What’s new in the treatment of vitiligo

By the middle of the twentieth century, vitiligo was a condition with little therapeutic possibilities. At this time, 8-methoxypsoralen, a molecule purified from the plant Ammi majus was introduced for the first time, used initially with sunlight exposure1 and later on with ultraviolet (UV) A, a therapy that is yet valuable today for generalized forms of vitiligo.2 By the same years, corticosteroids were also introduced and found successful in several dermatological ailments; newer molecules of higher potency were progressively discovered and tried with significant repigmentation rates reported in localized forms of vitiligo.3 These two medications, with some modifications were prescribed during the second half of the twentieth century in numerous vitiligo patients with noticeable success. Other molecules used during these years offered different degrees of effectiveness and some examples are 5-methoxypsoralen, phenylalanine, khellin, 5-fluoruracil, anapsos, folic acid, levamisole, antioxidants, tretinoin, calcipotriol and other pharmacological agents,4 some of which did not reach popularity because of lack of proven efficacy or were abandoned because of significant side-effects. During the 60s and 70s melanocyte grafting, and more recently in the 80s and 90s cultured pigment cell transplantation, were introduced as important tools in the dermatological armamentariun for vitiligo; by providing a new source of pigment cells implanted into achromic lesions of patients with refractory and stable disease not responding to diverse or prolonged therapies, additional patients began to experience a cure for depigmented skin, and remarkable repigmentation similar to that obtained with psoralen + UVA (PUVA) and other treatments was since then observed and reported by different investigators.5 Another contribution for the management of vitiligo proposed rather recently was narrow-band UVB; with this specific UV spectrum high repigmentation figures were obtained as reported with PUVA with the advantage of not requiring psoralens and, therefore, without the hazards of phototoxicity, cataract formation and possible development of skin cancer due to DNA alterations. Smaller but similar devices for UVB microphototherapy, were also used for localized disease, with interesting results.6 Aside from the usefulness of total body topical psoralen photochemotherapy7 other variations of this therapeutic approach have also been reported, such as the one described in this issue of the Journal of the European Academy of Dermatology and Venereology with a topical 8-methoxypsoralen cream plus local phototherapy four times a week in which the risk of phototoxicity is reduced, as this pharmacological presentation has a limited phototoxic effect lasting 4 h; remarkable repigmentation was achieved on the affected areas of a patient with vitiligo; however, as the lesions were located on the face, an area of not much difficulty to repigment, additional patients should be treated to detect the possibilities of this interesting treatment on different anatomical areas. Decreased levels of catalase, the scavenger for highly reactive substances accumulating in the epidermis of patients with vitiligo has been detected during recent years; this finding originated an interesting molecule for vitiligo therapy, pseudocatalase, based upon its ability to remove hydrogen peroxide from the depigmented epidermis;8 although in vitro experiments and the clinical response in several patients are encouraging, this treatment needs further confirmation with more patients, and if the results are favourable it will certainly open additional possibilities for newer therapies by neutralizing the effect of reactive molecules provoking vacuolation and further damage to pigment cells. Some recent advances include the use of a special diathermosurgery device for very precise removal of depigmented epidermis previously to the successful transplantation of in vitro cultured epidermal sheets,9 and erbium yttrium–aluminium–garnet or CO2 lasers used for the same purpose. Today, as never before, we have an acceptable spectrum of many effective treatments for vitiligo; however, as an average and considering all affected anatomical locations, the best repigmentation rates do not reach figures beyond 70–75%, with acral regions and lesions with leucotrichia being the most difficult to repigment and with the lowest recovery rates. The affected anatomical area becomes then a very important factor that can anticipate the repigmentation outcome, with ‘hard’ areas for hands and feet or lip-tip vitiligo, ‘intermediate’ areas for the trunk and proximal extremities, and ‘bland’ areas for the face and neck. But why do these areas have a different repigmentation response? The number of hair follicle units per area (melanocytes within reservoir) and the amount of epidermal melanocytes in every one of these anatomical locations (melanocytes per mm2) (e.g. being higher in facial regions and lower on the acral areas), may be a partial explanation for this response, but