Serena Gianfaldoni1 and Torello Lotti2
1 Department of Dermatology, Università degli Studi Guglielmo Marconi, Rome, Italy
2 Centro Studi per la Ricerca Multidisciplinare e Rigenerativa, Università degli Studi Guglielmo Marconi, Rome, Italy
Vitiligo is an acquired, chronic, pigmentary disorder characterized by the progressive loss of cutaneous melanocytes and/or abnormality in their normal function, resulting in hypopigmented skin areas which progressively become amelanotic.
It is a fairly common skin disease whose worldwide prevalence has been estimated to range between 0.5% and 2.0% . The incidence of vitiligo varies in different countries and ethnicities, ranging from 0.1% to over 8.8% . The highest rates of incidence have been recorded in India, Mexico, and Japan  while the lowest rates are reported in Caucasians of northern Europe, such as Finland, England, and Denmark [1, 2, 4]. Apart from a real difference in vitiligo’s incidence, maybe related to the both genetic and environmental factors, the data is surely complicated by the different modalities in conducting the epidemiological analysis , and to the different psychological impact of the disease in patients of different races [5, 6]. It seems reasonable that the major color contrast between vitiliginous and not‐vitiliginous skin observed in dark‐skinned people leads to a deep psychological stigma, forcing patients to dermatological consultation .
Today, it is generally accepted that vitiligo equally affects both genders [7, 8], and that the higher prevalence in females reported by some studies is only due to a greater negative psychological effect of the disease on women than on men, so that they present for treatment more frequently .
Vitiligo may develop at any age. Most patients (79%–80%) present the disease before 30 years of age [3, 9, 10]. Even if childhood‐onset vitiligo (before age 12 years) is also common, affecting about 32%–37% of all patients [10, 11], rarely has vitiligo been described in newborns and infants .
Vitiligo can be subdivided according the morphological appearance, the extension, and the evolution of the disease.
Among the different morphological features of the disease (Table 8.1), classical vitiligo is characterized by asymptomatic, milk‐white macules and patches with well‐defined borders. Lesions may be singular or multiple, varying in form and size. At first, they are usually small, round, or oval in form, and affect limited cutaneous areas. As the disease progress, lesions tend to enlarge, involving new skin areas, and sometimes coalescing into bigger lesions of figurative aspect .
Table 8.1 Subtypes of vitiligo.
|Subtypes of vitiligo||Characteristics|
|Classical vitiligo||Milk‐white macules, with different sizes and distribution. Particular variants are the punctata, which is characterized by little, punctate‐like, depigmented macules, and the follicular, which involves the follicular reservoir with poor cutaneous lesions.|
|Inflammatory vitiligo||Erythematous halo surrounding the white patches.|
|Trichrome vitiligo||Hypopigmented area between the central amelanotic zone and the peripheral normal skin.|
|Quadrichrome vitiligo||Variant of trichrome vitiligo with foci of repigmentation at the follicular ostia.|
|Pentachrome vitiligo||Lesions show the occurrence of five shades of color, from white to black.|
|Blue vitiligo||Bluish appearance of skin color.|
An uncommon subtype of vitiligo is the inflammatory one, characterized by an erythematous halo surrounding the white patches.
Another rare variant of vitiligo is trichrome vitiligo , which is characterized by a central amelanotic area, surrounded by a hypopigmented halo and, finally, by peripheral normal skin. In darker‐skinned people, a quadrichrome vitiligo may also be described. Clinically, it is characterized by the presence of repigmentation foci at the follicular ostia. Even rarer, the pentachrome vitiligo, in which lesions show the occurrence of five shades of color from white to black , may be also detected.
Finally, another subtype of vitiligo is the blue one, which is characterized by a bluish appearance of skin color, as a result of the presence of dermal melanophages .
Even if vitiliginous patches are more often localized on body folds, periorificial, and sun‐exposed areas (face and digits), the disease may affect different parts of the body, both cutaneous and mucosal. The Koebner phenomenon, consisting of the development of new lesions at sites of skin trauma, is characteristic of vitiligo.
Occasionally, vitiligo patients may show the damage of the hair follicles’ melanocytes, which results in depigmented hairs (also known as “leukotrichia”).
In some cases, they may also present abnormalities of the melanocytes localized in different districts (e.g. eyes, ears, brain, heart, and lungs) [14, 15], and nail abnormalities (e.g. longitudinal ridging, leukonychia, absent lunula, onycholysis, and others) .
Classically, vitiligo may be classified on the basis the extension of the disease, in localized, generalized, or universalis forms.
