Are You Confident of the Diagnosis?
What you should be alert for in the history
Vitiligo is defined as an acquired disorder in which melanocytes almost exclusively are destroyed causing depigmented macules on the skin. There are several types of vitiligo, i.e. vitiligo vulgaris, unilateral (or segmental vitiligo) and focal vitiligo. All forms of vitiligo are included in the category of leukoderma or depigmenting disorders.
The fair skinned patient commonly notes that skin especially on the face, hands, arms or other exposed skin will burn very easily in the springtime when first spending hours in the sunlight. Parents often note in small children that scrapes on the knees or elbow heal but leave “a white scar” after healing.
Individuals with dark skin will note that skin is turning light or white. Usually there are no preceding symptoms but about 5% of patients have an inflammatory form of vitiligo in which the leukoderma is preceded by a red, itchy rash. In this form the borders between white and normal skin has an erythematous rim.
Characteristic findings on physical examination
Vitiligo affects males and females equally and often begins early in life before the age of ten years. Half develop it by age 20 years and 95% before the age of 40 years. It is a disorder that affects young people although it can begin much later in life.
Patients with vitiligo vulgaris or bilateral or generalized vitiligo early in the disease will have depigmentation of the finger tips, knuckles, the ventral side of the wrist, the axillae, the toes, ankles, around the eyes and mouth and along the hair line (Figure 1, Figure 2).
Patients with unilateral or segmental vitiligo will note rapid onset and spread of depigmentation on one side of the body in a typical pattern. Most commonly it affects one part of the face, i.e. the upper or mid part of the face, one side of the neck or a segment on the trunk (Figure 3, Figure 4). These are not dermatomal patterns but segments (Figure 5). Unilateral vitiligo spreads for a limited period, maybe one to two years and is self limiting.
In contrast to bilateral vitiligo, the follicles and follicular melanocytes are affected in about half of those with this form of vitiligo. The hairs within the depigmented patch are white. In these latter individuals, medical therapy cannot be successful.
The third type of vitiligo is focal vitiligo (Figure 6, Figure 7). It can be the precursor to bilateral vitiligo. More often the patient will note loss of pigmentation on one part of the body, i.e. the genitalia, some spots on the tibia, several spots on the trunk. It remains localized to these regions. The follicles typically are affected and the hair within the patch is white. In all types of vitiligo, the epidermis is clinically normal with no atrophy, scaling, vesicles or other abnormal findings (Figure 8, Figure 9).
The diagnosis is made on clinical findings, i.e. inspection of the skin. The pattern of depigmentation noted above is usually characteristic. The absence of symptoms or other clinical manifestations or preceding rashes is helpful. Occasionally a patient will exhibit depigmentation in a very atypical pattern. With time the pattern becomes more characteristic. At times it can be difficult to make a diagnosis for certain.
Although biopsies are usually not obtained to confirm the diagnosis of vitiligo, if performed, a sparse mononuclear infiltrate may be observed (Figure 10) with a diminution/absence in the number of melanocytes seen with dopa oxidase staining (Figure 11) or by an S-100 stain.
Who is at Risk for Developing this Disease?
The precise prevalence of vitiligo is unknown. Data from Scandinavian countries suggest in the European population about one person in 200 develops vitiligo in his or her lifetime. There are small communities in eastern Europe and in India where the prevalence can go as high as 8%. It is not known if this high rate is genetically based or caused by some environmental factor, although most observers favor a genetic basis.
It is a general opinion that the prevalence of vitiligo is similar in all populations and ethnic groups worldwide. Thus one might guess that about one per two hundred individuals would be affected. In the primary family (parents, siblings and children) the prevalence is about one per 20, that is, a tenfold increase. Still that means 5% of the individuals in the primary family will be affected and 95% will not be. Consistent with this data is the observation that only about one in three people with vitiligo have a family history of vitiligo in the primary family.
What is the Cause of the Disease?
The cause of vitiligo is unknown. There is a consensus that at least three factors are involved. The factors are dependent on inheritance of a set of three genes that cause melanocytes to be susceptible to destruction and the immune system to be hyperactive, and that a potential factor in the environment that activates the genes.
Most likely the activation (or suppression) of the genes causes release of cytokines by lymphocytes and/or keratinocytes that induce apoptosis of the melanocytes and some surrounding keratoinocytes and Merkel cells. The melanocytes undergo involution and the skin becomes devoid of pigment cells. In a few intervening weeks the pre-existing melanin is shed and the skin turns white. Keratinocytes apparently repair and are replaced quickly. Merkel cells are not replaced but seem to have minimal impact on white skin.
