Vitiligo

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Practice Essentials

Vitiligo is an acquired pigmentary disorder of the skin that is characterized by circumscribed, depigmented macules and patches. The condition is frequently associated with disorders of autoimmune origin, with thyroid abnormalities being the most common. See the image below.



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Trichrome vitiligo.

Signs and symptoms

Vitiligo lesions are characterized as follows:

Initial lesions occur most frequently on the hands, forearms, feet, and face, favoring a perioral and periocular distribution.

Clinical variants

See Clinical Presentation for more detail.

Diagnosis

Although the diagnosis of vitiligo generally is made on the basis of clinical findings, biopsy is occasionally needed for differentiating vitiligo from other hypopigmenting or depigmenting disorders.

Microscopic examination of involved skin shows a complete absence of melanocytes in association with a total loss of epidermal pigmentation. Superficial perivascular and perifollicular lymphocytic infiltrates may be observed at the margin of vitiliginous lesions, consistent with a cell-mediated process destroying melanocytes.

Other documented histologic findings include the following:

Loss of pigment and melanocytes in the epidermis is highlighted by Fontana-Masson staining and immunohistochemistry testing.[2, 3]

See Workup for more detail.

Management

Nonsurgical treatments

Surgery

The basic types of repigmentation surgery include the following[6, 7] :

See Treatment and Medication for more detail.

Background

Vitiligo is a pigmentary disorder of the skin, which is characterized by circumscribed depigmented macules and patches. Vitiligo is a progressive disorder in which some or all of the melanocytes in the affected skin are selectively destroyed. Vitiligo affects 0.5-2% of the world population, and the average age of onset is 20 years. While vitiligo may be more obvious in patients with darker skin, this disorder does not have a racial or ethnic predilection.[8]

Pathophysiology

Vitiligo is a multifactorial polygenic disorder with a complex pathogenesis. It is related to both genetic and nongenetic factors. Although several theories have been proposed about the pathogenesis of vitiligo, the precise cause remains unknown. Generally agreed upon principles are an absence of functional melanocytes in vitiligo skin and a loss of histochemically recognized melanocytes, owing to their destruction. However, the destruction is most likely a slow process resulting in a progressive decrease of melanocytes. Theories regarding destruction of melanocytes include autoimmune mechanisms, cytotoxic mechanisms, intrinsic melanocyte defects, oxidant-antioxidant mechanisms, and neural mechanisms, as follows:

Because none of these theories alone is entirely satisfactory, some have suggested a composite hypothesis.

Genetics of vitiligo

Vitiligo is characterized by incomplete penetrance, multiple susceptibility loci, and genetic heterogeneity.[14] Family and twin studies have shown that inheritance is complex and likely involves both genetic and environmental factors.[15] Additionally, it is believed that genetic factors may influence the age of onset of vitiligo.[16] The inheritance of vitiligo may include genes associated with the biosynthesis of melanin, a response to oxidative stress, and regulation of autoimmunity.[17]

Current research has not identified any associations with a certain HLA type in a consistent manner. There is reason to believe that segmental vitiligo and nonsegmental vitiligo may have distinct genetic mechanisms, which could account for their different responses to treatment.

Epidemiology

United States

In the United States, the relative rate of vitiligo is 1%.

International

Vitiligo is relatively common, with a rate of 1-2%. Approximately 30% of vitiligo cases occur with a familial clustering of cases.

Sex

A female preponderance has been reported for vitiligo, but it is not statistically significant and the discrepancy has been attributed to an increase in reporting of cosmetic concerns by female patients.

Age

Although vitiligo may appear at any time from birth to senescence, onset is most commonly observed in persons aged 10-30 years. The average age of onset for vitiligo is approximately 20 years. The age of onset is unlikely to vary between the sexes.

Physical Examination

Vitiligo is almost always diagnosed clinically upon physical examination. Vitiligo manifests as acquired depigmented macules or patches surrounded by normal skin. The macules are chalk or milk-white in color and are well demarcated. Lesions can be round, oval, or linear in shape. The borders may be convex.[1] Lesions enlarge centrifugally over time at an unpredictable rate. Lesions range from millimeters to centimeters in size. A Wood lamp may be necessary to see lesions on patients with lighter skin.

