Vitiligo is an acquired pigmentary disorder consisting of depigmented macules and patches due to a selective loss of melanocytes. This condition affects approximately 0.5% to 2% of the worldwide population, with no gender or racial preference. The prevalence in the United States and Europe is estimated to be 1%.¹ Although vitiligo can occur at any age, 50% of people develop the condition before 20 years of age.²

Vitiligo may be stable or progressive. In the same patient, it is possible to have simultaneous improvement of some lesions and progression of others. The condition is unique in that it is oftentimes unpredictable, both in terms of progression and therapeutic response to any given treatment. As such, the condition continues to be a therapeutic challenge. Although many therapies can achieve some degree of repigmentation, complete and sustained response is uncommon and difficult to achieve. In this chapter, we outline an approach to vitiligo using an algorithm that takes into account medical, surgical, and supportive treatment options.

Patients present with slowly growing, sharply demarcated white macules or patches, often triggered by inciting events such as trauma, stress, and sunburn. Although vitiligo can appear anywhere on the body, it is commonly present as a periorificial loss of pigment on the face and often involves the digits, flexor wrists, elbows, axillae, nipples, umbilicus, knees, and anogenital regions.¹

Vitiligo is caused by a complex interaction between genetic, environmental, and immunological parameters that together make individuals vulnerable to developing the condition.⁴ Although studies have shown that there is a genetic basis for the development of vitiligo, this does not function in a simple Mendelian pattern. Rather, the genetic component is multifactorial and polygenic.⁵,⁶ For example, twin studies have shown that the concordance for generalized vitiligo in monozygotic twins is 23%,⁷ which provides strong evidence for a genetic component while showing that nongenetic factors play a very important role as well. Studies have shown that up to 20% of patients report a relative with vitiligo,¹ and the risk in Caucasian, Indo-Pakistani, and Hispanic first-degree relatives is 7.1%, 6.1%, and 4.8%, respectively.⁷

A number of genes and susceptibility loci have been identified based on population-based studies. In recent years, over 50 genes have been identified. The large majority of implicated genes encode immunomodulatory proteins, as well as melanocyte components that regulate pigmentary variation, including autoimmune antigens.⁸,⁹,¹⁰ Many newly identified genes play a role in immune regulation, apoptosis regulation, and melanocyte function and encode proteins that interact both physically and functionally.¹⁰ Many of these susceptibility loci are also associated with other autoimmune conditions, providing further evidence for the genetic association of vitiligo with these other disorders.⁵,¹⁰ Up to approximately one-third of patients with vitiligo have increased frequencies of comorbidities, including thyroid disease, pernicious anemia, systemic lupus erythematosus, alopecia areata, rheumatoid arthritis, inflammatory bowel disease, diabetes mellitus, and myasthenia gravis, as compared with the general population.¹,⁵,¹¹

Vitiligo is a multifactorial disorder related to both genetic and environmental factors.⁸ The selective loss of melanocytes results in the clinically apparent white patches of vitiligo. Patients often identify and attribute vitiligo onset to illness, physical injury, sun exposure, specific medications, pregnancy, and emotional stressors.² There are major theories on the pathogenesis of vitiligo, including autoimmune, oxidative stress, neural-based, and defective melanocyte adhesion theories. The theory taking hold is convergence theory, in which an oxidative event in melanocytes triggers the immune processes that result in the development of vitiligo.¹,¹²,¹³

One of the most widely accepted theories of vitiligo is the autoimmune theory. The autoimmune theory of vitiligo describes the destruction of melanocytes by autoantibodies against melanocyte antigens or by cytotoxic T cells.¹ Studies have shown increased serum levels of CD8+ T cells in patients with vitiligo compared with healthy controls, and the levels of melanocyte-specific CD8+ lymphocyte levels correlate with disease activity.¹⁴,¹⁵ Likewise, a decreased ratio of both helper T cells and suppressor T cells has been found in the serum of patients with vitiligo.¹⁶ There is also evidence of antimelanocyte antibodies in patients with vitiligo, and levels of antibodies may correlate with disease activity, extent of involvement, and comorbidity with other autoimmune disorders.¹ However, what is not yet known is whether this immune-mediated process is primary to the
development of vitiligo or secondary to another process. Studies have also examined the role of cytokines in vitiligo and have found that there is an increase in tumor necrosis factor-α, interferon-γ (IFN-γ), interleukin (IL)-10, and IL-17 in the serum or vitiliginous skin as compared with nonlesional skin.⁸,⁹,¹⁴,¹⁵ The central role of the IFN-γ/CXCL10 pathway in vitiligo pathogenesis is increasingly emphasized. A recent series of studies have shown the central role of the IFN-γ/STAT/CXCL10 pathway in the progression and maintenance of depigmentation. CXCL10, an IFN-γ-induced chemokine, was elevated in skin and serum, and CXCR3, its chemokine receptor, was found to be expressed on pathogenic T cells.¹⁷,¹⁸,¹⁹ The association of vitiligo with other autoimmune disorders further supports an autoimmune etiology.

Individuals with vitiligo have also been reported to have compromised antioxidant responses. For example, oxidant stress levels are thought to be responsible when individuals develop vitiligo after sunburns or exposure to phenolic chemicals.²⁰ Some studies have shown increased levels of reactive oxygen species, including superoxide dismutase, in affected vs nonaffected skin.²¹ This may affect melanocytes in a number of ways, including effects on signal transduction pathways and disruption of the oxidation-reduction balance in the endoplasmic reticulum of affected skin. Disruption of this balance results in the accumulation of misfolded proteins, which activates the unfolded protein response and results in cessation of normal protein synthesis, upregulation of heat-shock proteins, and even apoptosis.²⁰

Recently, more research has pointed toward a convergence of oxidative stress and autoimmune processes resulting in melanocyte loss.⁴ One proposed pathway for this is via inducible heat-shock protein 70 (HSP70), postulating that stress causes melanocytes to release HSP70, which subsequently triggers or enhances the autoimmune response in vitiligo.¹³,²² In one study, skin biopsies comparing lesional and nonlesional skin of patients and age-matched controls demonstrated a correlation between HSP70 expression and disease activity.²²