Key points

Introduction

Vitiligo is a cutaneous illness caused by melanocyte destruction or damage, resulting in reduced or absent pigmentation of the skin, hair, and/or mucous membranes. Vitiligo affects 0.5% to 2% of the world’s population. Vitiligo is caused by a genetic propensity paired with environmental triggering that initiates the self-recognition of melanocytes. Autoimmune destruction of melanocytes is the leading theory supported by patient and family history of autoimmunity, absence or reduction of melanocytes on biopsy, presence of lymphocytes at the periphery of active vitiligo lesions, and the detection of antimelanocyte antibodies in the sera of patients with vitiligo. Other theories of the pathogenesis of vitiligo and include neuronal triggers, Koebner phenomenon, and oxidative damage. Each of these is likely contributory to disease development.

The Koebner phenomenon is a traumatic induction of lesions. In the setting of vitiligo, the Koebner phenomenon triggers melanocytorrhagy, a rounding of melanocytes and loss of adhesion to surrounding cells in the epidermis. This process results in functional loss of pigment production. Free radicals and tetrahydrobiopterin pathway–generated oxidative species seem to further induce loss of melanocyte activity and enhance damage to melanocytes. The combination of events results in apoptosis of the melanocyte and cell loss.

Introduction

Vitiligo is a cutaneous illness caused by melanocyte destruction or damage, resulting in reduced or absent pigmentation of the skin, hair, and/or mucous membranes. Vitiligo affects 0.5% to 2% of the world’s population. Vitiligo is caused by a genetic propensity paired with environmental triggering that initiates the self-recognition of melanocytes. Autoimmune destruction of melanocytes is the leading theory supported by patient and family history of autoimmunity, absence or reduction of melanocytes on biopsy, presence of lymphocytes at the periphery of active vitiligo lesions, and the detection of antimelanocyte antibodies in the sera of patients with vitiligo. Other theories of the pathogenesis of vitiligo and include neuronal triggers, Koebner phenomenon, and oxidative damage. Each of these is likely contributory to disease development.

The Koebner phenomenon is a traumatic induction of lesions. In the setting of vitiligo, the Koebner phenomenon triggers melanocytorrhagy, a rounding of melanocytes and loss of adhesion to surrounding cells in the epidermis. This process results in functional loss of pigment production. Free radicals and tetrahydrobiopterin pathway–generated oxidative species seem to further induce loss of melanocyte activity and enhance damage to melanocytes. The combination of events results in apoptosis of the melanocyte and cell loss.

Epidemiology

One half to two percent of the population has vitiligo worldwide. Historically in the American literature, about half of cases of vitiligo begin in childhood, with a slight female predominance. A recently published Chinese population-based survey of more than 17,000 people confirms that this trend is still true, and seems to transcend cultures and countries. The investigators reported that 0.56% of subjects had vitiligo. A slight female predominance was noted in childhood, but lost in adulthood.

There are sometimes deviations from this trend in prevalence, as population-based genetic differences and/or environmental factors may affect disease presentation. Prevalence of 0.18% of vitiligo was reported in a population-based study of 2194 Egyptian children living in the Sinai desert, suggesting that lifestyle and socioeconomic status can affect the prevalence.

Pathophysiology

It has been recently demonstrated that atopy seems to have a linkage to early-onset (ie, childhood) vitiligo in both European and American cohorts. The specific mechanism of interaction is unknown, but this has been demonstrated previously in another pediatric cutaneous autoimmune entity, alopecia areata. The only association now noted with atopy is the presence of raised borders, with the notation of inflammatory vitiligo as a subtype. At present, no therapeutic differences in response to treatment have been reported in the literature based on atopy in vitiligo, other than the possible greater severity of disease over time.

Vitiligo is a polygenic or multifactorial disease, 23% of identical twins with vitiligo having an identical twin with vitiligo. Genetically vitiligo has been linked to more than a dozen genes in genome-wide association studies in the United States, Europe, and China. The genes thus far identified as participatory in vitiligo support a role for different aberrations of immunity in the process of moving from autoimmune antibodies to loss of pigment.

The genetic aberrances that contribute to the development of vitiligo include genetic alteration or polymorphism in pigmentation genes that allow these genes to trigger the recognition of self more easily. Genes involved include tyrosinase, an enzyme that promotes melanin production (TYR), OCA2, the pigment gene that is abnormal in oculocutaneous albinism type 2, the melanin transcription downregulator HERC2, and MC1R, the α–melanocyte-stimulating hormone receptor.