There are a number of candidate genes that have been identified. The best described and known is the NALP-1 gene that was discovered 10 years ago, being associated with vitiligo and systemic lupus erythematosus. It was studied later and shown to be closely associated with vitiligo alone in some patients, with autoimmune disorders such as thyroiditis in others, and with both disorders in still other groups of patients. It is also associated with diabetes mellitus, adrenal insufficiency and pernicious anemia.
NALP-1 gene is expressed in Langerhans cells and T lymphocytes and is involved in immune reactivity to bacterial antigens, in the production of various cytokines, and induction of apoptosis, the probable mechanism by which melanocytes are destroyed.
Systemic Implications and Complications
Vitiligo is not usually associated with systemic disorders, although as noted above, about 15% of patients will have thyroid dysfunction of some type. A small percentage have diabetes mellitus and rarely a person with vitiligo will have adrenal insufficiency or pernicious anemia. Generally a work up is not indicated unless the patient has symptoms suggestive of these disorders.
As the defect causing leukoderma is absence of melanocytes, in order to get the color to return, it is necessary to replace melanocytes. The skin can do this if stimulated properly. The melanocytes within hair follicles are the reservoir for repigmentation (Figure 12).
Melanocytes divide too slowly and migrate at too slow a rate for them to migrate across a large macule of depigmentation. Melanocytes come from the follicles. As they proliferate and repopulate the epidermis, freckles will be seen to form around the follicular orifices that, with time, merge and coalesce to repigment the epidermis.
Not all skin has follicles. Glabrous (smooth) skin found on the dorsum of the fingers, ventral surface of the wrist, below the ankles and on the genitalia is devoid of follicles. These areas cannot repigment in response to medical treatments. Occasionally the hair follicle is affected by vitiligo, especially unilateral or segmental vitiligo. The hair coming from such a follicle will be white. Such skin cannot respond to medical therapy because the reservoir has been destroyed (Figure 13).
Vitiligo can be treated medically or on occasion surgically. Medical therapies include applications of topical medications and/or exposure to various forms of ultraviolet light. Typically, phototherapy and topical agents are combined. Surgical therapies are limited to those with limited depigmentation such as those with unilateral (segmental), focal vitiligo, or those with very stable bilateral vitiligo. For some adults with very extensive vitiligo, depigmentation is the optimal treatment.
Optimal Therapeutic Approach for this Disease
The traditional topical medications available for the treatment of vitiligo are topical steroids, the calcineurin inhibitors such as Protopic and Elidel, or Dovonex. All of these uses are off label and not approved by the FDA for vitiligo, but have been used for many years. Data has been published for each of the agents to suggest reasonable efficacy.
Vitiligo begins before the age of 20 years in half of those affected. Thus vitiligo is a young person’s disorder. It can start even in small children aged 2 or 3 years. For such young children, treatment can be deferred if lesions are not obvious. Children respond better than adults, especially on the face.
Vitiligo can be treated with topical steroids but these usually are of lower potency, such as hydrocortisone 2.5% or desonide 0.05% applied once daily. Around the eyes the medication should be limited in application. Children can be treated with Protopic (tacrolimus), 0.03% or Elidel (pimecrolimus) or Dovonex (calcipotriene).
One easy schedule that avoids prolonged exposure to any of these medications is application of the steroid once nightly for 2 weeks followed by application of one of the other agents once nightly for 2 weeks. This cycle is repeated for at least 3-6 months. Most data is published for use of Protopic. However, Elidel has been shown to be useful. Dovonex has the least published support; however, it can be used for those who prefer not to expose their child or themselves to the calcineurin inhibitors.
Small children are not good candidates for phototherapy. One way to obtain ultraviolet light is to treat during the summer months. The child is permitted to play outdoors during the morning hours without sun protection. At lunch, the child is covered with clothing and sunscreens to avoid sunburn. Teenagers can be given phototherapy.
The use of topical medications is also useful in adults. This author uses more potent steroids for older patients. Mometasone is available for teenagers and clobetasol or fluocinonide can be used for adults. They are used in the same fashion as for children. One easy way to prescribe these medications is to have the patient apply the steroid for the first 2 weeks of each month and the alternate medication for the last 2 weeks of each month.
Ultraviolet light seems to be very helpful for successful treatment. One theoretical basis for using topical agents is to halt the process that is destroying the melanocytes. The purpose of the ultraviolet light is to stimulate proliferation and migration of melanocytes from hair follicles into the interfollicular epidermis and enhancement of melanin production. There are various sources of ultraviolet light. The easiest is natural sunlight. It provides all types of UVB and UVA and is readily accessible in summers and in equatorial countries. Care must be taken to avoid sunburn that can spread vitiligo.
