What is Vitiligo (white spots)?
Vitiligo (vit-uh-lie-go) causes the skin to lose its natural color. Patches of lighter skin appear. Some people develop a few spots. Others lose much more skin color. Vitiligo can also affect other parts of your body. A section of hair can turn white. Some people lose color inside their mouths. Even an eye can lose some of its colors. What causes this color loss is still a mystery. We do know that Vitiligo is not contagious. It is not life-threatening.
But Vitiligo can be life-altering. Some people develop low self-esteem. They may no longer want to hang out with friends. They can produce severe depression. Most people have Vitiligo for life, so it’s crucial to develop a coping strategy that helps many people learn about it. Another helpful approach is to connect with others who have Vitiligo.
Introduction
Leukoderma and hypopigmentation are general terms used to designate disorders characterized by the lightening of the skin. They are classically the result of decreased epidermal melanin content (melanin-related), but they may be secondary to a decreased blood supply to the skin (hemoglobin-related). Hypo-melanosis is a more specific term that denotes an absence or reduction of melanin within the skin; amelanosis signifies the total absence of melanin.
Depigmentation usually implies a total loss of skin color, most commonly due to the disappearance of pre-existing melanin pigmentation, as in vitiligo. The term pigmentary dilution is used to describe a generalized tightening of the skin and hair, as in oculocutaneous albinism; this may be apparent only if affected Individuals are compared with unaffected relatives.
Cutaneous hypo-melanosis is often classified into two groups:
- • melano-cytopenic hypo-melanosis, caused by a partial or total absence of epidermal and follicular melanocytes
- • melano-penic hypo-melanosis, the number of epidermal and follicular melanocytes is average, but the pigment cells fail to synthesize average amounts of melanin and transfer it to surrounding keratinocytes.
Melano-cytopenic hypo-melanosis may be hereditary and congenital due to a defect in melano-blast differentiation, proliferation, migration, and survival, or it may be acquired. In the latter case, functional melanocytes often disappear due to their destruction (e.g., external trauma, such as cryosurgery or an autoimmune attack).
The factors controlling melanocyte survival may also play a role in the postnatal disappearance of dermal melanocytes. Melanopenic hypo-melanosis may result from several complex pathologic mechanisms, including melanosome abnormalities (e.g., their biogenesis, melanization, transfer, or degradation) or melanin removal.
Diagnosis of leukodermas
I should thoroughly examine any patient with a leukoderma under visible and UVA light (i.e., ~365 nm wavelength in a Wood’s lamp). Under visible light, it is sometimes difficult to distinguish between hypo-melanosis and amelanosis. The latter is particularly useful in circumscribed leukodermas, individuals who have pigmented skin (types I or II) very lightly, and neonates.
Most leukodermas are diagnosed clinically following a complete history and physical examination. Still, the greater the loss of epidermal pigmentation, the more marked the contrast on Wood’s lamp examination. This technique is also helpful in differentiating hypomelanotic macules from hemoglobin-related leukodermas; for example, nevus anemic becomes inapparent.
Epidemiology of Vitiligo
Vitiligo affects 0.5–2% of the general population worldwide2, and it may appear any time from shortly after birth to late adulthood. The average age of onset is approximately 20 years. Although patients with vitiligo often attribute the onset of their disease to specific life events (e.g., physical injury, sunburn, emotional distress, illness, or pregnancy), except for the Koebner phenomenon, there is no proof that these factors cause or precipitate vitiligo.
Clinical Features
The most common presentation of vitiligo is amelanotic (i.e., milk- or chalk-white) macules or patches surrounded by normal skin. The lesions characteristically have discrete margins, and they can be round, oval, irregular, or linear in shape. The borders are usually convex as if the depigmenting process were “invading” the surrounding customarily pigmented skin. Lesions enlarge centrifugally over time, and the rate may be slow or rapid.
Vitiligo macules and patches range from millimeters to centimeters in diameter and often vary in size within areas of involvement. In darkly pigmented individuals or after tanning of uninvolved skin, the contrast between vitiliginous areas and the surrounding skin is striking. The lesions may be subtle or inapparent in lightly pigmented individuals without using a Wood’s lamp. Vitiligo is usually asymptomatic, but pruritus is sometimes noted.
Vitiligo can develop anywhere in the body. Interestingly, it usually prefers hyperpigmented sites, such as the face, dorsal aspect of the hands, nipples, axillae, umbilicus, and sacral, inguinal anogenital regions. Facial vitiligo typically occurs around the eyes and mouth (i.e., periorificial), and on the extremities, it favors the elbows, knees, digits, flexor wrists, dorsal ankles, and shins.
In acrofacial vitiligo, periungual involvement of one or more digits may be associated with lip depigmentation; however, either can be an isolated finding. Many of the common sites of involvement are subjected to repeated trauma, pressure, or friction. Vitiligo on the palms, soles, lips and oral mucosa in lightly pigmented individuals may not be evident without Wood’s lamp examination.
