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Jun 4, 2015 - ation and detachment. ... status. Stress-dependent melanocyte detachment has ...... causes more embarrassment and self-consciousness —.
PRIMER Vitiligo Mauro Picardo1, Maria L. Dell’Anna1, Khaled Ezzedine2, Iltefat Hamzavi3, John E. Harris4, Davinder Parsad5 and Alain Taieb2 Abstract | 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

Correspondence to M.P. e-mail: [email protected] Cutaneous Physiopathology, San Gallicano Dermatologic Institute, IFO IRCCS, via Elio Chianesi 53, 00144 Rome, Italy. Article number: 15011 doi:10.1038/nrdp.2015.11 Published online 4 June 2015

Vitiligo is an acquired, chronic depigmenting dis­order of the skin. Although the exact cause is still under debate, the disease results from the selective loss of melanocytes, which in turn causes pigment dilution in the affected areas of the skin and/or mucosa. Melanocyte precursors can be found in the hair follicle bulge; differentiated, pigment-­producing melanocytes reside in the basal layers of the epidermis and the hair matrix (FIG.  1) . Depending on the disease course, skin and hair are affected to different degrees. Clinically, skin lesions present as milky white, non-scaly patches with distinct margins1,2. According to international consensus3,4, vitiligo is classified into three major forms; namely, non-­ segmental vitiligo (or simply, vitiligo), segmental vitiligo and mixed vitiligo (BOX 1). Non-segmental vitiligo is the most common form and is characterized by symmetrical, bilateral white patches. The lesions are typically distri­buted in an acrofacial pattern (hands and feet, peri­ orificial facial involvement) or scattered symmetrically over the entire body, and evolve unpredictably over time. The hairs on the involved skin remain pigmented initially but after a prolonged time, leukotrichia (whiteness of the hair) might develop. The involvement of non-cutaneous melanocytes such as ocular and cochlear melanocytes is controversial3,5–9. Segmental vitiligo accounts for 5% to 16% of overall vitiligo cases10,11 and shows unilateral

distribution, which totally or partially matches a cutaneous segment, of recognizable but difficult to interpret pattern12. The onset is usually at an earlier age than for non-segmental vitiligo and rapidly involves the follicular melanocyte reservoir (FIG. 1), which results in hair whitening 12,13. The course of non-segmental vitiligo is unpredictable, whereas that of segmental vitiligo is typically of sudden onset with rapid stabilization over a few months after partial or complete depigmentation of the affected segment. Mixed-type vitiligo shows segmental involvement initially, but a second phase with the onset of bilateral vitiligo patches usually follows4. In this Primer article, we summarize the clinical presen­tation and management of vitiligo, and we highlight underlying degenerative and inflammatory p­rocesses that lead to melanocyte degeneration.

Epidemiology Vitiligo is the most common depigmenting disorder worldwide (TABLE 1). The largest epidemiological study was performed in 1977 on the island of Bornholm in Denmark, where the disease was found to affect 0.4% of the population14. In the predominantly black population of the French West Indies, similar results were obtained15. Overall, the estimated worldwide prevalence is 0.5% to 2% but peaks of up to 8.8% have been reported in India, possibly relating to the inclusion

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PRIMER Author addresses Cutaneous Physiopathology, San Gallicano Dermatologic Institute, IFO IRCCS, via Elio Chianesi 53, 00144 Rome, Italy. 2 Service de Dermatologie et Dermatologie Pédiatrique, Centre de référence pour les maladies rares de la peau, INSERM 1035, Université de Bordeaux, Bordeaux, France. 3 Multicultural Dermatology Center, Department of Dermatology, Henry Ford Hospital Detroit, Michigan, USA. 4 Division of Dermatology, Department of Medicine, University of Massachusetts Medical School, Worcester, USA. 5 Department of Dermatology, PGIMER, Chandigarh, India. 1

of chemically induced depigmentation16,17. Reports from Mexico and Japan also indicate high incidences of vitiligo17. A study, which included a large Chinese population 18 and, therefore, possibly bypassed the selection bias of hospital-based studies, confirms an overall prevalence of 0.6%, with lower prevalence of the segmental form (2.5% of the total prevalence) and higher prevalence of focal vitiligo (36%) than reported in other studies. Differences in disease classification, lack of simple laboratory tests, varied populations and inconsistent reporting by patients could account for this variability in epidemiological data. Moreover, discrepancies between prevalence and incidence data might be attributable to a higher reporting rate in countries in which the social and cultural stigma is considerable or the population has darker skin and, therefore, more prominent lesions19–23. Most cases of non-segmental vitiligo occur sporadically. Between 15% and 20% of patients have one or more first-degree relatives with vitiligo24. Adults and children of both sexes are equally affected, even if women seek treatment more frequently, probably as a consequence

Epidermis Epidermal melanocyte Sebaceous gland

Dermis Hair

Bulb

Bulge (keratinocyte and melanocyte stem cell)

Bulb melanocyte Dermal papilla

Figure 1 | The hair follicle unit.  The anatomical distribution differentiated and Nature of Reviews | Disease Primers immature melanocytes is shown. The melanocyte stem cells reside in the bulge of the hair follicle, which is located next to the sebaceous gland, whereas differentiated melanocytes are located in the papilla and the epidermis.

of greater social burden19,20. The prevalence increases with age (0.5% in children