Doi:10.1016/j.det.2007.04.009

New and Experimental Treatments of Vitiligo Torello Lotti, MD, Francesca Prignano, MD, Department of Dermatological Sciences, University of Florence, Via Lorenzo il Magnifico, 104, 50129, Florence, Italy cutaneous hypopigmentation, and this article is In recent years, the interest in vitiligo, among dedicated to the introduction of and discussion all the other hypopigmentation disorders, is in- about the most recent and innovative researches creasing, partly because of the aesthetic challenge in the treatment of vitiligo and other depigment- represented by the disease itself and partly as a ing disorders. It also provides a description of the reaction to the intolerable discrimination against newly developed techniques that are in the hands the affected subjects. Vitiligo is not an unmanage- of dermatologists, dermato-cosmetologists, and able disease, and many studies on new therapeutic protocols showed a relevant efficacy, even if we We cannot ignore the fact that among all the are far from the ultimate therapy This interest hypomelanoses, vitiligo is the most remarkable in vitiligo has the effect of discovering alternative and challenging and that almost all the research and, in some cases, more efficient treatment mo- and innovations made in the field of hypopigmen- dalities to be used in other primitive or secondary tation treatment are caused by the continuous hypomelanoses, such as piebaldism, pityriasis alba, efforts to reach the ultimate therapy for vitiligo.
posttraumatic and postinfectious hypopigmenta- We must be fully aware that not all hypopigmen- tation disorders respond in the same way to the different treatment modalities. Several hypomela- noses are reversible and do not require any resetting completely the appearance and function treatment. In contrast, therapy of permanent of the healthy skin. Melanocytes usually respond hypomelanoses is difficult and often unsuccessful.
slowly to the different treatments, so it could take Multiple treatment options are available for de- several months to reach acceptable results in term pigmentation caused by vitiligo, whereas the treat- of repigmentation. Affected subjects must be ment of leukoderma in disorders such as nevus aware of this process and acquiesce with the depigmentosus, hypomelanosis of Ito, tuberous possibility of a long-term therapy. Newly avail- sclerosis, and piebaldism is limited. Because of able treatments for hypopigmentation are medi- their inflammatory etiology, postinflammatory cal, physical, and surgical, alone or in association hypopigmentations may be well treated with clas- sical approaches (eg, topical corticosteroids andphototherapy). Conversely, disorders such as ocu- locutaneous albinism are not currently capable ofundergoing repigmentation therapy.
stimulated by UV light in terms of effectiverepigmentation must be confirmed, the efficacyof UVB light in vitiligo is probably caused by the production of high levels of cis-urocanic acid, a metabolic product that causes cutaneous 0733-8635/07/$ - see front matter Ó 2007 Elsevier Inc. All rights reserved.
doi:10.1016/j.det.2007.04.009 are related to less erythema, no phototoxic effects, and no epidermal thickening after long-term irra- diation. No statistical differences exist betweenPUVA, NB-UVB, or broadband UVB regarding UVB narrow band microphototherapyUVB narrow band excimer laser and Ultraviolet B narrow band microphototherapy This new therapeutic approach evolved from the consideration that vitiligo patients undergoing phototherapy were receiving a high cumulative dose of radiation during their lives, which led to secondary cutaneous disorders, such as photo- aging, telangiectasias, and excessive tanning.