These antigens may compete at altered major histocompatibility complex loci that allow for further promotion of self antigens. HLA-A*02:01 has been linked to enhanced development of vitiligo.

Recent studies support the age-old theory that vitiligo is an antibody-dependent cellular immune destruction of pigment cells. First, there are data on production of antibodies to melanocytes by patients with vitiligo and by melanoma patients who develop vitiligo while undergoing therapy. Second, recent biopsy studies have demonstrated that early vitiliginous lesions have dendritic cells consistent with antigen-presenting cells, whereas older lesions contain mature T cells. This finding demonstrates that antigen presentation occurs early on in vitiligo, whereas the inflammatory process may be more cell mediated at a later time. Furthermore, mature T cells have been identified at the border of vitiliginous lesions.

A variety of altered immune processes must occur to generate vitiligo, including autoreactive T-cell augmentation and B-cell activation resulting in autoantibody production, thereby creating a target for aberrant T cells. B- and T-cell genes linked to vitiligo include CTLA4, BACH2, CD44, IKZF4, and LNK. Abnormalities in the innate immune system, such as the NLRP-1 (formerly NALP-1) gene and CASP-7 (an apoptosis gene), have also been described. The exact mechanism by which these play a role in vitiligo is not fully elucidated, but is putatively thought to be related to enhanced inflammatory activity. In a study of 620 Chinese children with vitiligo, abnormalities of humoral and cellular immunity have been noted in children with active vitiligo, the former with segmental active disease and the latter with generalized vitiligo. Lower percentages of CD3+ and CD4+ T cells and a lower CD4+/CD8+ ratio are noted with active generalized disease, and complement C3 and C4 were depressed with segmental disease.

Antioxidant vitamin processing seems to be an issue in some individuals with vitiligo. Postulation of exaggerated oxidative stress in patients with vitiligo has resulted in a plethora of antioxidant vitamin regimens.

The final common pathway of melanocyte destruction in vitiligo seems to be associated with melanocytorrhagy, a poor cellular attachment of melanocytes in the epidermis resulting in extreme susceptibility to the Koebner phenomenon, that is, traumatic damage. This phenomenon promotes apoptosis/cellular death of the melanocyte.

Vitamin D deficiency and/or metabolic alterations have been linked to many autoimmune diatheses, such as systemic lupus erythematosis, multiple sclerosis, and diabetes mellitus. The role of vitamin D in immunity has not been fully defined, but people with the Apa I-A variant genotype carriers have higher levels of vitamin D and reduced risk of vitiligo. This fact is not surprising, as it has been shown that patients with low vitamin D levels (25-hydroxyvitamin D <15 ng/dL) are more likely to develop polyautoimmunity in the setting of vitiligo. This finding is noted in adults and children older than 3 years. Thus it is clearly important to maintain good levels of vitamin D (as measured by 25-hydroxyvitamin D) in vitiligo patients.

Other triggers of vitiligo include contact allergens such as paraphenylenediamine, an ingredient in hair dyes that seems to trigger both oxidative stress and contact allergy in some individuals. Teenagers with vitiligo or a strong family history of vitiligo may do well to avoid hair dyes. Chemical-induced vitiligo presents most commonly on the head and neck and hands. Recently a group of investigators identified a pathway called the unfolded response, which seems to trigger interleukin (IL)-6 and IL-8, previously implicated as vitiligo-associated immunogenic agents.

Tan/brown and hazel/green categories of eye color have been associated with development of vitiligo, demonstrating that pigment type may contribute to disease or perhaps promote allergenicity of melanocytes.

Prognosis

The prognosis of vitiligo depends on the type. Segmental vitiligo tends to spread over a few months to years throughout the entire skin segment involved. Nonsegmental vitiligo has a slow and steady spread gradually with age if not otherwise treated. There are occasional patients with rapidly progressive, generalized color loss termed vitiligo universalis, a very aggressive subtype of nonsegmental disease.

Comorbid autoimmune diseases may develop over time. Such diseases are often associated with larger body surface area, but it is unclear whether these diseases trigger each other or whether they reflect greater genetic tendency to vitiligo.

