Handbook of Vitiligo: Basic Science and Clinical Management Iltefat H. Hamzavi, Bassel H. Mahmoud, Prescilia N. Isedeh
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Overview of vitiligo1

Bassel H. Mahmoud,
Iltefat H. Hamzavi
Vitiligo is an acquired pigmentary disorder of the skin and mucous membranes that is characterized clinically by the development of well-circumscribed white macules and patches of skin and hair with absence of melanocytes microscopically (Taieb & Picardo 2007).
 
Historical background
The Roman physician Celsus introduced the term ‘vitiligo’ in the 2nd century AD, and the history of psychosocial effects was described in Vedic literature (Millington & Levell 2007). ‘Vitiligo’ is derived from the Latin vitium, meaning ‘blemish’ (Nair 1978). The Latin derivation relates to the white, glistening flesh of calves (vitelius). Vitiligo was first described more than 3500 years ago (Figure 1.1). Both pre–Hindu Vedic and ancient Egyptian texts describe depigmented macules. In the Charaka Samhita, one of the first textbooks of Ayurvedic medicine, svitra (‘whiteness’) is recorded as a diagnosis. Other descriptions are included in the Quran and Buddhist scripts. An accurate description also exists in a collection of Japanese Shinto prayers, Amarakosa, dating from 1200 BC. In the Ebers Papyrus, an Egyptian collection dating from 1500 to 3000 BC, leprosy is recorded as a pale swelling, distinct from vitiligo. However, there is no such demarcation between the two diseases in either the Bible or the first European description of the disease by Hippocrates. In certain Hindu texts, a person who is said to have committed a particular offense of insulting a religious teacher (guru droh) in a previous life will suffer from vitiligo in the next life (Chaturvedi et al. 2005). Treatment described in both ancient Egyptian and Indian writings depicts psoralen-containing plants, such as Ammi majus and Psoralea corylifolia, being applied to pale macules and then exposed to sunlight (McKenna 1957), now known as photochemotherapy.
The Indian Manu Smirfi (200 BC) used the term Sweta Kushtha (‘white disease’) in reference to vitiligo. Skin disorders were indicated earlier in the Chinese literature, when Dohi wrote of Pin-yiian-hon-lun. In ancient Arabic books, white skin was expressed with terms such as baras and bohak. In Chapter 13 of Leviticus in the Old Testament, there is reference to certain skin conditions using the Hebrew word Zara'at, which has been interpreted as the sign of a sin, symbolizing a punishment sent by God (Thomson 1991). Cases of vitiligo were not known to Europeans in the Middle Ages. The 16th-century Italian physician Mercurialis defined the pathogenesis of vitiligo in his book De Morbus Cutaneis (On Diseases of the Skin).
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Figure 1.1: Vitiligo through the ages.
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In the 17th-century's Yi Dynasty in Korea, the medical textbook Doney Bogam described the skin disorders of vitiligo, tinea versicolor, nevus depigmentosus, nevus anemicus, and albinism as a single hypopigmentary disorder (Hann & Chung 1997). Treatment is similarly described as if for a single disease entity. In 18th and early 19th century Europe, the French physician Claude Nicolas Le Cat published work on ethnic differences in skin pigmentation, describing several cases of vitiligo that started in small areas and progressed symmetrically over the hands and face, as well as depigmentation following burns from boiling (the phenomenon of Koebnerization). Jawaharlal Nehru, a former prime minister of India, ranked vitiligo alongside malaria and leprosy as the three major medical ‘curses’ afflicting his country (Singh et al. 1974).
At the end of the 19th century, Moriz Kaposi of Vienna described the histopathology of vitiligo as the lack of pigment granules in the deep rete cells. William Gottheil described vitiligo as a form of pigment cell atrophy. In Bergen, Gerhard Hansen observed the presence of small rods within ‘lepra cells ’ and thus established a clear pathogenesis for leprosy. Pierre Louis Alphée Cazenave of France made the link between vitiligo and alopecia areata. In the early 20th century, the cause of vitiligo was attributed to damage to peripheral nerves. In 1959, Aaron Lerner reported a patient with transverse myelitis whose vitiligo was limited to the skin above the lesion (Lerner 1959). He proposed that normal pigmentation resulted from a balance of the effects of melanocyte-stimulating hormone secreted from the pituitary on darkening the skin and the release of a substance from the peripheral nerves that lightened them. In 1947, Medhat El Mofty of Egypt revived the ancient treatment of vitiligo by successfully using 8-methoxypsoralen orally with sunlight. It was an additional two decades before an artificial ultraviolet A (UVA) source was used in combination with 8-methoxypsoralen orally. In addition, khellin, a nonpsoralen oral agent, was found to be effective in treating vitiligo when combined with natural sunlight. Even though vitiligo, unlike leprosy, it is not an infectious disease, the stigma associated with vitiligo in some societies has not changed (Roelandts 2002).
 