These considerations led to the development of which involved so-called ''microphototherapy''. Microphototherapy is based on a photo expo-sition limited to well-defined areas, and it avoids immune suppression. Melanogenesis is thought to the collateral effects associated with diffuse photo- be stimulated by UVB radiation through the therapy (eg, photoaging, erythema, and burns) activation of nitric oxide-cGMP-proteinkinase G pathway, and/or by the activation of the cAMP- TL-10) with a wavelength peak at 311 nm that is pathway by alpha-melanotropin, and/or through selectively delivered to the white patches. It en- melanocyte-stimulating hormone receptor-bind- ables drastic reduction of the total dose of radia- ing activity and melanocortin receptor gene ex- tion and the most common side effects related to the exposition to UV rays: excessive tanning of The first data on the use of UVB in the treatment the nonaffected skin, photoaging, telangiectases, of vitiligo (broadband UVB: 280-320 nm) ap- and the risk of neoplasms. It also avoids an peared in 1990, whereas the first report on UVB increase in the chromatic contrast between normal narrow band (NB-UVB) therapy (NB-UVB: 311 and lesional skin. With this treatment, one can Æ 2 nm) appeared in 1997 This latter study administer different doses of UVB radiation in showed that NB-UVB were more effective, com- different areas of the body (ie, the hands need pared with topical UVA treatment, in the treat- more UVB than the eyelids to repigment), which ment of vitiligo, with faster repigmentation and optimizes the treatment by tailoring it to each less contrast between normal and depigmented skin. Subsequent meta-analysis on nonsurgical The initial dose of radiation is 20% less than treatments for vitiligo showed that results obtained the minimum erythema dose, which is evaluated with UVB and NB-UVB therapy were almost the through the exposition of affected and unaffected same as results obtained with psoralen plus Ultra skin to increasing doses of UVB (80, 160, 240, Violet A (PUVA). A combination of UVB and 320, 400 mW/cm2) at least 3 days before the be- other therapies, such as pseudocatalase, calcipo- ginning of the treatment. During the following triol, and phenylalanine, was considered.
sessions, each patch is uniformly irradiated. In Treatment protocols vary in different studies, ''sensitive'' areas (eg, eyelids), 80% of minimum with an initial dose of irradiation ranging from erythema doses are used. The radiation dose is 0.075 J/cm2 to 0.25 J/cm2 and increasing by 20% increased by 20% at each session. When erythema after each treatment until a slight erythema is occurs, the dose is lowered by 20% in the ery- reached. Cumulative doses are lower than in thematous area only. Some skin areas can resist PUVA therapy, however. Stating the major ad- photostimulation better and are irradiated with vantages of avoiding psoralen side effects and higher regimens (up to twice the dose of the low cumulative dose of radiation, evidence-based most sensitive areas). Sessions are repeated every guidelines for the treatment of vitiligo indicate 21 to 30 days until repigmentation is reached, that NB-UVB phototherapy is recommended for generalized vitiligo UVB treatments can be Partial repigmentation is often seen after at safely used in pregnant women and children and least three to six sessions (63% of the cases), beginning just after 2 months of treatment as treatment duration (ranging from 17-57 months a pigment pitting around each follicular ostium of therapy in this study) and lower mean duration (follicular repigmentation) usually accompanied by an evident interfollicular repigmentation. Pho- This technique, which is among the newest tographic evaluation is useful to assess the clinical ones, should deserve further attention, and results, and Wood's light is used for lighter perhaps focus on the treatment of other diseases that occur with hypomelanosis. Similarly, mono- In a recent study, 734 patients were irradiated chromatic excimer light has shown similar positive using this protocol every 2 weeks for 12 consec- effects in the repigmentation of vitiligo patches utive months At the end of the study period, 69.8% of patients (n ¼ 510) achieved normal pig-mentation on more than 75% of the treated areas, 21.12% (n ¼ 155) achieved 50% to 75% repig-mentation on the treated areas, and only 9.4% Low levels of catalase in the epidermis of (n ¼ 69) showed less than 50% repigmentation patients who have vitiligo increase H2O2 levels, with no statistical significance between segmental which inhibits 6-BH4 metabolism and melanogen- and nonsegmental vitiligo. (In 5 patients in this esis. The use of creams containing pseudo- group the vitiligo was aggravated.) The results of this study are similar to those obtained by to- progression and induce repigmentation. Pseu- tal-body UVB irradiation in international studies, docatalase acts as a substitute for impaired levels enriched by the advantages of fewer side effects.
of catalase, degrading excessive hydrogen perox- Microphototherapy is particularly useful in ide and allowing recovery of enzyme activities.