Clinical features

History

Vitiligo ( Fig. 1 ) usually presents in the spring with the appearance of lesions that are hypopigmented or depigmented, or that appear on tanning of the skin in fair-skinned individuals. Lesions may be segmental along the lines of Blaschko ( Fig. 2 ), which are embryonic developmental lines that run like bands around the abdomen and down the extremities, or nonsegmental (ie, generalized) involving the periorificial skin, skin folds (eg, intertriginous), and pressure points of the hips and extremities. Mixed segmental and nonsegmental cases do occur, but are rare and represent a phenomenon of loss of heterozygosity, whereby an individual has the global genetic tendency toward a disease but also locally has a more severe genetic burden in a segment. Segmental cases are most common in childhood, representing one-fifth to one-third of all cases, with 87% of cases presenting by age 20 years, and spread limited to the segment involved. When pigmentation is not fully lost, areas of complete, partial, and full repigmentation may create a trichrome pattern known as trichrome vitiligo. The natural history of generalized disease is slow extension of lesions over time if left untreated. Rarely, generalized extension may occur rapidly, resulting in vitiligo universalis, which represents less than 1% of adult and pediatric cases.

Nonsegmental vitiligo of the hands. Note the prominence of lesions in an African American patient. Lesions are localized on the fingertips and over joints, extending up the hand toward the wrist.

Segmental vitiligo of the face on the right cheek in a teenage male. Note that the area follows the lines of Blaschko.

Comorbidities

Comorbidities of vitiligo include: (1) secondary autoimmune conditions, (2) deficiencies of vitamins (see pathophysiology section and later discussion), (3) psychological interplay, and (4) symptomatology. These issues are not necessarily mutually exclusive, and the issues are reviewed in this section.

Generalized or nonsegmental vitiligo is associated with a personal and familial tendency to autoimmune illnesses, the most common being thyroid disease (5.4%), rheumatoid arthritis (1.1%), psoriasis (1.1%), and alopecia areata (0.8%) (numbers in parentheses indicate the incidence in children as reported by their parents without sensitive testing). Thyroid disease is more common in girls, and hypothyroidism is 6 times more common than hyperthyroidism. Prolonged vitiligo, female sex, and extensive surface area may increase the risk of autoimmune thyroid disease in children with vitiligo. Of children with autoimmune thyroid disease, 2% with Hashimoto thyroiditis and 4.6% with Graves disease will have comorbid vitiligo, with Graves disease being seen with vitiligo in younger patients.

Adults with vitiligo have thyroid disease (12%) and pernicious anemia (1.3%), with 3.7% of patients having elevations of thyroid-stimulating hormone without notable thyroid disease. Outside the United States studies have also linked vitiligo to celiac disease, pemphigus vulgaris, and Addison disease. Family members may also report vitiligo, type 2 diabetes, and Addison disease. Polyautoimmunity can rarely be seen in the setting of Schmidt syndrome or one of the other polyglandular autoimmune polyendocrine (polyglandular) syndromes. Other syndromes associated with vitiligo include the rare Vogt-Koyanagi-Harada syndrome, which is a combination of autoimmune attack on multiple pigmented tissues including the eye, ear, meninges, and skin.

Segmental disease involves a limited genetic area, usually on the trunk or hips, and may not be associated with polyautoimmunity unless nonsegmental vitiligo develops. Some children may have segmental vitiligo in the setting of other autoimmune illnesses such as alopecia areata; in this case, the fact that they have alopecia areata confers a risk of autoimmunity. In nonsegmental vitiligo, worldwide data support a strong association with autoimmune thyroid disease on sensitive testing (10.7%–26%).

Vitamin D deficiency is common in the general population, despite addition of vitamin D to milk in the United States. When patients (age ≥3 years) with vitiligo have vitamin D deficiency with levels at or below 15 ng/mL, secondary autoimmune diseases arise more frequently including thyroid problems, type 2 diabetes, and lupus anticoagulant. It is therefore important to screen, treat, and give long-term supplementation according to Institute of Medicine (IOM) and American Academy of Pediatrics (AAP) recommendations to maintain vitamin D levels and, it is hoped, general health in vitiligo patients. Furthermore, vitamin D deficiency should be suspected in the setting of generalized dull coloration and confetti-like hypopigmentation.