The most common sites of vitiligo involvement are the face, neck, forearms, feet, dorsal hand, fingers, and scalp. When found on the face, lesions may favor a periocular or perioral distribution. In the setting of widespread or generalized vitiligo, lesions may also occur around the genital region, areola, and nipple. Additionally, lesions may occur in regions frequently subjected to trauma, such as bony prominences, elbows, and knees. Koebner phenomenon is defined as the development of vitiligo in sites of trauma, such as a cut, burn, or abrasion. Koebnerization may occur in as many as 20-60% of vitiligo patients.[18]

Body hair in vitiliginous macules may be depigmented. This is known as leukotrichia, and it may indicate a poor prognosis with regard repigmentation therapy.[19] Spontaneous repigmentation of depigmented hair is unlikely to occur.

Clinical Variants

Trichrome vitiligo is a clinical variant characterized by an intermediate zone of hypopigmentation located between the depigmented center and the peripheral unaffected skin. The natural evolution of the hypopigmented areas is progression to full depigmentation. This results in three shades of color in the same patient, as in the image below. The presentation and shades of trichrome vitiligo varies depending on the natural skin color of the patient.



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Trichrome vitiligo.

Marginal inflammatory vitiligo is a very rare variant in which a red, raised border is present at onset or may appear several months or years after initial onset. Mild pruritus may be present. See image below.



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Marginal inflammatory vitiligo.

Quadrichrome vitiligo is another variant of vitiligo, which reflects the presence of a fourth color (dark brown) at sites of perifollicular repigmentation. 

Clinical Classifications of Vitiligo

Vitiligo may be divided into two groups: segmental and nonsegmental. It is important to note that other classification systems exist that choose to break down types of vitiligo based on having a localized or generalized distribution, with localized implying the lesion is restricted to a specific area and generalized implying more than one area is involved. However, the distinction between segmental and nonsegmental may be the most useful to the clinician, as it has an impact on progression, prognosis, and treatment.

Segmental vitiligo

This type manifests as one or more macules that may follow the lines of Blaschko. It is unilateral and does not cross the midline. Segmental vitiligo usually has an early onset and rapidly spreads in the affected area. The course of segmental vitiligo can arrest, and depigmented patches can persist unchanged for the life of the patient. This type of vitiligo is not associated with thyroid or other autoimmune disorders. See the image below.



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Segmental vitiligo.

Nonsegmental vitiligo

Nonsegmental vitiligo has served as an umbrella term to include all types of vitiligo that cannot be classified as segmental vitiligo.[20] Of note, nonsegmental vitiligo is more strongly linked than segmental vitiligo to markers of autoimmunity or inflammation such as halo nevi and thyroid antibodies.[21]

Examples of nonsegmental vitiligo include the following (see the image below):

Subtypes of generalized vitiligo include the following:



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Nonsegmental vitiligo.

Laboratory Studies

Although the diagnosis of vitiligo generally is made on the basis of clinical findings, biopsy is occasionally helpful for differentiating vitiligo from other hypopigmentary disorders.

Because of the association with other autoimmune diseases and endocrinopathies, further testing may be necessary in patients with suggestive signs or symptoms to rule out an underlying condition. Vitiligo may be associated with thyroid disease, diabetes mellitus, pernicious anemia, Addison disease, and alopecia areata. Appropriate tests should be performed only in the presence of signs or symptoms of associated disease.[4, 29]

Laboratory work for vitiligo may include the following:

Histologic Findings

Microscopic examination of involved skin shows a complete absence of melanocytes in association with a total loss of epidermal pigmentation. Superficial perivascular and perifollicular lymphocytic infiltrates may be observed at the margin of vitiliginous lesions, consistent with a cell-mediated process destroying melanocytes. Degenerative changes have been documented in keratinocytes and melanocytes in both the border lesions and adjacent skin. Other documented changes include increased numbers of Langerhans cells, epidermal vacuolization, and thickening of the basement membrane. Loss of pigment and melanocytes in the epidermis is highlighted by Fontana-Masson staining and immunohistochemistry testing.[2, 3]