More recently, the Vitiligo Global Issues Consensus Conference 2011–2012 (VGICC), on the bases of the clinical features and natural history of the disease, has proposed another classification, which recognizes three main types of vitiligo: the nonsegmental vitiligo (NSV), the segmental vitiligo (SV), and the indeterminate forms (Table 8.2) .
Table 8.2 Classification of vitiligo based on the clinical features and natural history of the disease.
|Segmental vitiligo (SV)||One or more vitiliginous patches, in a linear or flag‐like pattern of mosaicism, with a unilateral dermatomal distribution||Unisegmental|
|Nonsegmental vitiligo (NSV)||Heterogeneous group of pigmentary disorders with different localization, usually in a symmetric pattern||Acrofacial|
Mucosal (more than one side affected)
Mixed (associated with segmental vitiligo)
|Unclassified or indeterminate||Focal|
Mucosal (only one side)
NSV is most common form of vitiligo. It is represented by a heterogeneous group of pigmentary disorders with different localization, but which usually involve several body parts, in a symmetric pattern. Typically, NSVs develop in young people between the ages of 10 years and 30 years, have an unpredictable course, and may be associated with comorbidities.
Among NSVs, the most commonly described is the generalized vitiligo (also known as “vitiligo vulgaris” or “common vilitigo”), characterized by multiple lesions in a symmetrical pattern. Although it may affect any part of the cutaneous areas, common vitiligo is most common on the face, the digits, and trauma‐exposed areas.
Another common form of NSV is the acrofacial one, characterized by white patches localized on the face, the head, and on the distal end of the extremities, but that can later progress to widespread forms.
In some cases a mixed vitiligo, consisting of segmental and nonsegmental vitiliginous lesions, may be also be described . Recently, a particular subtype of mixed vitiligo following Blaschko lines has been also described .
Universal vitiligo is another variant of NSV, the most commonly described in adulthood, where it usually represents the evolution of a common form. Clinically it consists of complete or nearly complete skin depigmentation (80%–90% body’s surface). Scalp hair involvement is common, and some patients may also show mucosal lesions.
More rarely, a mucosal vitiligo, characterized by the involvement of the oral and genital mucosa, and sometimes associated with the more common skin lesions, has been described.
More rare variants of NSV are the punctata, the minor or the follicular one. The first one is characterized by punctate‐like, depigmented macules; the second one by a partial defect in pigmentation, which seems to be limited to dark‐skinned individuals; while the third one is a form of generalized vitiligo with poor cutaneous lesions involving the follicular reservoir.
SV is less common than NSV, representing about 5%–16% of overall vitiligo cases . Unlike NSV, SV is characterized by an early age of onset, rapid stabilization, and less common association with comorbidities. Clinically, it is characterized by one or more vitiliginous patches, in a linear or flag‐like pattern, with a unilateral dermatosomal distribution. On the basis of the lesions localization, SV may be classified as unisegmental, bisegmental, or multisegmental. Among these, the unisegmental type is the most commonly described. It consists of the presence of one or more vitiliginous lesions, localized on one side of the body, usually respecting the midline. A particular manifestation of SV is poliosis, which is characterized by a patch of white hair .
Finally, there is undetermined vitiligo, which comprises the focal and the mucosal forms. The first one is characterized by small isolated lesions, without a segmental localization, that do not evolve to NSV after a period of at least two years; the second one is characterized by lesions affecting only one mucosa.
Vitiligo, in particular the nonsegmental forms, is characterized by important comorbidities. The increased risk of developing autoimmune diseases of vitiligo patients is a well‐known data (Table 8.3) . Even if at the moment no laboratory biomarker are available to evaluate the possible association with autoimmune comorbidities, it is recommended to rule out the presence of associated diseases thought the commonest autoimmune antibodies and clinical laboratory data (e.g. anti‐thyroid peroxidase Ab, anti‐thyroglobulin Ab, anti‐thyroid, anti‐parietal gastric cell antibody, total IgE, anti‐nuclear Ab, and others).
Table 8.3 Common autoimmune diseases associated with vitiligo.
Moreover, recent studies underline the possible association of vitiligo with different diseases, such as endocrinologic ones (e.g. hypoparathyroidism) and systemic inflammatory disorders (e.g. obesity, metabolic syndrome) .
Genetics of Vitiligo
To date, more than 30 loci for vitiligo susceptibility have been identified. Among these, only 10% of genes encode for molecules relevant in the normal melanogenesis process (e.g., TYR which encodes for Tyrosinase, MC1R which encodes for melanocortin receptor and regulates the melanogenesis), while the major part of the genes encode for HLA haplotypes (e.g. HLAs‐A2, ‐DR4, ‐DR7, –DQB1*0303) and other proteins, which are implicated in both cellular and humoral immune responses (Table 8.4) [25–28]. Interestingly, some genetic mutations are relevant in determining the association of vitiligo with different comorbidities.
