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Vitiligo; Types, Causes, Symptom, Diagnosis, Treatment

Vitiligo (vit-ill-EYE-go) is a disorder in which white patches of skin appear on different parts of the body. This happens because the cells that make pigment (color) in the skin are destroyed. These cells are called melanocytes (ma-LAN-o-sites). Vitiligo can also affect the mucous membranes (such as the tissue inside the mouth and nose) and the eye.

Vitiligo is an asymptomatic but cosmetically disfiguring disorder that results in the formation of depigmented patches on the skin and/or mucosae [rx,rx]. Vitiligo can be segmental or non-segmental depending upon the morphology of the clinical involvement [rx]. It can be classified as progressing or stable based on the activity of the disease. Further, the extent of involvement can be limited (localized disease) or extensive (generalized disease).

The patches of skin affected become white and usually have sharp margins. The hair from the skin may also become white. Inside the mouth and nose may also be involved. Typically both sides of the body are affected. Often the patches begin on areas of skin that are exposed to the sun. It is more noticeable in people with dark skin. Vitiligo may result in psychological stress and those affected may be stigmatized

Types of Vitiligo

Classification attempts to quantify vitiligo have been analyzed as being somewhat inconsistent, while recent consensus has agreed to a system of segmental vitiligo (SV) and non-segmental vitiligo (NSV). NSV is the most common type of vitiligo.

Non-segmental

In non-segmental vitiligo (NSV), there is usually some form of symmetry in the location of the patches of depigmentation. New patches also appear over time and can be generalized over large portions of the body or localized to a particular area. Extreme cases of vitiligo, to the extent that little pigmented skin remains, are referred to as vitiligo Universalis. NSV can come about at any age (unlike segmental vitiligo, which is far more prevalent in teenage years).

Common areas include

backs of the hands
arms
eyes
knees
elbows
feet
mouth
armpit and groin
nose
navel
genitals and rectal area

However, patches can also appear in other areas

Non-segmental vitiligo – is further broken down into sub-categories:
Generalized – There is no specific area or size of patches. This is the most common type.
Acrofacial – This occurs mostly on the fingers or toes.
Mucosal – This appears mostly around the mucous membranes and lips.
Universal – Depigmentation covers most of the body. This is very rare.
Focal – One, or a few, scattered white patches develop in a discrete area. It most often occurs in young children.

Classes of non-segmental vitiligo include the following

Generalized vitiligo – the most common pattern, wide and randomly distributed areas of depigmentation
Universal vitiligo – depigmentation encompasses most of the body
Focal vitiligo – one or a few scattered macules in one area, most common in children
Acrofacial vitiligo – fingers and periorificial areas
Mucosal vitiligo – depigmentation of only the mucous membranes

Segmental

Segmental vitiligo (SV) differs in appearance, cause, and frequency of associated illnesses. Its treatment is different from that of NSV. It tends to affect areas of skin that are associated with dorsal roots from the spinal cord and is most often unilateral. It is much more stable/static in the course and its association with autoimmune diseases appears to be weaker than that of generalized vitiligo.SV does not improve with topical therapies or UV light, however surgical treatments such as cellular grafting can be effective.

Causes of Vitiligo

A disorder in which your immune system attacks and destroys the melanocytes in the skin
an autoimmune disorder, in which the immune system becomes overactive and destroys the melanocytes
a genetic oxidative stress imbalance
a stressful event
harm to the skin due to a critical sunburn or cut
exposure to some chemicals
a neural cause
heredity, as it may run in families
a virus
Family history (heredity)
A trigger event, such as sunburn, stress or exposure to industrial chemicals

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Symptoms of Vitiligo

Focal. Depigmentation is limited to one or a few areas of your body.
Segmental. Loss of skin color occurs on only one side of your body.
Generalized. Pigment loss is widespread across many parts of your body.
The armpits and groin (where the leg meets the body)
Around the mouth
Eyes
Nostrils
Navel
Genitals
Rectal areas.
Premature whitening or graying of the hair on your scalp, eyelashes, eyebrows or beard
Loss of color in the tissues that line the inside of your mouth (mucous membranes)
Loss or change in color of the inner layer of your eye (retina)

Diagnosis of Vitiligo

Vitiligo

The doctor will use a family and medical history, physical exam, and tests to diagnose vitiligo. The doctor may ask questions such as

Do you have family members with vitiligo?
Do you or family members have any autoimmune diseases?
Did you have a rash, sunburn, or other skin problem before the white patches appeared?
Did you have some type of stress or physical illness?
Did your hair turn gray before age 35?
Are you sensitive to the sun?
Taking a small sample (biopsy) of the affected skin to be examined
Blood tests
An eye exam.