The incidence of body leuko-trichia varies from 10% to >60%, as follicular melanocytes are often spared in vitiligo. The occurrence of leuko-trichia does not correlate with disease activity, but it is rarely seen in the absence of depigmentation of the surrounding epidermis 5).
Vitiligo of the scalp most often presents as one or several localized patches of white or gray hair (poliosis) but scattered white hairs due to involvement of individual follicles or even total depigmentation of all the scalp hair. In general, spontaneous re-pigmentation of depigmented hair in vitiligo does not occur. Isolated early graying or whitening before 30 years of age has been suggested to represent a form of vitiligo.
Clinical variants
Vitiligo ponctué, an unusual clinical presentation of vitiligo, is characterized by multiple small (confetti-like), discrete amelanotic macules, sometimes superimposed upon a hyperpigmented macule. Although a hyperpigmented margin around a macule of leukoderma has been said to be specific for vitiligo, this is not a standard feature.
Erythema is occasionally observed at the margins of vitiligo lesions, which is referred to as inflammatory vitiligo or “vitiligo with raised inflammatory borders” a figurate papulosquamous variant has also been described. Blue vitiligo can result when vitiligo develops in areas already affected by postinflammatory hyperpigmentation.
Trichrome vitiligo features a hypopigmented zone between normal and depigmented skin. The intermediate zone does not have a gradation of color from white to normal but a uniform hue. The number of melanocytes is intermediate in this zone, suggesting slower centrifugal progression than in typical vitiligo. In quadrichrome vitiligo, a fourth darker color is present at sites of perifollicular repigmentation. Pentachrome vitiligo with five shades of color (black, dark brown, medium brown [natural skin], tan and white) has also been described.
One of the manifestations of vitiligo is the isomorphic Koebner phenomenon (IKP), characterized by the development of vitiligo in sites of trauma (e.g., a laceration, burn, or abrasion). The IKP is more common in patients with progressive non-segmental vitiligo, but it can also affect those with segmental vitiligo. There appears to be a minimum threshold of injury required for the IKP to occur, questioning the hypothesis that minor trauma, such as friction from clothes (in the absence of actual injury), can induce vitiligo lesions.
Clinical classification of vitiligo
Multiple classification systems for vitiligo have been proposed, leading to confusing terminology. Two primary forms are recognized: (1) the segmental form, which usually does not cross the midline, and (2) the non-segmental form, also called vitiligo Vulgaris.
Segmental and non-segmental vitiligo are occasionally seen in the same patient, with involvement of >1% of the body surface area and the presence of leukotrichia or halo nevi representing predictors of the evolution from the former to the latter. However, genetic and clinical data strongly suggest that they represent two distinct forms of vitiligo.
The following classification scheme divides vitiligo into:
- Localized:
• Focal: one or more macules in one area, but not clearly in a segmental distribution
• Unilateral/segmental: one or more macules involving a unilateral segment of the body; lesions usually stop abruptly at the midline
• Mucosal: mucous membranes alone
Generalized:
• Vulgaris: scattered patches that are widely distributed
• Acrofacial: distal extremities and face
• Mixed: various combinations of segmental, acrofacial, and Vulgaris
Universal:
• Complete or complete depigmentation.
The Course of the disease
The onset of vitiligo is usually insidious. Many patients become aware of the depigmented patches, especially in sun-exposed areas, during the summer, when tanning increases the contrast between involved and uninvolved skin.
Clinical erythema rarely precedes vitiligo. The exact evolutionary appearance of early lesions is unknown. Still, it is postulated that there is progressive, uniform loss of pigment until a discrete white macule is apparent, which is followed by centrifugal enlargement.
The course of vitiligo on a case-by-case basis is unpredictable. It becomes more extensive by the appearance of new depigmented macules, enlargement of pre-existing lesions, or both processes. The natural course of the disease is usually one of slow progression, but it may stabilize for an extended period or spread rapidly. Total body involvement that develops within a few weeks or even a few days is known.
The definitions for active and stable vitiligo are not universally accepted. Some degree of sun-induced or spontaneous regimentation is joint in vitiligo, but complete and stable spontaneous repigmentation is rare. Furthermore, there is no validated scoring system available to assess vitiligo activity.
Vitiligo and Ocular disease
Uveitis is the most significant ocular abnormality associated with vitiligo. The uveal tract (iris, ciliary body, and choroid) and retinal pigment epithelium contain pigment cells. The most severe form of uveitis is seen in the Vogt–Koyanagi–Harada (VKH) syndrome.
This multisystem disorder is characterized by uveitis, aseptic meningitis, otic involvement (e.g., dysacousia), vitiligo, especially in the head and neck region, and associated poliosis. Alezzandrini syndrome is a rare disorder characterized by whitening scalp hair, eyebrows, and eyelashes and depigmentation of the skin on the forehead, nose, cheek, upper lip, and chin associated with ipsilateral visual changes. There is decreased visual acuity and an atrophic iris in the affected eye.