patients affected by segmental vitiligo and bi- Narrow band UVB-activated topical pseudocata- lateral symmetrical vitiligo in whom the total lase has been proposed for vitiligo treatment, amount of body surface involved is less than but although some repigmentation has been ob- 20%. The only side effect occasionally reported served in approximately 60% of patients treated is transient erythema, rarely followed by desqua- with this modality, the degree of contribution of the UVB radiation to these results is not known tered to patients who have actinic sensitivity (eg, systemic lupus erythematosus, xeroderma pigmen- Some authors report positive results after tosum, porphyriasis, cutaneous viral infections) or topical administration of tacrolimus ointment patients treated with topical or systemic photosen- 0.1%, particularly on sun-exposed areas of the skin (eg, face and neck) Tacrolimus seemsto work selectively by inhibiting T-lymphocyteactivation, which blocks the production and secretion of proinflammatory cytokines, such as tumor necrosis factor-a, whose levels are in- After the consistent results obtained by narrow creased in vitiligo skin but not in healthy controls band microphototherapy with light source devices . This finding suggests that repigmentation such as BIOSKIN, another innovationdstill ex- could be partly associated with reduced levels of perimentaldwas introduced: excimer laser ther- tumor necrosis factor-a in affected skin. The asso- apy and monochromatic excimer light therapy ciation of tacrolimus ointment with excimer laser with monochromatic UV rays at 308 nm. These 308 nm seems an effective treatment for vitiligo, therapies are not so different from the ''classical'' but the possibility of unexpected sunburns must narrow band radiation. They are capable of selectively treating single hypopigmented patches similarly active in the treatment of vitiligo and sparing nonaffected areas. A recent study analyzed the effects of excimer laser in 24 patients A recent approach to the treatment of vitiligo and reported total repigmentation in the treated is based on the thought that UV ray-induced areas in 12% of subjects (n ¼ 7), partial (25%- melanogenesis is partly caused by UV-induced 75%) repigmentation in 25% (n ¼ 6), less than turnover of membrane phospholipids that gener- 25% repigmentation in 25% of patients, and no ate prostaglandins and other products, maybe results in 20.8% of patients (n ¼ 5) The representing the activating signal for repigmenta- efficacy of the treatment seems to be related to tion. Some authors observed in vitro enhancement of melanogenesis by PGE2, and in a recent study responsive to medical treatment and in patients vitiligo patients with less than 5% skin involve- who have piebaldism or persistent depigmentation ment were treated with a topical a gel that con- caused by halo nevi, thermal burns, trauma, or tained 166.6 mg/g PGE2 applied in the evening inflammation. Surgical options are considered for patients who have vitiligo with areas of involve- 24 patients evaluated at the end of the study pe- ment more than 2 to 3 cm that contain depig- riod, 15 reported marked (50%-75%) to complete mented hairs or involvement of sites such as the repigmentation (6 focal vitiligo, 7 vitiligo vulgaris, lips or fingers, which are unlikely to have a satis- 2 segmental vitiligo), whereas 6 patients showed factory response to medical therapy. It is manda- 25% to 50% improvement and 6 showed minimal tory that the disease be stable; stability is the most or no improvement. The observed side effects were critical factor in the selection of patients with episodes of mild irritation after exposure to sun- recalcitrant vitiligo as candidates for surgical light. Although the exact mechanism of repigmen- repigmentation. Some authors suggest surgically tation is not clear, different mechanisms have been treating vitiligo patches only if stable for at least 2 suggested, including (1) influencing melanocyte years and performing a minigrafting test before responsiveness to neuronal stimulation, (2) mela- the graft to evaluate the positive response and the nocyte proliferation, and (3) direct or second mes- absence of koebnerization at the donor site after 2 senger-mediated interaction with melanocytes to 3 months follow-up Active vitiligo has through the stimulation of tyrosinase activity.
a higher risk for graft failure, recurrence of depig- Other mechanisms that do not directly involve mentation, and koebnerization at the donor site melanocytes have been proposed, but one of the . Other important factors that affect graft out- most interesting focuses on the immunosuppres- come in patients who have vitiligo include the lo- sive role of in vitro and in vivo PGE2. Other cation and type of disease, with 95% success rates trials should be undertaken to evaluate the correct for test grafting in segmental or focal vitiligo ver- use of topical prostaglandin analogs in patients sus 50% or less in generalized vitiligo A re- cent review on this argument showed that better Patients who have vitiligo exhibit reduced surgical results can be obtained in segmental viti- levels of intracellular calcium in keratinocytes and ligo and in patients younger than age 20 melanocytes The calcium decrease parallels Because of the multiple, time-intensive pro- increased thioredoxin levels, which could inhibit cedures involved in autologous transplantation, tyrosinase activity and melanogenesis. Derivatives these techniques are best suited for repigmenta- of vitamin D act on melanocyte receptors for 1,25- tion of limited areas of leukoderma, with priority dihidroxy-vitamin D, modifying the altered calcium given to exposed sites. They are reserved for homeostasis and permitting a more rapid repigmen- adolescents and adults who are firmly motivated.