Treatment of Vitiligo

Medical Treatment

Some of the more common medical treatments for vitiligo include

Classical immunosuppressants and immunomodulators probably act on these T-lymphocytes and inhibit their activation and proliferation. Methotrexate, azathioprine and systemic corticosteroids (prednisolone, dexamethasone, betamethasone) have been successfully employed to halt the progression of active vitiligo, though repigmentation is variably reported in different studies [rx,rx,rx,rx].

Corticosteroid creams

When applied to white patches very early in the disease, corticosteroids may help to bring some color back to the skin by decreasing the inflammation that leads the skin to have fewer pigment cells. Don’t let the word “steroids” put you off. Corticosteroids are medications, not the type of anabolic steroids that athletes use.

Photochemotherapy

It is also known as PUVA. PUVA therapy has two steps: first, a medication called psoralen is either applied to the white patches of skin or taken orally; then, the skin is exposed to ultraviolet light, sometimes from the sun but more often from an artificial source like a UVA lamp. This turns the affected skin pink, which in time tends to fade to a more natural (often slightly darker) color. You’ll want to ask your doc about side effects of PUVA treatment — including a possibility of severe sunburn and skin blistering.

Narrow-band ultraviolet B (UVB) therapy

This treatment is more widely used than PUVA. It’s similar, except that the ultraviolet light used is UVB instead of UVA. UVB treatment doesn’t require psoralen, eliminating some of the risk associated with PUVA.

Combining psoralen and light therapy

This treatment combines a plant-derived substance called psoralen with light therapy (photochemotherapy) to return color to the light patches. After you take psoralen by mouth or apply it to the affected skin, you’re exposed to ultraviolet A (UVA), UVB light or excimer light. These approaches tend to have better results than just medication or just light. You may need to repeat treatments up to three times a week for six to 12 months.

Antioxidants

Antioxidants administered either topically or systemically have shown promise though results are variable [rx,rx]. Polypodium leucotomos, ginkgo Biloba [rx], pseudo catalase, khellin, vitamin C, vitamin E and polyunsaturated fatty acids like alpha-lipoic acid have been employed with variable outcomes in previously published studies. Minocycline has been found to be beneficial in vitiligo in a series of studies. The effect stems from its successful anti-oxidant role [rx]. It has been observed in some studies that hydrogen peroxide accumulates in the epidermis of vitiligo lesions.

Removing the remaining color (depigmentation)

This therapy may be an option if your vitiligo is widespread and other treatments haven’t worked. A depigmenting agent is applied to unaffected areas of skin. This gradually lightens it so that it blends with the discolored areas. The therapy is done once or twice a day for nine months or longer.

Medicines (such as creams) that you put on the skin
Medicines that you take by mouth
A treatment that uses medicine plus ultraviolet A (UVA) light (PUVA)
Removing the color from other areas so they match the white patches.

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Spot Treatment: Topical Oxsoralen

Much more complicated is the use of topical Oxsoralen (8-MOP). Oxsoralen is highly phototoxic (likely to cause a sunburn), and the phototoxicity lasts for 3 days or more. This should be performed only as an office procedure, only for small spots, and only by experienced physicians on well-informed patients. As with oral psoralens, 15 or more treatments may be required to initiate a response, and 100 or more to finish.

Spot Treatment: Mini Grafting

Mini grafting, which involves transplanting the patient’s normal skin to vitiligo affected areas, maybe a useful technique for refractory segmental vitiligo macules. PUVA may be required following the procedure to unify the color between the graft sites. The demonstrated occurrence of Koebnerization in donor sites in generalized vitiligo restricts this procedure to patients who have limited skin areas at risk for vitiligo. “Pebbling” of the grafted site may occur.

Whole Body Treatment: PUVA Photochemotherapy (Oral Psoralens + UVA Irradiation)

For more widespread vitiligo, treatment with oral psoralen + UVA (PUVA) is practical. This may be done with sunlight and trimethylpsoralen (Trisoralen) or with artificial UVA (in the doctor’s office or at an approved phototherapy facility) and Trisoralen or Oxsoralen-Ultra.

Afamelanotide

This is an analog of a melanocyte-stimulating hormone. A randomized study conducted at two academic medical centers found that the combination of afamelanotide implant and narrow-band UVB phototherapy resulted in statistically superior and faster repigmentation, compared with narrow-band UVB monotherapy (JAMA Dermatol. 2015 Jan;151(1):42-50).

Abatacept (Orencia)

This is a soluble fusion protein consisting of human cytotoxic T-lymphocyte–associated antigen 4 (CTLA4), which prevents T-cell activation. A phase I trial is underway at Brigham and Women’s Hospital in Boston to determine if weekly self-injections of the agent lead to clinical improvements of vitiligo lesions. The primary outcome measure changes in repigmentation with abatacept therapy based on the VASI score.