Epidemiology
The prevalence of vitiligo ranges from 0.5% to 2% in the general population and from 0% to 2.16% in children (Kruger & Schallreuter 2012). The prevalence of 8.8% in India seems high; these data refer to prevalence in patients with vitiligo within one skin institute in Delhi (Shah et al. 2008). Prevalence of the disease is around 1% in the United States and Europe. A predominance in women is due to their willingness to express concern about cosmetically relevant issues. Half of all patients develop the disease before 20 years of age, but it may appear at any age, sometimes as early as 6 weeks after birth. Vitiligo has a bimodal age of onset, with children developing the disease between the ages of 1 and 10 years and adults between 20 and 50 years. Onset at an advanced age may raise concerns about associated diseases, 4such as thyroid dysfunction, rheumatoid arthritis, diabetes mellitus, and alopecia areata. One study found that the mean age of onset in patients with unilateral vitiligo was 16.3 years, compared to 24.8 years in patients with bilateral vitiligo (Kruger & Schallreuter 2012).
 
Ethnic variation
There is no difference in rates of occurrence in skin types or race. India is considered to have the highest prevalence in the world, with an equal distribution between men and women, but women are more likely to seek treatment. The peak in females occurs in the first decade of life, whereas the male peak prevalence is in the fifth decade of life (Kyriakis et al. 2009). Vitiligo is more frequently diagnosed in spring and summer (64.4%), most likely because of the increased contrast between white vitiliginous skin and tanned skin induced by the sun (Kruger & Schallreuter 2012).
 
Associated symptoms and diseases
A study by Arunachalam and colleagues showed that inflammation and pruritus, the use of drugs that can induce psoriasis, a family history of psoriasis, cardiovascular disease, hypertension, and type 2 diabetes mellitus were all significantly correlated in patients with vitiligo and psoriasis comorbidity (Arunachalam et al. 2014). Inflammation and pruritus in vitiligo macules and a family history of cardiovascular disease were the most significant predictors in patients having both psoriasis and vitiligo, whereas the presence of organ-specific autoantibodies was significantly associated with patients having only vitiligo (Arunachalam et al. 2014).
In a retrospective chart review of 1873 medical records of patients with vitiligo performed at Henry Ford Hospital from January 1, 2002, to October 31, 2012, the prevalence of autoimmune disease was compared to the general US population. Results showed that patients with vitiligo had a 15-fold increased risk of thyroid disease, a 2-fold increased risk of irritable bowel syndrome, and a 4-fold increased risk of pernicious anemia and lupus. There was a 31-fold increased risk of alopecia areata, a 182-fold increased risk of linear morphea, and a 36-fold increased risk of myasthenia gravis. All of these diseases showed a statistically higher prevalence in patients with vitiligo (P < 0.05) (direct communication with Liza Gill and Iltefat Hamzavi).
 
Psychological impact
Skin color plays a major role in an individual's perception of health, wealth, worth, and desirability. Vitiligo generally is not a symptomatic disease, but its effects can be psychologically devastating, resulting in low self-esteem, poor body image, and difficulties in forming intimate relationships. Although vitiligo equally affects people of all 5races and ethnicities, it has a more negative impact on quality of life (QoL) in patients with darker skin types, as it is more easily noticeable. Commonly reported characteristics that are independent predictors of a worse health-related quality of life (HRQL) include having highly contrasting dark skin, being female, having more severe and extensive vitiligo, having a prolonged duration of vitiligo, and failing treatment (Bhandarkar & Kundu 2012).
The assessment of response to treatment should include the individual's perception of the response along with repigmentation itself. The measurement of change in QoL after treatment is an important tool for assessing treatment success. One study showed that a moderate response to treatment led to satisfaction in patients and their families because of a reduced visibility of vitiligo, supporting the important psychological role played by treatment. Kent and al-Abadie (1996) showed that even with excellent cosmesis, the feeling of stigma and fear of rejection is sustained.
With regard to marital status, a study from China showed that subjects with vitiligo had statistically significantly worse and less stable relationships compared to control subjects. Vitiligo of the hands and face is considered the most disfiguring, and genital vitiligo was associated with fear because it was mistakenly believed to be associated with sexually transmitted diseases (Wang et al. 2011). In the Indian culture, vitiligo in women can have severe social consequences, even affecting their ability to find a partner. Patients with vitiligo tend to have increased levels of anxiety, depression, adjustment disorders, obsessive symptoms, and hypochondria. It was shown that psychological stress increased the levels of neuroendocrine hormones, leading to alterations of the immune system and the level of neuropeptides, which may be the initial steps in the pathogenesis of vitiligo. A QoL assessment should be made during the initial consultation and followed up during treatment to assess ongoing patient satisfaction. Treating physicians and patients may have different scores with regard to QoL. Studies have suggested that vitiligo has a mental and emotional burden comparable to hand eczema or psoriasis and that females tend to suffer more than men. The worst QoL scores are seen in patients with universal vitiligo. The use of cosmetics at all stages of treatment may be important to the patient's QoL (Bhandarkar & Kundu 2012).
 