Narrow band ultraviolet B has come into vogue in the last 10 years. It is administered 2 to 3 times weekly. It seems to be helpful in combination with topical agents. Narrow band ultraviolet light is available usually in physicians’ offices. It seems to be the most efficacious form of light treatment.
PUVA (psoralens and exposure to ultraviolet A) is a standard form of treatment. It has fallen out of use with reports of excessive squamous cell carcinomas and some melanomas occurring in a group of patients using PUVA for treatment of psoriasis. It still is available, although 8-methoxypsoralen (Oxsoralen Ultra) is not readily available. UVA boxes have become harder to find.
Some patients live too far from phototherapy centers to get light treatments 2 or 3 times weekly. Such patients can use local tanning parlors with exposures of 15 or 20 minutes twice weekly. This is considered less optimal than narrow band ultraviolet but at times it is the only practical source of ultraviolet light. Most tanning parlors have units that emit in the UVA (340-400nm) spectrum.
Surgical therapies are used to replace a missing reservoir of melanocytes. Glabrous skin has no hair follicles. Often those with unilateral (segmental) vitiligo have white hair, an indicator that the reservoir has been destroyed. These patients have limited areas of depigmented skin and are the best candidates for surgical therapy. The surgery is a form of autograft (Figure 14, Figure 15).
The epidermis from white skin is removed by one of several techniques such as dermabrasion or laser ablation. Epidermis from pigmented skin is transferred to the white skin. The melanocytes attach to the denuded white skin and repigmentation occurs. Only a few specialized centers provide this therapy.
Depigmentation is a treatment that is indicated for adults with very extensive depigmentation on the face, neck, chest, arms and hands. Often the depigmentation is too extensive to repigment or does not respond. These individuals can be treated with monobenzone 20% applied once daily. The process usually is slow, taking up to a year. Patients are advised to depigment visible skin first and continue the process later if they so choose.
Monobenzone is no longer available commercially as Benoquin. It is made in local formulating pharmacies. At times, the concentration can be increased to 30% or 40% although these higher concentrations tend to be irritating. Depigmentation is an excellent therapy for carefully selected patients and produces a very good result. Individuals of any ethnic background or skin color can be depigmented successfully and satisfactorily (Figure 16, Figure 17).
Treatment should be given for at least 3-4 months. The patient should be examined for evidence of repigmentation, i.e. freckles around hair follicles on the exposed skin. This is done best with the help of a Wood’s lamp. If there is no repigmentation visible, treatment probably should be discontinued and tried again 6 months later. If there is evidence of repigmentation, therapy should be continued for an additional 3 months and progress assessed again.
Patients often show excellent responses over a period of 6 months or more; however when therapy is discontinued, the depigmentation usually recurs. Unfortunately the best therapy, i.e. a medication that would permanently stop the destruction of melanocytes, is not available and so treatment must be started again. Were such a medication available the problem of vitiligo would be mostly resolved.
Unusual Clinical Scenarios to Consider in Patient Management
Vitiligo usually begins before the age of 40 years. Elderly adults in the 6th decade of life or older who develop vitiligo might be at risk for leukemia or lymphoma or metastatic melanoma. Patients should be asked about moles, disappearing moles, moles that were removed or prior skin cancers. More intensive work up can be indicated based on the history. Simple blood tests can screen for leukemias.
What is the Evidence?
Gupta, S, Olsson, MJ, Kanwar, AJ, Ortonne, JP. “Surgical management of vitiligo”. Blackwell Scientific. 2007. (This is a very comprehensive presentation of all forms and methods of surgically treating vitiligo. It will be useful for those contemplating using surgical grafting for treating patients with vitiligo.)
Nordlund, J, Ortonne, JP, Le Poole, IC, Nordlund, JJ, Boissy, RE, Hearing, VJ, King, RA, Oetting, W, Ortonne, JP. “The Pigmentary System: Physiology and Pathophysiology”. Vitiligo vulgaris. 2006. pp. 551-598. (This is a very detailed and indepth presentation on vitiligo and its ramifications, treatments, associations and complications.)
Nordlund, JJ, Boissy, RE, Hearing, VJ, King, RA, Oetting, W, Ortonne, JP. “The Pigmentary System: Physiology and Pathophysiology”. 2006. (This book is a comprehensive and in-depth presentation of the basic science of melanocytes, melanin and melaninzation and a review of most of the clinical disorders of pigmentation. The authors when possible associate the basic science information with the clinical syndromes.)
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