Approach Considerations

Various types of medications, phototherapy, laser therapy, and surgical therapy exist. However, it is important to note that in patients with lighter skin, no intervention may be needed. Instead, diligent sun protection may be the best strategy in order to avoid the surrounding normal skin from becoming more tan and making the lesions more obvious. When therapy is necessary, topical steroids, topical calcineurin inhibitors, and narrow-band ultraviolet (UV)–B phototherapy are widely used and are now considered the mainstays of treatment. However, treatment must be individualized and patients should be made aware of the risks associated with therapy. No single therapy for vitiligo produces predictably good results in all patients, and the response to therapy is highly variable.

Some types of vitiligo or lesions in certain locations may be more or less responsive to treatment. Segmental vitiligo and an age of onset younger than 14 years have been associated with more refractory disease.[30]

During therapy, pigment cells arise and proliferate from the pilosebaceous unit, spare epidermal melanocytes,[31] and the border of lesions, and migrate up to 2-4 mm from the edge.

Medical Care

Phototherapy

Phototherapy induces satisfactory repigmentation in a majority of patients with early or localized disease.[4] Prolonged phototherapy courses should be encouraged, as a treatment period of at least 6 months may be necessary to accurately assess the responsiveness to the phototherapy.[32] It should be noted that phototherapy causes the normal skin surrounding the lesions to tan, thereby making the lesion more noticeable. This may be cosmetically unacceptable in some patients; therefore, careful counseling surrounding patient expectations and results is necessary before beginning treatment.

Narrowband UV-B (NB-UVB) is widely used and has become the first choice of phototherapy for adults and children with generalized vitiligo. Wavelengths of 311-312 nm typically are used. Treatment frequency is 2-3 times weekly. This treatment can be safely used in children, pregnant women, and lactating women. However, phototherapy may be difficult in pediatric patients who may be unable to cooperate. Short-term adverse effects of NB-UVB include burning, pruritus, and xerosis.

Psoralen photochemotherapy involves the use of psoralens combined with UV-A radiation and is also known as PUVA. Psoralens can be applied either topically or taken orally, followed by exposure to artificial UV-A radiation or natural sunlight. Adverse effects include phototoxic effects, nausea, and risk of skin cancer.

PUVA has largely been replaced by NB-UVB, which is highly effective and has fewer adverse effects. Literature reviews from 2017 have shown that NB-UVB therapy has an overall better response than therapy with PUVA.[32] Additional advantages of NB-UVB over PUVA include shorter treatment times, no drug costs, no nausea, and no need for subsequent photoprotection.

Laser therapy

The excimer laser produces monochromatic rays at 308 nm to treat limited, stable patches of vitiligo. This new treatment is an efficacious, safe, and well-tolerated treatment for vitiligo. However, therapy is expensive. Localized lesions of vitiligo are treated twice weekly for an average of 24-48 sessions.

Excimer laser has been combined with both topical tacrolimus and short-term systemic corticosteroids in the setting of segmental vitiligo, which is a type known to be more resistant to repigmentation in some patients.[33] Studies suggest that segmental vitiligo has a better repigmentation response with excimer laser treatment used at earlier stages of the disease.[34]

Additionally, the use of khellin 4% ointment in combination with monochromatic excimer light (MEL) at 308 nm has been investigated and may be a valid therapeutic option worthy of consideration in the treatment of vitiligo.[35]

Topical therapies

Steroids

A topical corticosteroid preparation is often chosen as a first-line treatment for localized vitiligo because it is easy and convenient for patients.. The results of therapy have been reported as moderately successful, particularly in patients with localized vitiligo and/or an inflammatory component to their vitiligo. Depending on the area being treated, a moderately potent topical steroid can be applied daily for a period of months and then tapered depending on response. Patients should be monitored closely for the possibility of steroid atrophy.

