The aetiopathogenic mechanisms of vitiligo are still poorly understood, and this has held back progress in diagnosis and treatment. Up until now, treatment guidelines have existed at national levels, but no common European viewpoint has emerged. This guideline for the treatment of segmental and nonsegmental vitiligo has been developed by the members of the Vitiligo European Task Force and other colleagues. It summarizes evidence-based and expert-based recommendations (S1 level)

Vitiligo is an acquired depigmenting disorder that affects 0.5% to 2% of the world population. Three different forms are classified according to the distribution of lesions; namely non-segmental, segmental and mixed vitiligo. Vitiligo is associated with polymorphisms in genes involved in the immune response and in melanogenesis. However, environmental factors are required for the development of manifest disease. In general, the diagnosis is clinical and no laboratory tests or biopsies are required. Metabolic alterations are central to current concepts in pathophysiology. They induce an increased generation of reactive oxygen species and susceptibility to mild exogenous stimuli in the epidermis. This produces a senescent phenotype of skin cells, leads to the release of innate immune molecules, which trigger autoimmunity, and ultimately causes dysfunction and death of melanocytes. Clinical management aims to halt depigmentation, and to either repigment or depigment the skin, depending on the extent of disease. New therapeutic approaches include stimulation of melanocyte differentiation and proliferation through α-melanocyte-stimulating hormone analogues and through epidermal stem cell engineering. Several questions remain unsolved, including the connection between melanocyte depletion and stem cell exhaustion, the underlying degenerative mechanisms and the biological mediators of cell death. Overall, vitiligo is an excellent model for studying degenerative and autoimmune processes and for testing novel approaches in regenerative medicine. For an illustrated summary of this Primer, visit: http://go.nature.com/vIhFSC.

Oral supplementation with AP containing alpha-lipoic acid before and during NB-UVB significantly improves the clinical effectiveness of NB-UVB, reducing vitiligo-associated oxidative stress.

Several hypotheses have been made about the pathogenesis of vitiligo, and some of them have considered a systemic involvement in the course of the disease. Evidence has been presented on the role of oxidative stress as the initial event in melanocyte degeneration. In accordance with this view, we determined the levels of some antioxidants, i.e., superoxide dismutase, catalase, reduced glutathione, and vitamin E, in erythrocytes and/or peripheral blood mononuclear cells from patients with active or stable vitiligo and from a control group of healthy subjects. In erythrocytes the parameters evaluated were not significantly different. On the contrary, in peripheral blood mononuclear cells, superoxide dismutase activity was increased in both groups of patients, whereas catalase activity, reduced glutathione and vitamin E levels were decreased exclusively in subjects with active disease. The imbalance of antioxidants was associated with hyperproduction of reactive oxygen species due to a mitochondrial impairment as cyclosporin A, an inhibitor of the permeability transition pores opening, significantly reduced the reactive oxygen species production. Moreover an alteration of the mitochondrial transmembrane potential and a higher percentage of apoptotic cells were observed in active vitiligo patients. Based on these results, we suggest that, in vitiligo, mitochondria might be the target of different stimuli, such as reactive oxygen species generation, cytokines production, catecholamine release, alteration of Ca2+ metabolism, all of which capable of inducing melanocyte degeneration.

SummaryVitiligo is an acquired depigmenting disorder characterized by the loss of functioning epidermal melanocytes because of multifactorial and overlapping pathogenetic mechanisms. Besides the immunological approach, the study of the metabolic deregulations leading to toxic damage of the melanocytes appears to be more and more relevant. It was only last year that the first in vitro evidence supporting the link and the temporal sequence between the immune response and the cellular oxidative stress was provided, suggesting that the intrinsic damage of the melanocytes is primitive. What can be the guide line of the multiple altered metabolisms? A compromised membrane could render the cell sensitive to the external and internal agents differently, usually ineffective on the cell activity and survival. The primitive altered arrangement of the lipids may affect the transmembrane housing of proteins with enzymatic or receptorial activities, also conferring on them antigenic properties.