Table 8.4 Genetic alterations which may be detected in vitiligo patients.
|BACH2||BTB and CNC homology 1, basic leucine zipper||B cell transcriptional repressor|
|CCR6||Chemokine receptor type 6||Regulation of B cell differentiation|
|CD 44||CD44 antigen||T cell regulator|
|CD80||B cell activation antigen B7–1||T cell priming by B cells, T cells and dendritic ones|
|CLNK||Mast cell immunoreceptor signal transducer||Immunoreceptor signaling|
|CTLA4B||Cytotoxic T lymphocytes antigen 4||Inhibition of T cells|
|FOXD3||Forkhead box D3||Transcriptional regulator of neuronal crest|
|FOXP1||Forkhead box P1||Regulation of lymphoid cell development|
|FOXP3||Forkhead box p3||Transcriptional regulator of T reg cells function and development|
|GZMB||Granzyme B||Mediator of T cell and NK apoptosis|
|HLA A‐B‐C||Leukocyte antigen B or C α chain||Presentation of peptides antigen|
|HLA‐A||Leukocyte antigen A α chain||Presentation of peptides antigen|
|HLA‐DRB1‐DQA1||Major histocompatibility complex (MHC) class II||Presentation of peptides antigen|
|IFIH1||Interferon‐induced RNA helicase||Regulation of innate antiviral immune responses|
|IL2RA||Interleukin 2 receptor||Regulation of lymphocyte response to bacteria|
|PTPN22||Lymphoid specific protein tyrosinase phosphatase nonreceptor 22||Regulation T cell receptor signaling|
|RERE||Atrophin like protein 1||Regulation apoptosis|
|TG/SLA||Thyroglobulin SRC like adaptor isoform C||Regulation of antigen receptor signaling in T and B cells|
|TICAM1||Toll‐like receptor adaptor molecule 1||Innate antiviral immune responses|
|TSLP||Thymic stromal lymphoprotein||Regulation of T cell and DC (dendritic cell) maturation|
|UBASH3A||Ubiquitin associated and SH3 domain containing||Regulation of T cells signaling|
|XBP1||X‐box binding protein 1||Transcriptional regulator of MHC class II|
Epigenetics in Vitiligo – The Importance of Environmental Factors
Many data support the deep impact of environmental factors in the development of vitiligo.
Apart from the variable prevalence of the disease in different countries, it has been estimated that most cases of vitiligo are sporadic and up to 20% of patients report an affected relative. Moreover, the incidence of concordance of vitiligo in monozygotic twins is only 23% .
Even if their exact mechanism of action is still unclear, the role of different environmental factors (Table 8.5) in vitiligo pathobiology is well‐known, as is the importance to recognize them in order to limit the incidence and the progression of the disease.
Table 8.5 Trigger factors that may be involved in vitiligo onset.
Despite new research and progress, the pathogenesis of vitiligo is still enigmatic and many theories have been proposed about it in recent decades (e.g. autocytotoxic, biochemical, inflammatory, melanocytorrhagy, neurohumoral, and others) [25, 30]. Each theory can be considered valid, and does not exclude the others.
Nevertheless, recent data support that vitiligo is a Tcell mediated autoimmune disease, triggered by oxidative stress [21, 31, 32]. The progressive accumulation of reactive oxygen species (ROS) in melanocytes causes DNA damage, lipid, and protein peroxidation. This leads to the alteration of different proteins, which show the partial or complete loss of their functionality (e.g. inhibition of tyrosinase by the high concentrations of hydrogen peroxide) . Also, keratinocytes show significant damage from oxidative stress, leading to a deficit of their trophic support to melanocytes .
Health‐Related Quality of Life
Although vitiligo is mainly a cosmetic disease without any symptoms, it carries a significant social stigma. Different studies underline how vitiligo has a deep impact on the quality of life (QoL) of patients, who often suffer from shame, embarrassment, and low self‐confidence and socialization [35, 36]. This is important data, because vitiligo is considered as a psychosomatic disease, in which either physical and psychological factors are involved in the onset and course of the disorder .
Apart for patients with comorbidities, vitiligo is generally asymptomatic and its effects on QoL are more related to psychological problems, than the exclusive physical issues. Recently, Lilly et al.  proposed a new specific instrument for estimating QoL in vitiligo: the “Vitiligo Quality of Life” (VitiQoL). This method is based on the analysis of three main factors: stigma, participation limitation, and behavior.
Overall, women had poorer QoL (higher VitiQoL scores) than men. Dark skin phototypes seem to suffer more from their condition than low phototype . Moreover, QoL seems to be better in more educated patients , even if different studies do not confirm this data .