Calcineurin inhibitors

Topical tacrolimus ointment (0.03% or 0.1%) and pimecrolimus cream are effective therapies for vitiligo, particularly when the disease involves the head and neck. These may be used in combination with topical steroids. Studies have suggested that augmenting topical calcineurin inhibitors with laser therapy or NB-UVB may yield better treatment results.[36, 37]

Vitamin D analogs

Vitamin D analogs, particularly calcipotriol and tacalcitol, have been used as topical therapeutic agents in vitiligo. They target the local immune response and act on specific T-cell activation. They do this by inhibition of the transition of T cells (early to late G1 phase) and inhibition of the expression of various proinflammatory cytokines that encode tumor necrosis factor-alpha and interferon-gamma. These vitamin D3 compounds influence melanocyte maturation and differentiation, in addition to up-regulating melanogenesis through pathways that are activated by specific ligand receptors (eg, endothelin receptor and c-kit).[38] More research is needed to examine the effectiveness of calcipotriol as a treatment for vitiligo, as it remains controversial.[39, 40, 41] Some studies have found that the addition of calcipotriol to combination treatments involving NB-UVB, PUVA, or topical steroids improved repigmentation,[39, 40] while others have found no significant differences.[40, 41] While the role of calcipotriol in vitiligo therapy is still not completely clear, it is more likely that it could act as a supplemental therapy rather than a monotherapy.

Afamelanotide

Afamelanotide is an emerging treatment for vitiligo that is a long-lasting synthetic analog of alpha-melanocyte–stimulating hormone (α-MSH).[42, 43] Afamelanotide binds to the melanocortin-1 receptor and stimulates melanocyte proliferation and melanogenesis. The premise of the treatment the knowledge that patients with vitiligo exhibit defects in the melanocortin system, which manifest as decreased levels of α-MSH in both systemic circulation and skin lesions.[44] Afamelanotide is delivered as a subcutaneous implant. A 55-patient phase I/II study showed that when used in conjunction with NB-UVB, a 7- to 10-day release implant of 16 mg afamelantotide produced faster repigmentation of facial and upper extremity lesions than NB-UVB alone. Adverse reactions included hyperpigmentation of normal skin, nausea, and abdominal pain.[43, 45]

Janus kinase (JAK) inhibitor therapy

Oral tofacitinib and other JAK inhibitors have revolutionized the treatment of vitiligo. They are often combined with the other treatment modalities mentioned. Other forms of targeted immunotherapy are also emerging as treatment options.[46, 47]

Topical JAK inhibitor therapy also may be an emerging option.[48] A small proof-of-concept study using twice-daily topical ruxolitinib 1.5% showed promising results.[49] Outcomes measured using the Vitiligo Area Scoring Index (VASI) showed 23% overall improvement at week 20. Further research is needed, but topical JAK inhibitor therapy may offer promise in vitiligo treatment.

Topical ruxolitinib also showed efficacy in a 2019 randomized, placebo-controlled, double-blind, prospective trial. Repigmentation noted at 24 weeks in patients with vitiligo continued to increase up to 1 year.[50]

Systemic corticosteroid therapy

Systemic steroids (prednisone) have been used, although this treatment method is not recommended owing to its toxicity.

Depigmentation therapy

If vitiligo is widespread and attempts at repigmentation do not produce satisfactory results, depigmentation may be attempted in very carefully selected patients.

The long-term social and emotional consequences of depigmentation must be considered. Depigmentation should not be attempted unless the patient fully understands that the treatment results in permanent depigmentation. Some authorities have recommended consultation with a mental health professional to discuss potential social consequences of depigmentation.[51]

A 20% cream of monobenzylether of hydroquinone is applied twice daily for 3-12 months. Burning or itching may occur. Allergic contact dermatitis may be seen.[52] The toxicity of monobenzylether of hydroquinone has been deemed mild; however, no research has been performed on the safety of using the drug over large surface areas of skin to induce widespread pigmentation.[53] Accordingly, it is suggested that depigmentation therapy be limited to the lesions that are most bothersome to the patient, such as ones on the face and hands.

Surgical Care

Surgical alternatives exist for the treatment of vitiligo; however, because of the time-consuming nature of surgical therapies, these treatment regimens are limited to segmental vitiligo or localized vitiligo that is limited to a small region.