Psychological impairment affects 51.1% of children with severe emotional impairments, with 10.7% of children aged 4 to 16 years with less than 25% vitiliginous body surface area (BSA) having moderate to severe deficits on the Children’s Dermatology Life Quality Index (CDLQI). Psychological comorbidities (eg, poor functioning, poor self-image) become more common with age, with lower rates in younger vitiligo sufferers (<10 years of age) and almost universal presence in teenagers with vitiligo, with 13% of teenagers experiencing severe psychological impairments. Girls aged 8 to 18 years report impairment of quality of life with genital disease, whereas adults report sexual dysfunction in association with larger surface areas and genital involvement. Occurrence of vitiligo during the age of sexual debut may create lifelong psychological issues, suggesting that either early medical therapy, which works better (especially in the first 2–5 years of disease), is required, or early psychological intervention is required.

Although many parents may wish to defer therapy because their child is not bothered by lesions, a recent study demonstrated that whereas 45.6% (0–6 years) and 50% (7–14 years) of children are not bothered by their lesions, only 4.1% of teenagers (15–18 years) feel similarly. Therefore, it is reasonable to initiate therapy in an effort to reduce self-consciousness at a later date. As facial and leg lesions seem to be most associated with self-consciousness, these sites should be addressed early.

Pruritus is noted in some cases of vitiligo (30.1%) and can be a sign of psychological distress, including self-consciousness and susceptibility to bullying, in children with vitiligo. Children with pruritus or burning sensation should be observed more carefully, and referred for psychological counseling where appropriate. Teasing and bullying is more common in the setting of facial disease and greater than 25% BSA for children aged 4 to 16 years, and these children and their parents should be offered psychological support.

Cosmetic therapies are of great importance in helping children avoid unwanted attention. These treatments include self-tanners, cosmetic cover-up, and bleaching in psychologically stable teenagers with extensive disease. The process of bleaching is dramatic psychologically, and mandates prescreening with a psychologist or psychiatrist and a mature age for participation in decision making.

A simple comorbidity of vitiligo is loss of pigmentation in the nevi, termed the halo nevus. The halo nevus is a melanocytic nevus that develops an immune process, which causes a lightening of the surrounding skin and eventual immune removal by the body. Unless the central nevus is irregular, these are considered benign in nature. Presence of a halo nevus and leukotrichia suggest that a generalized rather than a segmental variant of vitiligo is present.

The risk of skin cancer has been feared in the past in patients with vitiligo, owing to the lack of protective melanin; however, in adults the risk seems to be one-third that of spousal controls.

Differential diagnosis

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  Congenital Hypopigmentation (appearing before the age of 2 years in most cases)

  
  
  
  
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    Nevus depigmentosus

    
    
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    Tuberous sclerosis/hypomelanotic macules

    
    
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    Waardenburg syndrome

    
    
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    Piebaldism

  
  
  
  
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  Acquired Hypopigmentation

  
  
  
  
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    Inflammatory disorders

    
    
    
    
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      Pityriasis lichenoides chronica

      
      
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      Mycosis fungoides

    
    
    
    
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    Autoimmune illnesses

    
    
    
    
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      Scleroderma (salt and pepper pigmentation)

      
      
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      Discoid lupus (scarring associated with dyspigmentation)

      
      
    • •
      

      Lichen sclerosus et atrophicus

    
    
    
    
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    Infectious reduction in pigmentation

    
    
    
    
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      Progressive macular hypomelanosis

      
      
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      Tinea versicolor

    
    
    
    
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    Postinflammatory pigment alteration

    
    
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    Dermatitis

    
    
    
    
    • •
      

      Atopic dermatitis

      
      
    • •
      

      Pityriasis alba

      
      
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      Seborrheic dermatitis

    
    
    
    
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    Environmental

    
    
    
    
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      Allergic contact dermatitis–induced pigment loss

      
      
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      Chemical leukoderma (can be induced by hair-dye ingredients, imiquimod, and topical contact sensitizer agents used medically)

    
    

  
  