Genetics and precipitating factors
Vitiligo appears to have a genetic predisposition in a non-Mendelian pattern, with a polygenic and multifactorial inheritance. More than 120 genes regulate mammalian pigmentation. Each of them, including those regulating the immune system, represent potential candidate genes for vitiligo (Passeron & Ortonne 2005). Most cases of vitiligo are sporadic, but up to 20% of patients report an affected relative. The frequency of vitiligo among first-degree relatives in white, Indo-Pakistani, and Hispanic populations is 7.1%, 6.1%, and 4.8%, respectively, compared 6to an estimated worldwide frequency of 0.14–2%. Monozygotic twins with identical DNA have only a 23% concordance in developing vitiligo, suggesting a significant nongenetic component. Recent genome-wide scans performed on families with numerous members presenting with vitiligo have clearly revealed the linkage of susceptibility loci. In India, this increase was about 4.5-fold in close biologic relatives. Another study of 160 white relatives living in the United States showed a relative risk for vitiligo of about 7 for parents and about 12 for siblings. The results of a study that included 2247 Chinese patients and their families showed a different age of disease onset depending on the subtype of vitiligo. Many candidate genes for vitiligo have been proposed. A linkage study performed on 56 families strongly suggested that region 6p21.3e21.4 contains a major genetic factor contributing strongly to the vitiligo phenotype. The decrease of BCL2 expression, an MITF-dependent KIT transcriptional target in melanocytes, increases their susceptibility to apoptosis. One of the candidate genes could be FOXD3, located on chromosome 1 (1p32ep31) and a transcription factor that suppresses melanoblast development from the neural crest. FOXD3 regulates endodermal differentiation, including the thyroid, pancreas, adrenals, and gut, and other FOX factors are involved in autoimmune syndromes (Spritz 2012). A Chinese study found that vitiligo pathogenesis involves a complex interplay between immune regulatory factors and melanocyte-specific factors, and highlighted similarities and differences in the genetic basis of vitiligo in Chinese and white populations (Tang et al. 2013).
Human leukocyte antigen (HLA) haplotypes HLAs-A2, -DR4, -DR7, and -DQB1*0303 may contribute to vitiligo susceptibility. Different ethnicities have different HLA-associated susceptibilities. The strongest associations of vitiligo with particular HLA haplotypes are in patients and families with various vitiligo-associated autoimmune syndromes (Spritz 2011).
 
Pathogenesis
Numerous factors that may act independently or in concert have been implicated in the development of vitiligo. They include trauma, exposure to sunlight, stress, infections, malignancies, neural abnormalities, melatonin receptor dysfunction, impaired melanocyte migration, some drugs, endocrine diseases, and cytotoxic compounds. The actual pathogenesis is under debate and has been attributed to autoimmune causes, oxidative stress, and sympathetic neurogenic disturbance (Le Poole & Luiten 2008). Vitiligo typically starts in sun-exposed areas of the skin during the summer months, which may be preceded by sunburn, pregnancy, skin trauma, or emotional stress. Half of all patients develop the disease before 20 years of age, but it may appear at any age—as early as 6 weeks after birth. The cause of damage to melanocytes and their later disappearance in vitiligo remains unclear (Le Poole et al. 1993).
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There are several pathophysiologic theories regarding vitiligo. The most prominent are autoimmune, neurohumoral, and autocytotoxic, with each likely to partially contribute to the disease process. It has been noted that in melanoma, patients who developed hypopigmentation had a better prognosis, indicating that a common immune response to melanocytes is responsible for both hypopigmentation and tumor control. Cellular immunity is proposed to be mediated by CD8+ and CD4+ cell infiltrations of the vitiligo area with melanocyte-specific CD8+ cells. The dysfunction of CD4+ cells enhances autoimmune mechanisms; macrophages, dendritic cells, and Langerhans cells seem to be involved; and cytokines affecting pigmentation have been found. New-onset vitiligo has followed bone marrow transplants and lymphocyte infusions for the treatment of leukemias and lymphomas. A humoral immunity theory of vitiligo has been investigated, in which there is a direct correlation between antibody levels and disease activity in the sera of patients, although these antibodies lack specificity. The sera is able to damage melanocytes in vitro by complement activation and antibody-dependent cellular cytotoxicity, and associated antibodies may also be able to damage melanocytes in vivo (Norris et al. 1988).
The neurohumoral hypothesis suggests that dysregulation of the nervous system may damage melanocytes in vitiligo. The facts supporting this theory are that melanocytes and nerves arise from neural crest cells, and segmental vitiligo (SV) follows the distribution of nerves. The autocytotoxic hypothesis suggests that toxic metabolites from the environment or from melanin synthesis pathways damage the melanocytes of genetically susceptible individuals.
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Figure 1.2: The convergence theory of vitiligo.
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The oxidative stress hypothesis explores superoxides, where H2O2 accumulation degrades the active site of catalase, reducing its function. It has been demonstrated that both lesional and nonlesional skin from patients with vitiligo have abnormally low levels of the catalase enzyme, which correlates with high H2O2 levels throughout the epidermis (Laddha et al. 2013). The melanocytorrhagy hypothesis, on the other hand, explains the Koebner phenomenon, as it proposes that minor friction or stress could induce upward migration and loss of melanocytes. Other theories include decreased calcium uptake reported in keratinocytes in the skin, which inhibit melanogenesis through downregulation of tyrosinase activity (Song et al. 1994). Mosenson and coworkers reported that modified inducible heat shock protein 70 (HSP70i) prevented T-cell–mediated depigmentation and that the use of HSP70iQ435A therapeutically in a different, rapidly depigmenting model after loss of differentiated melanocytes resulted in a 76% recovery of pigmentation (Mosenson et al. 2013).
The triggering factors for the loss of melanocytes in vitiligo are not understood. It has been suggested that many external triggering factors (e.g. mechanical traumas) could play a role in the expression of vitiligo, as the depigmentation predominantly is located on skin exposed to repeated friction and pressures. Current thinking is that vitiligo represents a spectrum of diverse pathophysiologic disorders that manifest as a common phenotype. The convergence theory states that all of the aforementioned factors contribute to vitiligo pathogenesis. Generalized vitiligo can be explained further by autoimmune mechanisms, whereas the neurohumoral hypothesis may be responsible for segmental or focal vitiligo (Le Poole et al. 1993). Figure 1.2 summarizes the current understanding of the convergence theory of vitiligo. In essence, oxidative stress is the initial event, resulting in an autoreactive response.
 
