in universal vitiligo patients by cryotherapy. J Eur Acad Dermatol 2000: 14: 149152. 58. Kim YJ, Chung BS, Choi KC. Depigmentation therapy with Q-switched ruby laser after tanning in vitiligo universalis. Dermatol Surg 2001: 27: 969970. 59. Ghersetich I, Brazzini B, Lotti T, et al. Alternative treatments for vitiligo. In: Lotti T, Hercogov J, eds. Vitiligo: problems and solutions. New York: Marcel Dekker, Inc., 2004: 285.

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