Vitiligo is characterized by the progressive disappearance of pigment cells from skin and hair follicle. Several in vitro and in vivo studies show evidence of an altered redox status, suggesting that loss of cellular redox equilibrium might be the pathogenic mechanism in vitiligo. However, despite the numerous data supporting a pathogenic role of oxidative stress, there is still no consensus explanation underlying the oxidative stress-driven disappear of melanocytes from the epidermis. In this study, in vitro characterization of melanocytes cultures from non-lesional vitiligo skin revealed at the cellular level aberrant function of signal transduction pathways common with neurodegenerative diseases including modification of lipid metabolism, hyperactivation of mitogen-activated protein kinase (MAPK) and cAMP response element-binding protein (CREB), constitutive p53-dependent stress signal transduction cascades, and enhanced sensibility to pro-apoptotic stimuli. Notably, these long-term effects of subcytotoxic oxidative stress are also biomarkers of pre-senescent cellular phenotype. Consistent with this, vitiligo cells showed a significant increase in p16 that did not correlate with the chronological age of the donor. Moreover, vitiligo melanocytes produced many biologically active proteins among the senescence-associated secretory phenotype (SAPS), such as interleukin-6 (IL-6), matrix metallo proteinase-3 (MMP3), cyclooxygenase-2 (Cox-2), insulin-like growth factor-binding protein-3 and 7 (IGFBP3, IGFBP7). Together, these data argue for a complicated pathophysiologic puzzle underlying melanocytes degeneration resembling, from the biological point of view, neurodegenerative diseases. Our results suggest new possible targets for intervention that in combination with current therapies could correct melanocytes intrinsic defects.

The occurrence of oxidative stress has been proposed as a pathogenetic mechanism for melanocyte degeneration in vitiligo. In order to evaluate this possible correlation we focused on the lipid component of cell membranes. We observed in vitiligo melanocytes, through FACS methods, an increased median fluorescence intensity of rhodamine 123 and C11-BODIPY581/591 indicating a spontaneous higher production of reactive oxygen species (ROS) and membrane lipoperoxidation, associated with an altered pattern of cardiolipin (CL) distribution, defined on the basis of the fluorescence pattern after staining with 10-nonyl acridine orange. We confirmed membrane peroxidation by confocal and contrast-phase microscopes and demonstrated impaired activity of the mitochondrial electron transport chain (ETC) complex I. Finally, we observed increased apoptotic events following exposure to the pro-oxidant cumene hydroperoxide by Annexin V/propidium iodide fluorescence. We hypothesize that in vitiligo melanocytes lipid instability, with a defect in the synthesis or recycling of CL, induces ETC impairment and ROS production. In basal conditions melanocytes maintain the redox balance whereas following chemical or physical stress ROS-mediated membrane peroxidation is increased with a possible further CL oxidation, leading to cell death or detachment.

The possible role for a defective mitochondrial functionality in the pathogenesis of vitiligo was investigated by measuring intracellular levels of reactive oxygen species and of antioxidants, the activity of Krebs cycle enzymes, as well as the effects of inhibitors of the electron transport chain, in peripheral blood mononuclear cells from patients with active or stable disease vs. normal subjects. Plasma glyoxal levels were also determined in the same groups of subjects as an index of systemic oxidative stress. In patients with vitiligo in active phase, we observed an increased intracellular production of reactive oxygen species with a consequent imbalance of the prooxidant/antioxidant equilibrium, whereas plasma did not show apparent alterations in glyoxal levels, ruling out a systemic oxidative stress. In patients with stable disease, the balance between pro-oxidants and anti-oxidants seems to be maintained. Moreover, a marked increase in the expression of mitochondrial malate dehydrogenase activity and a specific sensitivity to electron transport chain complex I inhibitor were observed. Overall, these data provide further evidence for an altered mitochondrial functionality in vitiligo patients.