Clinical types
Vitiligo is classified based on a clinical picture of two major forms:
1. Segmental vitiligo (dermatomal or Blaschko linear)
2. Nonsegmental vitiligo (NSV)
NSV is subclassified into generalized, acrofacial, and universal vitiligo; NSV may start as acrofacial vitiligo but later progress to generalized or universal vitiligo. Focal vitiligo may evolve into SV or NSV. Reporting the involved sites is important, as some cases of NSV exhibit a flexural or extensor distribution suggesting different etiologies. Universal vitiligo involves more than 80% of the skin. The Vitiligo European Task Force (VETF) defines NSV as ‘an acquired chronic pigmentation disorder characterized by white patches, often symmetrical, which usually increase in size with time, corresponding to a substantial loss of functioning epidermal and sometimes hair follicle melanocytes.’ Separating SV from other types of vitiligo is important because of its prognostic clinical implications (Ezzedine et al. 2012).
Sites of predilection of generalized vitiligo are the periorificial regions, elbows, knees, digits (areas of trauma), flexor wrists, dorsum 9of the hands, nipples, axillae, umbilicus, sacrum, and inguinal and anogenital regions (penis, vulva, and anus). Leukotrichia is associated with depigmentation of the surrounding skin with frequent Koebnerization. SV occurs in a unilateral distribution that may match a dermatome. Vitiligo ponctue presents as confetti-like depigmented macules and may be associated with progressive unstable vitiligo (Amit G. Pandya, Skin of Color Society meeting, 2014). Trichrome vitiligo is characterized by depigmented and hypopigmented macules in addition to normally pigmented skin. Involvement of the scalp and other hair-bearing areas manifests with localized patches of gray or white hairs (Hann et al. 2000). In NSV, body hairs remain pigmented, but depigmentation may still occur with disease progression. Lesions enlarge centrifugally and can appear at any location, including the mucous membranes. The lesions of vitiligo are sensitive to ultraviolet light, so transient erythema can be observed following ultraviolet irradiation. Inflammatory vitiligo is characterized clinically by erythema at the margins of vitiligo macules. Depigmentation sometimes occurs around melanocytic nevi and melanomas, a phenomenon known as halo nevi. Depigmentation also occurs in about 1% of patients with melanoma. Ocular manifestations of vitiligo include iritis and retinal pigmentary abnormalities, typically with no visual complaints (Albert et al. 1979).
No consensus has been reached on defining the criteria for stability in vitiligo. More studies are needed to follow the course of disease and the correlation of the tests with the outcome of treatment-induced repigmentation. Correlation of the change in the level of serum autoantibodies with immunosuppressive therapies such as phototherapy can be helpful in defining stability. Hann and coworkers found that the response of vitiligo to systemic steroids correlates with the reduction in the percentage of cytotoxicity of melanocytes mediated by autoantibody and complement. In the same patient, at the same time, different lesions may show stability, regression, or progression. Studies of the site of the Koebner phenomenon may lead to a greater understanding of the concept of stability (Hann et al. 2000).
 