tation when used alone and when associated with Surgical therapies are not recommended for patients with a tendency to form keloids or Cucumis melo extracts have shown relevant su- develop hyperpigmentation after minor trauma, per-oxide-dismutase and catalase-like activities and success has not been reported in disorders of when associated with selective UVB therapy hypopigmentation, such as nevus depigmentosus In vitro and experimental data show an interesting performance of this vegetable extract, which is Techniques of surgical repigmentation involve well accepted by patients who have vitiligo and the transfer of melanocytes, melanocytes and family members of children affected by the keratinocytes, or full-thickness skin from normally disease. Excellent results have been observed in pigmented areas to hypomelanotic patches. Autol- association with focused UVB narrow band (BIO- ogous skin grafts can be divided into three major SKIN) treatment, which shows that the associa- groups: (1) grafting of normal skin (epidermis with tion represents a safe and effective treatment and or without dermis) that contains melanocytes, (2) is well tolerated and accepted by patients grafting of a noncultured epidermal or hair folliclesuspension that contains melanocytes, and (3)grafting of cultured melanocytes with or without keratinocytes, in suspension or as sheets The first group includes different techniques.
repigmentation in a subset of patients who have The thin dermo-epidermal grafts technique in- stable vitiligo that is refractory or partially volves replacing the achromic lesions of vitiligo with thin dermal and epidermal sheets that are hair follicles and the epidermis. The cells are put taken from the donor site with a dermatome at into a suspension for direct application to the a depth of 0.1 to 0.3 mm to avoid scarring.
recipient site without expansion by culture Superficial dermabrasion is used to prepare the This technique is relatively simpler and less time receiving site to the graft. This method is success- consuming than other methods (especially cell cul- ful in up to 80% of treated patients, avoids ture methods) and smaller areas can be treated, scarring, and permits repeated grafts from donor but rates of success are lower (30%-70%).
sites. A possible variation is so-called ''seed Cultural methods can be applied to surgical grafting,'' in which a thin piece of epidermal techniques. Cultured epidermis with melanocytes skin graft is taken from the donor site with with or without keratinocytes and cultured mela- a hand dermatome and minced into fragments nocytes with or without keratinocyte suspensions smaller than 1 mm2. These pieces are placed on can be applied to previously dermabrased re- the epidermal-abraded vitiligo lesions and covered cipient areas. The donor sites can be small, and with a specific medication for 5 to 7 days. Photo- the cells are seeded to stimulate melanocytes and therapy can follow surgery to enhance results.
keratinocytes until many more cellsdor even Suction-blister epidermal grafting using suction a thin epidermal sheetdare obtained and placed devices is another similar technique that is popu- on recipient sites previously prepared with one of lar and yields excellent results. Full-thickness the various methods. With this technique, satis- minigrafts (1-2 mm) have become one of the most factory results are obtained even when treating up common surgical methods to treat vitiligo. Multi- to 30% of total body surface, with more than 75% ple donor areas are harvested with a small punch repigmentation rate in more than half of treated (1-1.2 mm). Minigrafts are placed in the recipient patients Small donor areas can be used to areas, which are prepared depending on the graft cover large hypopigmented areas (up to 500 times type. The grafts range from the removal of larger than the donor site). The achieved repig- ''punches'' similar to those harvested from the do- mentation is relatively uniform, with only minimal nor area to liquid nitrogen-induced blisters, derm- textural changes. Cell cultures are more expensive abrasion, or laser ablation (eg, Er:YAG laser) and than other surgical methods, require specific labo- are sealed with sterile adhesive medication. This ratory facilities, and require a 2- to 5-week period method allows repigmentation in 1 to 3 months in 70% to 100% of cases by melanocytes spread- Side effects of vitiligo surgery include Ko¨bner phenomenon of the donor site, keloids, hyperpig- monly located on the medial upper arms, thighs, mentation, ''cobblestoning,'' scarring, and infec- or buttocks (''hidden'' sites).