Characteristics of vitiligo patients that may be a surgical candidate include the following:

Additionally, to be considered for surgery a lesion must be stable, which is to say that the vitiligo is not actively progressing. The most important factors indicating stability are as follows:

Five basic methods for repigmentation surgery have been described, as follows[6, 7] :

Micropigmentation[59] is another option. Tattooing can be used to repigment depigmented skin in dark-skinned individuals. Color matching is difficult, the color tends to fade, and the treatment can possibly provoke the appearance of new lesions. Alternatively, skin can be dyed with dihydroxyacetone preparations, although the color match is often poor.

Consultations

In cases where the patient’s vitiligo may be tied to an autoimmune disease or another underlying condition, referral to the respective specialist may be necessary. Consultation with an ophthalmologist may be warranted in cases with suspected ocular involvement or ocular symptoms. Additionally, psychological needs must be addressed on a continual basis with appropriate referrals to mental health specialists.[60]

Psychological and Social Impact

Because vitiligo affects a person’s physical appearance, there are various associated psychological and social impacts. Higher levels of depression and social anxiety have been reported in patients with vitiligo.[61] Patients may also experience low self-esteem, social stigmatization, shame, avoidance of intimacy, adjustment disorder, fear, suicidal ideation, and other psychiatric morbidities.[62] Lower measures of quality of life have been reported.[63, 64, 65] Specifically, visible vitiligo lesions have been associated with more emotional distress and stigmatization than nonvisible lesions.[66, 67] With regard to the pediatric population, adolescents are more likely to report lower quality-of-life measures and greater psychological and emotional distress than young children.[62, 68]

Medication Summary

The goals of pharmacotherapy are to reduce morbidity and to prevent complications.

Class Summary

Corticosteroids have anti-inflammatory properties and cause profound and varied metabolic effects. In addition, these agents modify the body's immune response to diverse stimuli. These drugs are used to stop spread of vitiligo and accomplish repigmentation. Data supporting the efficacy of such treatment is largely anecdotal. More study is needed to establish the safety and efficacy of systemic agents.

Class Summary

These agents are used with UV-A exposure for the treatment of localized or generalized vitiligo.

Class Summary

Immunomodulators suppress the activity of the immune system.

Class Summary

Vitamin D analogs may regulate skin cell production and differentiation.

What is vitiligo?How are vitiligo lesions characterized?Where are initial vitiligo lesions located?What are the clinical variants of vitiligo?How is vitiligo diagnosed?What are the findings of microscopic exam of the skin in vitiligo?What are histologic features of vitiligo?What are the nonsurgical treatment options for vitiligo?What is the role of surgery in the treatment of vitiligo?What is vitiligo?What is the pathophysiology of vitiligo?What is the role of genetics in the pathophysiology of vitiligo?What is the incidence of vitiligo in the US?What is the global incidence of vitiligo?How does the incidence of vitiligo vary by sex?What is the most common age of onset for vitiligo?Which physical findings are characteristic of vitiligo?What are the most common sites of vitiligo?What are findings of body hair characteristic of vitiligo?What is trichrome vitiligo?What is marginal inflammatory vitiligo?What is quadrichrome vitiligo?How is vitiligo classified?What is segmental vitiligo?What is nonsegmental vitiligo?What are the types of nonsegmental vitiligo?What are the subtypes of generalized vitiligo?What are the ocular abnormalities associated with vitiligo?What are the signs and symptoms of Alezzandrini syndrome associated with vitiligo?Which autoimmune conditions are associated with vitiligo?What is the role of melanin in the progression of vitiligo?What causes vitiligo in malignant melanoma?What are the differential diagnoses for Vitiligo?What is the role of biopsy in the workup of vitiligo?What is the role of lab studies in the workup of vitiligo?What are the histologic features of vitiligo?What are the treatment options for vitiligo?What is the role of phototherapy in the treatment of vitiligo?How is narrowband UV-B (NB-UVB) used to treat vitiligo?How is psoralen photochemotherapy (PUVA) used to treat vitiligo?What is the role of psoralen photochemotherapy (PUVA) in the treatment of vitiligo?What is the role of laser therapy in the treatment of vitiligo?What is the efficacy of combined excimer laser, topical tacrolimus, and short-term systemic corticosteroids in the treatment of vitiligo?What is the role of combined khellin 4% ointment and monochromatic excimer light (MEL) in the treatment of vitiligo?What is the role of topical corticosteroid in the treatment of vitiligo?What is the role of calcineurin inhibitors in the treatment of vitiligo?What is the role of vitamin D analogs in the treatment of vitiligo?What is the role of afamelanotide in the treatment of vitiligo?What is the role of Janus kinase (JAK) inhibitor therapy in the treatment of vitiligo?What is the role of systemic corticosteroids in the treatment of vitiligo?What is the role of depigmentation therapy in the treatment of vitiligo?What are the long-term social and emotional consequences of depigmentation as a treatment of vitiligo?How is depigmentation therapy administered for the treatment of vitiligo?What is the role of surgery in the treatment of vitiligo?When should surgery be considered for the treatment of vitiligo?How is lesion stability determined in vitiligo?What are the methods for repigmentation surgery for vitiligo?What is the role of micropigmentation in the treatment of vitiligo?Which specialist consultations may be needed to treat vitiligo?What is the psychological and social effect of vitiligo?What are the goals of drug treatment for vitiligo?Which medications in the drug class Vitamins are used in the treatment of Vitiligo?Which medications in the drug class Immunomodulator are used in the treatment of Vitiligo?Which medications in the drug class Psoralens are used in the treatment of Vitiligo?Which medications in the drug class Corticosteroids are used in the treatment of Vitiligo?Which medications in the drug class Calcineurin Inhibitors are used in the treatment of Vitiligo?