Clinical differential diagnosis
The differential diagnosis of vitiligo is broad, so thorough history taking and a detailed physical examination (sometimes with additional investigation) is needed for a definitive diagnosis.
Contact dermatitis, followed by hypo- or depigmentation, is a common condition that can present clinically as vitiligo. This can be induced by various chemicals, such as dyes, detergents, cleansers, insecticides, cosmetics, and antiseptics (Ghosh & Mukhopadhyay 2009). Nevus depigmentosus is a segmental hypopigmentation detectable in the first year of life and is stable in size in proportion to the child's growth. The defect is in the production of melanin pigment and not in the number of melanocytes. The distribution of piebaldism, 10an autosomal dominant disease presenting at birth with midline depigmentation and a white forelock, helps to confirm the diagnosis. Other differential diagnoses presenting with hypo- or depigmentation include infections such as leishmaniasis, leprosy, and treponematoses. Genetic syndromes that can mimic vitiligo clinically include hypomelanosis of Ito, tuberous sclerosis, Vogt–Koyanagi–Harada syndrome and Waardenburg syndrome. Many postinflammatory hypopigmentations secondary to an inflammatory skin disease such as atopic dermatitis, nummular dermatitis, psoriasis, pityriasis alba, and scars can also be confused with vitiligo. Neoplastic conditions that mimic vitiligo include amelanotic melanoma, halo nevus, and hypopigmented cutaneous T-cell lymphoma. Other idiopathic skin disorders that manifest with hypopigmentation include idiopathic guttate hypomelanosis, lichen sclerosus et atrophicus, lichen striatus, and progressive macular hypomelanosis (Alikhan et al. 2011).
Typically, there are key differentiating points between vitiligo and other clinically similar skin conditions. Vitiligo lesions are accentuated on Wood's lamp examination. Morphea and lichen sclerosus et atrophicus are associated with changes in skin texture. Pityriasis alba has a fine scale and is poorly defined. Tinea versicolor occurs more on the trunk and has a fine scale, and diagnosis can be confirmed by potassium hydroxide examination showing yeast and hyphae. Nevus depigmentosa tends to have scalloped borders and does not accentuate on Wood's lamp. It also does not progress over time.
Histopathologic evaluation also helps to differentiate vitiligo from other similar skin conditions. Vitiligo has few or no cellular infiltrates and few or no melanocytes compared to normal skin in the same patient unless that patient has unstable disease. Special stains such as DOPA, which detect melanocyte activity, can help to confirm the diagnosis (Kim et al. 2008). A study looking at the histopathology of active and stable vitiligo showed that actively spreading vitiligo corresponding to progressive depigmentation expressed spongiosis with microvesicle formation, clustered CD8 T lymphocytes in the epidermis, and dermal melanophage deposition. On the other hand, in stable vitiligo, lesions of sharp depigmentation rarely showed spongiosis, clustered CD8 T lymphocytes in the epidermis, or dermal melanophage deposition (Benzekri et al. 2013).
 
Associated disorders and autoimmune diseases
Vitiligo can be associated with autoimmune disorders, most commonly autoimmune thyroid disorders. Autoimmune disease can affect up to 24% of pediatric patients with vitiligo, and in 18.5% of a sample of 15,126 patients with vitiligo studied by Iacovelli and co-workers in 2005, it was found that the risk for thyroid disease is twofold in patients with vitiligo compared to patients without vitiligo, and the risk of elevated levels of thyroid antibodies in the same patients is more than fivefold higher. A higher incidence of thyroid microsomal antibody is found 11in patients with vitiligo and their families. Patients with generalized vitiligo are more likely to have autoimmune disorders than those with SV. Clinicians should be aware of the increased risk of thyroid disease in patients with vitiligo and be alert to its symptoms and signs. Up to 20% of patients with vitiligo have hearing loss caused by functional disorders of melanocytes of the stria vascularis. Ocular abnormalities associated with vitiligo include uveitis, iritis, choroidal anomalies, and fundal pigment disturbance. Other associated disorders include alopecia areata, Addison disease, type 1 diabetes mellitus, malabsorption syndrome, gonadal failure, pernicious anemia, chronic active hepatitis, corneal dystrophy, and enamel dystrophy (Iacovelli et al. 2005).
Patients with metastatic melanoma who develop vitiligo may have a favorable prognosis, as vitiligo may destroy malignant pigment cells. On the other hand, a higher incidence of nonmelanoma skin cancer has been reported in those with vitiligo, although not at a statistically significant level (Nordlund & Lerner 1979).
 
Investigative tools to rule out associated disorders
The diagnosis of vitiligo typically is made on a clinical basis and confirmed with a Wood's lamp, a device that emits UVA at a wavelength of 365 nm, which also can facilitate monitoring of the progress of lesions over time, especially in fair- and darker-skinned individuals, to assess the involvement of the palms and soles. In cases of a doubtful diagnosis, histopathologic evaluation is performed. Specimens should be obtained from both depigmented and normal skin for higher diagnostic accuracy (Kim et al. 2008).
In new-onset depigmentation, associated autoimmune disease should be investigated at the time of diagnosis. Recommended blood tests include thyroid studies, along with antithyroid peroxidase antibodies and/or antithyroglobulin, especially if signs of thyroid disease are present; antinuclear antibodies and screening for other organ-specific autoantibodies; fasting blood glucose levels; and a complete blood count to rule out pernicious anemia (Iacovelli et al. 2005). Additional serologic studies and ophthalmologic and audiologic examinations are of value in those who have symptoms or a positive family history (Hong et al. 2009).
A QoL assessment is advisable in all patients with vitiligo to assess the psychosocial impact and decide whether a referral to a social worker or counseling services is needed. Although vitiligo does not in itself cause a direct physical impairment, it poses a significant psychosocial burden, and improvement in QoL should be an important outcome measure.
 