tion. Careful handling of the donor and recipient Methodologic variations include flip-top trans- plants, in which the epidermis at the recipient site Treatment with tissue-engineered skin uses is not removed but rather used to form multiple biomaterials such as perforated membranes of hinged flaps, each covering an ultrathin 1- to 2- semi-synthetic biopolymers of hyaluronic acid mm graft harvested from the donor site using 100% esterified with benzyl alcohol. Epidermal a razor blade Single-hair grafting techniques culture obtained from normally pigmented sites is from donor sites on the scalp are particularly ef- optimally delivered to the recipient achromatic fective for treating hairy areas, such as the eyelids patches previously de-epithelized by laser abla- and eyebrows. Repigmentation of hairs in tion. Excellent and lasting repigmentation without areas of leukotrichia also has been observed side effects has been reported. Surgical repig- with this and other methods, which suggests a mi- mentation techniques can be used with other gration of melanocytes from the grafted epidermis therapeutic protocols, such as BIOSKIN micro- to the external root sheath of the hair follicle and then to the hair bulb. Posttransplantation sunlight . Cell culture techniques also can require exposure for 10 to 15 minutes per day or photo- the use of mitogens to enhance cell growth.
therapy can help stimulate melanogenesis In transplants of noncultured keratinocyte/ melanocyte suspensions, donor tissue from a shavebiopsy of the buttocks or full-thickness biopsy of In patients with extensive areas of depig- the scalp is digested with trypsin anddin the latter mentation or disfiguring lesions that do not res- casedcollagenase to obtain melanocytes from the pond to repigmentation therapies, therapeutic depigmentation of the residual pigmented areas Q-switched ruby laser, like chemical depigmenta- of the skin should be considered. Patients should tion, does not seem to kill follicular melanocytes.
be informed that therapeutically induced depig- Cryotherapy has been used recently for de- mentation is permanent and irreversible and that pigmentation in patients who have vitiligo be- they always will be at risk of suffering sunburns, cause of its known melanotoxic capabilities premature ageing, and cutaneous neoplasms. It is In this study, five patients were treated with one necessary to minimize sun exposure and apply to three sessions of cryotherapy, and all of them achieved complete depigmentation with no side effects. After 8 months follow-up, two patients proved the use of monobenzyl-ether of hydroqui- showed partial lentigo-like repigmentation on sun- none (MBEH) for depigmentation in patients who exposed areas, which was retreated with cryother- have vitiligo that involves more than 50% of their apy or chemical peeling. Repigmentation is still body surface area. People who suffer from a less a problem, however, as is the case with all depig- widespread vitiligo can benefit from depigmenta- tion therapy, however, particularly because alter-native modalities have been developed. Recently, the sequential use of 4-methoxyphenol and the Alternative treatments include light exposure have been reported as alternative options for de- L-phenylalanine (oral or topical), khellin (topical), melagenina I and II (topical), and topi- pigmentation therapy, with promising results.
cal minoxidil treatment. Homeopathy, ayurvedic medicine, and climatologic and balneologic thera- or mequinol) is a phenol derivative with melano- cytotoxic properties (similar to those of MBEH)that has been used in patients who have vitiligowith results comparable to those obtained by to MBEH because in many European countries treated successfully with medical, physical, and the latter is no longer available, mainly because surgical techniques with excellent results. Thera- of its side effects. As for MBEH, the indication peutic strategies are being developed to minimize for using 4-methoxyphenol includes only depig- the side effects of previous treatments and are mentation in patients who have vitiligo.
used for children with vitiligo. To reach optimal A recently developed depigmentation therapy clinical results in terms of repigmentation and for vitiligo is based on the use of Q-switched ruby minimizing side effects, narrow band UVB- laser, which has a wavelength of 694 nm and is focused treatment represents the treatment of capable of selectively destroying melanin and choice when vitiligo affects less than 10% of the melanin-containing structures of the skin The risk of scarring is minimal, and depigmenta-tion is rapidly achieved (7-14 days) comparedwith bleaching agents (1 month-1 year). Pain caused by the procedure can be managed easily [1] Njoo MD, Spuls PI, Bos JD, et al. Non surgical by applying a topical anesthetic cream before repigmentation therapies in vitiligo: meta-analysis the procedure. Because laser treatment is thought of the literature. Arch Dermatol 1998;134:1532-40.
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