Author

Krista Roncone, University of Virginia School of Medicine

Disclosure: Nothing to disclose.

Coauthor(s)

Barbara B Wilson, MD, Edward P Cawley Associate Professor, Department of Dermatology, University of Virginia School of Medicine

Disclosure: Nothing to disclose.

Specialty Editors

David F Butler, MD, Former Section Chief of Dermatology, Central Texas Veterans Healthcare System; Professor of Dermatology, Texas A&M University College of Medicine; Founding Chair, Department of Dermatology, Scott and White Clinic

Disclosure: Nothing to disclose.

Edward F Chan, MD, Clinical Assistant Professor, Department of Dermatology, University of Pennsylvania School of Medicine

Disclosure: Nothing to disclose.

Chief Editor

Dirk M Elston, MD, Professor and Chairman, Department of Dermatology and Dermatologic Surgery, Medical University of South Carolina College of Medicine

Disclosure: Nothing to disclose.

Additional Contributors

Mark G Lebwohl, MD, Chairman, Department of Dermatology, Mount Sinai School of Medicine

Disclosure: Received none from Amgen for consultant & investigator; Received none from Novartis for consultant & investigator; Received none from Pfizer for consultant & investigator; Received none from Celgene Corporation for consultant & investigator; Received none from Clinuvel for consultant & investigator; Received none from Eli Lilly & Co. for consultant & investigator; Received none from Janssen Ortho Biotech for consultant & investigator; Received none from LEO Pharmaceuticals for consultant & inves.

Naveed Sami, MD, FAAD, Assistant Professor, Department of Dermatology, University of Alabama School of Medicine

Disclosure: Nothing to disclose.

Vlada Groysman, MD, Medical Director, Cahaba Dermatology and Skin Health Center; Clinical Assistant Professor of Dermatology, University of Alabama at Birmingham School of Medicine

Disclosure: Nothing to disclose.

Acknowledgements

The authors and editors of Medscape Reference gratefully acknowledge the contributions of previous author, Seung-Kyung Hann, MD, to the development and writing of this article.

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Trichrome vitiligo.

Trichrome vitiligo.

Marginal inflammatory vitiligo.

Segmental vitiligo.

Nonsegmental vitiligo.

Trichrome vitiligo.

Marginal inflammatory vitiligo.

Segmental vitiligo.

Nonsegmental vitiligo.