Measuring tools
In 2004, due to the lack of quantitative tools to evaluate vitiligo treatment response using parametric methods, Hamzavi and coworkers designed a prospective, randomized, controlled, bilateral left-right comparison 12trial to develop a simple clinical tool – the Vitiligo Area Scoring Index (VASI) (Hamzavi et al. 2004). This index monitors the response of vitiligo treatment and the initial report was applied to patients treated with narrowband ultraviolet B (NB-UVB) phototherapy using parametric tests. The VASI score is based on an estimate of the overall area of vitiligo patches at baseline and the degree of macular repigmentation within these patches over time. The score is validated separately against physician and patient global assessments, and results have shown that it correlates well with both.
In 2007, due to the lack of consensus in the definitions and methods of assessment regarding vitiligo, the VETF proposed a consensus definition of the disease and the assessment of treatment outcomes using a system that combines analysis of the extent of disease, the stage of disease (staging), and disease progression (spreading) (Taieb & Picardo 2007). Assessment of spreading was based on Wood's lamp examination. The extent of the disease was evaluated using the ‘rule of nines’, a method of estimating the extent of burns, expressed as a percentage of total body surface. Staging was based on skin and hair pigmentation in white patches, and the disease was staged from 0 to 3 on the largest macule in each body region, except the hands and feet, which were assessed separately as one unique area.
 
Treatment options
An optimum treatment plan includes a thorough assessment of vitiligo with regard to its type, age of the patient, presence of associated disorders, and distribution of the lesions, which are fundamental to achieving a better outcome. Vitiligo treatment targets inhibition of the immune response to reduce melanocyte destruction, with the recovery of damaged melanocytes or stimulation of melanocyte migration from neighboring skin or adnexal structures (the density of hair follicles). Repigmentation occurs in the form of a diffuse, border spreading, or perifollicular pattern, which spreads and merges to finally cover the surface of the depigmented lesion. The melanocyte reservoir population is localized on the bulge area representing melanocyte stem cells that are the source of melanocytes for epidermal repigmentation. Counseling patients on therapeutic options, the prognosis, and response to treatment should focus on making sure that they have realistic expectations. Progressive disease occurs in patients with a family history of vitiligo, positive Koebner phenomenon, and NSV in the absence of therapy.
Vitiligo therapy should begin with a minimally invasive approach, reserving the most aggressive treatment options for cases where first-line therapies fail. Current primary pharmacologic treatment includes the use of topical corticosteroids, calcineurin inhibitors, vitamin D analogs, depigmenting agents, systemic drugs such as oral steroids and antioxidants, phototherapy, photochemotherapy, and surgery. In addition, because of the skin's innate immune system and the 13immune responses affecting melanocytes, other pharmacotherapies might include immunosuppressive drugs such as cyclosporine, cyclophosphamide, and azathioprine.
 
Topical therapy
Corticosteroids are the first-line therapy for the treatment of vitiligo through modulation of the immune response. The greatest response rates are seen in children and in head and neck lesions. Side effects include epidermal atrophy, telangiectasia, folliculitis, and systemic absorption. In children treated with medium- to high-potency topical corticosteroids, 29% had abnormal cortisol levels at follow-up. Systemic corticosteroids are not considered a conventional treatment for vitiligo, but they can be effective for immunosuppression when used as an adjunct to phototherapy; however, their use is limited because of side effects (Cockayne et al. 2002, Kim et al. 1999).
It is important to counsel the patient and family regarding the prognosis of vitiligo, as the course of the disease is unpredictable. It can take at least 6 weeks to see an initial response to treatment; in the authors’ experience, treatment should be attempted for at least 3 months with visits from the treating physician every 6 weeks. Digital images at each visit are important for all treatment modalities to engage patients in their treatment protocol.
Calcineurin inhibitors have immunomodulatory effects without the side effects of corticosteroids. Calcineurin is an intracellular protein in lymphocytes and dendritic cells. Compared to topical corticosteroids, calcineurin inhibitors produce equivalent or slightly inferior repigmentation rates, but an effect occurs earlier in the course of treatment. Combining tacrolimus with 308-nm laser therapy has produced a 100% response rate, with 70% achieving more than 75% repigmentation, compared to light therapy only. Topical calcineurin inhibitors are considered safe for short- and intermittent long-term use. Common side effects include erythema, pruritus, burning, and irritation. At this time, there is no scientific evidence to suggest an increased risk of cancer in adults or children using tacrolimus ointment (Silverberg et al. 2004). The response rate following the addition of tacrolimus in the above study is much higher than that found in our experience with our vitiligo patients, but it can improve the response to phototherapy.
Calcipotriene is a topical vitamin D3 analog that provides immunomodulatory effects and enhancement of melanocyte development and melanogenesis in vitiligo. Topical vitamin D3 analogs are safe for use in both children and adults, and the best results occur when combined with topical corticosteroids (Birlea et al. 2008).
Patients with vitiligo have a low activity of the enzyme catalase. One study reported that a pseudocatalase plus calcium combination cream associated with NB-UVB led to repigmentation in 90% of patients, accompanied by a cessation of active depigmentation. Pseudocatalase 14treatment plus NB-UVB is safe and well tolerated. Reported side effects include pruritus and burns secondary to radiation. Antioxidants therapy results in elevated catalase activity and a decrease in reactive oxygen species. Vitamin E, vitamin C, α-lipoic acid, Ginkgo biloba, topical catalase, superoxide dismutase, and polypodium leucotomos have all been used in vitiligo. Studies suggest that antioxidant therapy is effective, inexpensive, and well tolerated. There is good evidence supporting supplementation of oral antioxidants in conventional therapy, specifically NB-UVB phototherapy. Supplements are safe, widely available, and inexpensive; however, defining dosages and efficacy and determining side effects requires additional research (Schallreuter et al. 1995).
Studies have reported that oral or topical supplementation with L-phenylalanine, the amino acid precursor of L-tyrosine, followed by sunlight or UVA exposure induced repigmentation of vitiligo lesions. This result has not be replicated by other studies, however. Melanin biosynthesis starts with conversion of L-tyrosine to L-DOPA, subsequently is oxidized into dopaquinone, and finally can be transformed into black eumelanin, brown eumelanin, or pheomelanin (Antoniou et al. 1989).
 