Diagnostic recommendations

Therapeutic recommendations

Pharmacologic Treatment

Treatment of vitiligo remains uncommon among physicians according to the literature, especially because many physicians will not offer any therapy to patients. Studies from 1999 in the Netherlands and 2004 in Belgium reported that only 16% and 36% of dermatologists offered therapies to vitiligo patients. This lack of treatment may reflect the light skin tone of the patient population in the countries surveyed; however, since 2004 an improvement in the therapeutics of vitiligo has occurred with the conversion of most patients from psoralen and ultraviolet A (UVA) phototherapy to narrow-band ultraviolet B (UVB) phototherapy, the introduction of topical tacrolimus, the combination of corticosteroids and calcipotriene as a treatment option, and the introduction of the excimer laser to the armamentarium of dermatologists. A recent survey of dermatologists in Saudi Arabia indicated that 76% do not consider vitiligo purely cosmetic and that 69% offer therapy to their patients with vitiligo, suggesting either that physician attitudes and understanding of care have improved, or that physicians treating patients of color are more likely to treat vitiligo.

Unfortunately, long-term outcomes with these therapies are unknown. Similarly, the attitude of dermatologists and primary care physicians in the United States regarding vitiligo has never been reviewed.

The care of vitiligo in childhood is 5-fold. (1) Evaluation at onset to rule out presence of melanoma. At first presentation, a full-body skin examination is merited for all children (especially preteens and adolescents) with vitiligo that is nonsegmental in nature. (2) Identification and therapy for comorbid autoimmune conditions and vitamin deficiencies (reviewed earlier). (3) Therapy for vitiligo using topical and/or oral medications and/or phototherapy (see later discussion). (4) Psychological care of the child and their parents where appropriate. (5) Lifestyle alteration. Brief psychological screening of children and their parents to determine their level of concern should help identify children and parents requiring psychological referral.

Current medical treatments and their side effects ( Table 1 ) work through a variety of mechanisms that together can enhance a patient’s overall chances of repigmentation. Mechanisms of disease therapy by medications and procedures include rescue of damaged pigment cells, reduction in the inflammatory process, reduction in oxidative damage of pigment cells, induction of repigmentation from the hair follicles or edges of lesions, and grafting of dermal melanocytes using a variety of surgical procedures. Although vitiligo is autoimmune in nature it is a generalized inflammatory process, and as requires such conceptualization to understand the silent destruction of pigment that occurs in this illness. It is unfortunate that many health care providers and medical insurance carriers consider this illness cosmetic and do not offer patients therapy when desired.

Table 1

Types of therapy, mechanisms of action, and complications

Therapy	Mechanism of Action	Therapeutic Usage Patterns	Complication
Cosmetics	Cover up	For obvious skin lesions not covered by clothes	Allergy to cosmetics
Topical calcineurin inhibitors (eg, pimecrolimus, tacrolimus)	Anti-inflammatory	Sensitive skin areas: face, eyelids, intertriginous, groin	Irritation, redness, burning, pruritus Black-box warning suggests the product cannot be used before age 2 y and that the products may be associated with risk of skin cancer
Topical corticosteroids	Anti-inflammatory	Continuous or intermittent usage for cutaneous vitiligo alone or in combination with calcipotriene Class II agents preferred for longer-term usage in children (eg, mometasone furoate)	Skin thinning, irritation, contact allergy, risk of absorption, and HPA axis suppression with long-term usage over large body surface areas, no results
Photochemotherapy with psoralens and UVA	Anti-inflammatory, promotes melanocyte movement/migration	For localized resistant plaques unresponsive to other therapeutics; Oral PUVA not advised in children younger than 10 y owing to difficulties of compliance with ocular protection	Risk of phototoxic reaction, erythema, pain, tenderness, premature aging, blistering, Koebnerization of vitiligo, and potential risk of skin cancer based on data from psoriasis patients, no results, ocular toxicity
Narrow-band UVB/excimer (excimer laser risk is focal, Narrow-band UVB risks generalized)	Anti-inflammatory, stabilizing, promotes melanocyte migration, increase vitamin D levels	For generalized disease, unstable vitiligo and/or for lack of response to topical agents; excimer usually for limited surface area resistant to generalized narrow-band UVB or requiring higher dosages focally	Risk of phototoxic reaction, erythema, pain, tenderness, premature aging, blistering, and potential risk of skin cancer, no results, ocular toxicity
Grafting	Places melanocyte source in areas of depigmentation	For stable loss of pigment in a limited surface area (eg, long-standing segmental vitiligo)	Pain, scars, bleeding, secondary infection, cobblestoned skin (ie, irregular texture), no results

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