other unknown factors cannot be underestimated. Therefore, if we still have areas that are difficult to repigment with the available therapies, what could be a rational approach to treat vitiligo? Combination therapy would be a possible answer. With the current treatments that have been effective for the correction of diverse pathogenic factors involved in vitiligo skin such as modulation of T cells, controlling systemic immune alterations, reducing epidermal hydrogen peroxide, direct melanocyte stimulation with UV sources, antioxidants, etc., it is conceivable that with the combination of several of such therapies, the repigmentation response in vitiligo could be improved. Furthermore, if medical methods are combined with surgical interventions, particularly to ‘seed’ pigment cells within those areas where the melanocyte reservoir is depleted, or in those lesions where anatomically there are few possibilities for an appropriate response as happens in acral areas, this approach could facilitate recolonization by melanocytes, inducing a more rapid and efficient repigmentation. At present, pretending to increase the present percentages of repigmentation in vitiligo by monotherapy is probably far from reality, particularly for refractory disease and especially acral vitiligo; combination therapy could be an interesting option, but newer protocols evaluating the use of multitherapies should be tried. Meanwhile, according to a recent meta-analysis, the guidelines for vitiligo treatment should include class 3 topical corticosteroids for localized disease, PUVA and narrow-band UVB for generalized vitiligo, surgical interventions for segmental, stable and lip-tip vitiligo, and depigmentation with monbenzone or Q-switched ruby laser for residual pigmented macules in vitiligo universalis.10 Research is a priority in vitiligo in order to find the complete sequence of pathogenic events leading to depigmentation, and most certainly the recently described human genome will have much to do with this item. As stated by many, vitiligo is a multifactorial illness with diverse biomolecular alterations, and with different clinical manifestations such as unilateral and bilateral lesions, sometimes associated with endocrine or immune disorders; these facts lead us to the question: are we also dealing with different aetiological mechanisms for the single disease that we call vitiligo? Besides serious efforts to clarify the aetiology of vitiligo, future therapy should include better molecules for pigment cell manipulation. Melanocytes are ‘lazy’ and ‘slow’ cells with a limited capacity for repigmenting just a small area around their near vicinity. When a keratinocyte located at the edge of a healing ulcer, comes in contact with the surface without epithelium it switches its differentiating mode from a typical columnar cell into a proliferative mode; this has the characteristic appearance of a flat cell that does not stop dividing and migrating continuously on the ulcerated surface until complete epithelialization is accomplished. Melanocytes within a depigmented area in vitiligo arising from a pigmented hair (reservoir), however, do not originate perifolicular repigmentation beyond 10–12 mm at the most; similarly, melanocytes from a 1-mm graft, do not provide repigmentation extending more that 2 or 3 mm beyond the edge of the graft, a fact that becomes more evident as mentioned before in certain anatomical locations. If we had a safe molecule for topical use, with the ability of being a signal for continuous melanocyte division, for inducing neomelanogenesis and for stimulation of pigment cell migration, perhaps we would have the most powerful weapon to fight vitiligo. In this regard, previous studies in vitro demonstrated stimulation of melanocyte migration by basic fibroblast growth factor, leukotriene C4, transforming growth factor-α and endothelin-1, disclosing that this may be an interesting possibility.11 In addition, if small 1 mm islands of pigment cells are implanted into depigmented defects, probably not closer than 2–3 cm from each other, this combination therapy could create sufficient amounts of new melanocytes that would reproduce and spread repigmenting extensive areas. Microsurgical procedures could then become important methods for providing new pigment cells on those highly resistant vitiligo areas, whenever melanocytes no longer exist; however, a must should be stabilization of the depigmenting process and the simultaneous use of the already mentioned melanocyte-stimulating molecules. Similarly, cultured melanocytes could also provide a great supply of cells, but complete knowledge of melanocyte biology in vitro is necessary before pigment cell cultures may be used safely in daily routine. To conclude, unravelling the pathogenesis of vitiligo will lead us to find a treatment for arresting completely the mechanisms of depigmentation and to convert vitiligo into a definitive stable condition. Under these circumstances repigmentation should be rather simple to accomplish with a combination of medical and surgical treatments.