Phototherapy
Phototherapy with ultraviolet light has immunosuppressive and melanocyte stimulatory effects. NB-UVB phototherapy (Hamzavi et al. 2004) has proved to be safer and clinically more effective than psoralen ultraviolet A (PUVA) phototherapy in the treatment of vitiligo (El Mofty et al. 2006), yet PUVA phototherapy may have quicker results (Parsad et al. 2006). Adverse effects of PUVA therapy include erythema, dry skin, pruritus, nausea, an increased transaminase level, hypertrichosis, actinic keratoses, and lentigines. PUVA phototherapy carries an increased risk of both nonmelanoma skin cancer and melanoma in patients with lighter skin, but there are very few reports of carcinogenesis in patients with vitiligo in any skin type. Photochemotherapy with psoralens, khellin, and L-phenylalanine enhances the effects of phototherapy alone. Khellin has a stimulatory effect on melanogenesis and melanocyte proliferation when combined with UVA light. Khellin ultraviolet A (KUVA) phototherapy offers a promising alternative treatment approach for patients with vitiligo who are considering, or currently undergoing, PUVA therapy, as khellin has reduced mutagenic and carcinogenic properties over psoralen, does not cause phototoxic skin erythema (as seen with PUVA), and has equal efficacy (Kwok et al. 2002, Valkova et al. 2004).
 
Lasers
Monochromatic (308-nm) excimer lasers emit light in the ultraviolet range. Their mechanism of action is similar to conventional light therapy, but they allow targeted treatment with less total body irradiation. When used as monotherapy, repigmentation rates of more than 75% were 15seen in 16.6–52.8% of patients; response rates were as high as 95%. The 632.8-nm helium neon (HeNe) laser is used in patients with SV because it modifies the adrenergic dysregulation of cutaneous blood flow seen in SV and promotes melanogenesis, melanocyte growth, and migration. A major limitation to the widespread use of laser therapy is the cost of treatments and the difficulty in treating patients with large body surface area involvement (Passeron et al. 2004).
 
Surgical treatment
Surgical treatment is reserved for stable recalcitrant lesions and those unable to achieve favorable results with nonsurgical methods. Surgical treatment involves two main categories of intervention:
1. Grafting melanocyte-rich tissue
2. Grafting melanocyte cell suspensions
Adding light therapy may enhance repigmentation. Grafting of melanocyte-rich tissue using epidermal suction blistering is highly effective and has a response rate of 83–90% and an excellent side-effect profile, but with imperfect color matching. The advantage of this technique is that it does not cause scarring or the ‘cobblestoning’ seen with punch grafting and allows for coverage of larger areas (Tang et al. 1998). Split-thickness skin grafts (STSGs) offer the major advantage of being able to cover large areas with a single surgical procedure; however, this requires anesthesia and can leave cosmetically unpleasing harvest sites. Punch grafting is one of the most commonly used techniques and provides good repigmentation and cosmetic results. Complications of punch grafting include infection, cobblestone hyperpigmentation, imperfect color matching, Koebnerization at the donor site, keloid formation, and scarring at the donor site (Agrawal & Agrawal 1995).
Autologous melanocyte suspension transplant (AMST) involves harvesting tissue from a donor site and the release of individual cells into a suspension, which is transplanted onto de-epithelialized recipient skin. Some techniques transplant both keratinocytes and melanocytes, whereas others use only melanocytes. The major advantage of this technique is its ability to treat a large vitiliginous area from a small donor site. On the other hand, the use of complex laboratory equipment and the high costs involved severely limit the widespread implementation of autologous melanocyte cultures. In a large (n = 142) long-term study of the efficacy of noncultured melanocyte keratinocyte cell transplantation (MKTP) in patients with stable vitiligo vulgaris, Mulekar found that 56% of patients achieved repigmentation rates of more than 95%, which were retained until the end of the 6-year follow-up period (Mulekar 2005). A study conducted at the Henry Ford Multicultural Dermatology Clinic showed that 23 patients who underwent 29 procedures completed the 3- to 6-month follow-up period. Data for these 29 procedures showed excellent repigmentation (95–100%) after the MKTP in 17% of patients and good repigmentation (65–94%) in 31%. Fair (25–64%) and poor (0–24%) 16repigmentation were achieved in 10% and 41% of patients, respectively. The average percentage change in VASI was 45% (Huggins et al. 2012). AMST is an excellent alternative to tissue grafting; however, preparation of the suspension is complex and time consuming. This technique appears to work best in patients with segmental or focal vitiligo and can provide excellent results in locations that traditionally are difficult to treat.
 