Simvastatin

The notion of its use is based on STAT1 inhibition reducing interferon-gamma–dependent activation of CD8-positive T cells, according to Dr. Leachman. The concept has been successful in a mouse model, and a study in humans was recently completed by Dr. John Harris at the University of Massachusetts, Worcester. “What we have is the ability to apply an existing drug (Simvastatin) to the process and see if it works,” she said. “Wouldn’t it be cool if we could give a statin and improve vitiligo?”

Tofacitinib

This is a Janus kinase inhibitor commonly used for rheumatoid arthritis. According to Dr. Leachman, Janus kinase inhibition prevents STAT activation, “which prevents [interferon]-gamma production, which reduces activation of CD8-positive T cells via CXCL10 binding to CXCR3,

Stimulating melanocyte regeneration

α-MSH

Alpha melanocyte-stimulating hormone (α-MSH) – has inherent melanocyte-stimulating properties. It is synthesized in the keratinocytes after exposure to ultra-violet radiation. The damage created by ultra-violet radiation activates p53, which further mediates transcription of pro-opiomelanocortin (POMC), which is cleaved to form local melanocortin or α-MSH. α-MSH acts on its receptor (melanocortin1 receptor) and activates adenylate cyclase, which causes the formation of cyclic adenosine monophosphate (cAMP) from adenosine triphosphate (ATP). The subsequent activation of protein kinase A by cAMP brings about the activation of microphthalmia-associated transcription factor (Mitf) and c-AMP response element-binding protein (CREB), both of which have potential pro-differentiation and pro-survival effects on melanocytes. Melanocortin also lowers the oxidative stress inside the melanocytes [rx].
Phototherapy is currently first-line therapy for vitiligo, especially in patients with the widespread disease [rx, rx]and reviewed in this issue. Phototherapy and combination therapies for vitiligo}. While the mechanism of its therapeutic effects is not completely understood, repigmentation from phototherapy is probably due to its ability to induce immunosuppression, but also to the induction of melanocyte stem cell differentiation and proliferation [rx].

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WNT signaling

A recent study reported that melanocytes – from vitiligo patients had defective WNT signaling, a pathway that promotes the differentiation of melanocyte precursors in skin.
They hypothesized that this impaired signaling contributed to disease pathogenesis and, in particular, inhibited melanocyte regeneration and repigmentation during treatment. Studies using explanted human skin ex vivo suggested that WNT activators could enhance melanocyte differentiation [rx].
Another pathway – that have been of recent interest in vitiligo involves the activation of wnt-beta catenin signaling. This signaling is vital for differentiation of melanoblasts into functioning melanocytes and was found to be getting impaired on exposure to oxidative stress [rx].
JAK-STAT inhibitors – have shown promising results in the treatment of vitiligo, including successful repigmentation outcomes. These molecules have been tried in both topical and systemic formulations. Pan JAK inhibitor, tofacitinib and JAK-1,2 inhibitor, ruxolitinib, have been found successful in causing repigmentation in vitiligo [rx]. Similarly, statins (which are also HMG co-reductase inhibitors) were demonstrated to inhibit STAT1 signaling in ex-vivo studies, and simvastatin was found to result in significant repigmentation in a case report. Further, though phase 2 clinical trials are going on in ulcerative colitis, the inhibitors of CXCL-10 and CXCR3 could be tried further in vitiligo.

Surgical treatments of Vitiligo

Skin grafting – In this procedure, your doctor removes very small sections of your normal, pigmented skin and attaches them to areas that have lost pigment. This procedure is sometimes used if you have small patches of vitiligo.
Blister grafting – In this procedure, your doctor creates blisters on your pigmented skin, usually with suction. He or she then removes the tops of the blisters and transplants them to an area of discolored skin.
Tattooing (micro pigmentation) – In this technique, your doctor uses a special surgical instrument to implant pigment into your skin. It’s most effective in and around the lips in people with darker complexions.
Tattooing small areas of skin.

Key Points

Vitiligo results from the destruction of epidermal melanocytes by autoreactive cytotoxic T cells.
Melanocyte-specific autoimmunity in vitiligo is a result of the interplay among multiple factors, including genetic predisposition, environmental triggers, melanocyte stress, and innate and adaptive immune responses.
Genome-wide association studies have identified multiple risk alleles in patients with vitiligo, and most are associated with immune regulation.
Melanocyte defects contribute to initiating autoimmunity in vitiligo.
Environmental stressors, especially chemical phenols that mimic the amino acid tyrosine and the products that contain them, can induce and exacerbate vitiligo.
An optimal treatment strategy in vitiligo would stabilize melanocytes, suppress the autoimmune response and restore immune tolerance, as well as stimulate melanocyte regeneration, proliferation, and migration to lesional skin.
A better understanding of the key pathways involved in vitiligo onset and progression will enable us to develop treatments that have greater efficacy and a good safety profile.