Depigmentation therapy
Depigmentation therapy can provide a desirable cosmetic outcome when satisfactory results are unachievable using conventional treatments. Topical agents that depigment normal skin include hydroquinone and monobenzone, which are approved by the US Food and Drug Administration (FDA) for the treatment of vitiligo. Side effects include burning, itching, and contact dermatitis (Hariharan et al. 2010). The Q-switched ruby laser has been used for depigmentation in vitiligo universalis. The depigmentation is best approached in stages and evens skin tones in exposed areas over a period of 3–12 months (Njoo et al. 2000).
 
Micropigmentation
Micropigmentation (tattoo) is a useful tool for the treatment of stable vitiligo, especially in darker-skinned individuals; however, optimal results require a highly skilled operator. A permanent uniform pigmentation depends on the depth of injection of pigment granules, which should be inserted to approximately 1.5 mm, between the upper and mid-papillary dermis. Granules injected more superficially will be expelled shortly after the procedure, and macrophages will remove any pigment that is injected too deeply. The procedure is particularly useful on the lips, skin folds, nipples, and areolae, where other interventions are often limited. Additional tattooing every 1.5–2 years can overcome the mild fading of pigment that occurs over time. Adverse events include Koebnerization, allergic reactions to the tattoo pigment, and imperfect color matching (Mahajan et al. 2002).
 
Additional therapy
Treating the psychological manifestations of vitiligo not only may help a patient's overall sense of well-being but also may improve clinical outcomes. Although cosmetic agents have no effect on the disease itself, they help with the psychosocial burden of vitiligo, especially when it is extensive or the lesions are present on the face, head, and neck. One study found that 70% of females and 41% of males with vitiligo use camouflage. Doing so improved the patient's ‘feelings of embarrassment and self-consciousness’ and widened their ‘choice of clothing.’ Self-tanning agents provide semipermanent camouflage. Dihydroxyacetone (DHA), the active ingredient in most self-tanning agents, is FDA approved for the treatment of vitiligo. 17Makeup can help a great deal to disguise vitiligo lesions (Rajatanavin et al. 2008).
Protection of the vitiliginous areas with sunblock is important, as it helps prevent sunburn and thus may lessen photodamage and the chance that a Koebner phenomenon will occur. Sunscreens decrease tanning of the uninvolved skin and therefore lessen the contrast with vitiliginous lesions.
Other systemic medications that may have a therapeutic role in vitiligo include tumor necrosis factor alpha (TNF-α) inhibitors. Although they currently are not indicated for the treatment of vitiligo, preliminary findings suggest that this class of drugs may provide relief in certain patients, as some studies have shown higher levels of TNF-α in vitiligo lesions (Simon & Burgos-Vargas 2008). Minocycline has antibiotic, anti-inflammatory, immunomodulatory, and antioxidant properties. A recent study found that daily minocycline can halt the progression of vitiligo during and after therapy. Systemic immunosuppressants such as azathioprine increased the benefits of PUVA phototherapy in vitiligo (Radmanesh & Saedi 2006). Cyclophosphamide, given in pulse therapy with dexamethasone for the treatment of pemphigus vulgaris, induced repigmentation in a patient with vitiligo universalis who previously had been unresponsive to systemic steroids (Dogra & Kumar 2005, Gokhale & Parakh 1983).
 
Treatment plan
Choosing a treatment for vitiligo can be challenging, as there is no single modality of therapy that is effective in all types of this lifelong chronic disease. An optimum first-line therapy needs to be safe, effective, noninvasive, and inexpensive, whereas a second-line therapy is reserved for more extensive and refractory disease. It is important that every therapeutic option is tried for a long enough period of time, as repigmentation could take weeks to months before becoming clinically evident. An ‘acceptable’ response to a treatment option could take a few weeks and in the author's experience should be attempted for at least 3 months with about two visits over this period, combined with detailed documentation of repigmentation using serial digital high-quality photos at each visit to engage patients in their own treatment response and any decisions regarding to future treatments.
 
Prognosis
The course of vitiligo is unpredictable: it can be stable for a long time or rapidly progressive in certain types. Spontaneous repigmentation may occur on sun-exposed areas in a perifollicular pattern, but it does not usually cover the entire depigmented surface. Patients are more prone to an increased risk of sunburn within the white areas, as well as ocular diseases. It is crucial to make patients with vitiligo aware of this risk and explain the importance of daily sun protection.
18
 
Conclusion
Vitiligo can be a lifelong disease with a high psychosocial impact on patients. Offering support to patients and their families is an important part of the treatment process. There are many modalities of treatment for vitiligo, but unfortunately there is no ‘miracle cure’ at this time. Current evidence-based medicine with high-quality randomized controlled trials in peer-reviewed journals is essential to determine the effectiveness of available treatments and any future therapeutic options to avoid clinically irrelevant results. The VASI and VETF (Taieb & Picardo 2007) offer standardised evaluations of disease severity that considers the extent of disease, stage of disease, and disease progression. These tools will help investigators move forward with new vitiligo research and allow the results from different studies to be merged to draw conclusions and make optimum recommendations for treatment. This information must be shared with basic science investigators across the world in the context of a global registry. It is through this process of collaboration – learning what works and what does not – that we can improve the outlook for all patients with vitiligo.
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