Associated disorders
Although most vitiligo patients are otherwise healthy, generalized vitiligo is epidemiologically associated with several other autoimmune diseases, especially in patients with a family history of vitiligo or other forms of autoimmunity. The associated conditions include autoimmune thyroid disease, pernicious anemia, Addison’s disease, lupus erythematosus, rheumatoid arthritis, and adult-onset autoimmune diabetes mellitus.
Childhood vitiligo
Although vitiligo Vulgaris is the most common clinical type observed in children, the frequency of segmental vitiligo is significantly increased in children compared to adults (~15–30% versus ≤5–10%, respectively). The incidence of associated endocrinopathies is significantly less than in the adult vitiligo population. A family history of vitiligo is associated with an earlier age of onset24; among pediatric patients, those with a positive family history are more likely to develop vitiligo before seven years of age.
Differential Diagnosis
A nevus depigmentosus can be distinguished by its early onset (although lesions may not be clinically apparent until mid-childhood in lightly pigmented individuals) and hypopigmentation rather than depigmentation. When there is complete depigmentation, the differential diagnosis includes chemical or drug-induced (e.g., imatinib) leukoderma, postinflammatory depigmentation, the leukodermas associated with melanoma, and scleroderma, and the late stages of treponematosis and onchocerciasis.
If there is a single circular lesion on the trunk of a young person, a stage III halo nevus should be considered (see below). Early lesions or those with a partial loss of pigment need to be distinguished from postinflammatory hypopigmentation, pityriasis Versicolor, and other cutaneous infections (e.g., leprosy). Treatment with potent topical corticosteroids may also lead to hypomelanosis.
Treatment
The aims of vitiligo treatment are repigmentation and stabilization of the depigmentation process. Although there is still no therapeutic panacea for vitiligo, the available options yield satisfactory results in many patients. The choice of therapy depends on the disease’s extent, location, and activity and the patient’s age, skin type, and motivation to undergo treatment. In general, a period of at least 2–3 months is required to determine whether a particular treatment is effective.
The areas of the body that typically have the best response to medical therapy are the face, neck, mid extremities, and trunk, while the distal extremities and lips are the most resistant to treatment. Repigmentation usually appears in a perifollicular pattern and from the periphery of the lesions. The former pattern is not observed when the hairs within a vitiligo area are depigmented.
Corticosteroids
Topical corticosteroids are helpful for localized areas of vitiligo. A meta-analysis showed that approximately half of the patients with vitiligo affecting ≤20% of the body surface area achieved >75% repigmentation with either class 1 (superpotent) or class 2–3 (high-potency) topical corticosteroids; cutaneous atrophy was observed in 14% and 2% of these groups, respectively.
To minimize side effects, class 1 corticosteroids can be used in 6–8-week cycles or on a twice-weekly basis, alternating with topical tacrolimus or a less potent topical corticosteroid; treatment should be discontinued if there is no visible improvement after two months.
Systemic corticosteroids (high-dose pulsed therapy, mini-pulsed regimens, or a low daily oral dose) have been reported to arrest rapidly spreading vitiligo and induce repigmentation.
However, given the potential for serious side effects, the role of systemic corticosteroids in the treatment of vitiligo remains controversial. Intralesional corticosteroids should be avoided because of the pain associated with injection and the risk of cutaneous atrophy in approximately one-third of vitiligo patients who receive this treatment.
Topical calcineurin inhibitors
Multiple studies have shown that topical application of tacrolimus 0.1% ointment or pimecrolimus 1% cream twice daily can lead to repigmentation of vitiligo, with response rates in pediatric patients similar to those achieved with topical corticosteroids.
In addition, topical calcineurin inhibitors (TCIs) have enhanced repigmentation when combined with narrowband UVB phototherapy or the 308 nm excimer laser. The best results are obtained when these agents are used for facial lesions and combined with sun exposure, with the latter suggesting a synergistic
effect.
Photo(chemo)therapy
Narrowband UVB
In general, narrowband UVB (NB-UVB) is considered to be more effective than broadband UVB in the treatment of vitiligo). . The starting dose ranges from 100 to 250 mJ/cm2, which is increased in increments of 10–20% at each subsequent exposure until mild asymptomatic erythema is achieved within the lesions.
Treatments are administered two to three times per week, but not on two consecutive days30. . The advantages of NB-UVB over psoralen plus UVA (PUVA) therapy include shorter treatment times, a lack of gastrointestinal side effects, reduced phototoxic reactions, and no need for post-treatment photoprotection; in addition, NB-UVB can be used in children, pregnant or lactating women, and individuals with hepatic or kidney dysfunction.
Furthermore, NB-UVB produces less accentuation of the contrast between depigmented and normally pigmented skin32. NB-UVB has become the first choice of therapy for adults and children with generalized vitiligo, especially if it involves ≥20% of the body surface area or cosmetically sensitive areas that generally respond to treatment.
Psoralen plus UVA
Psoralen photochemotherapy involves the use of psoralens combined with UVA light. Psoralens can be administered orally (oral PUVA) or applied topically (topical PUVA), followed by exposure to either artificial UVA light or natural sunlight (PUVASOL). The psoralen most commonly utilized is 8-methoxy psoralen (8-MOP, methoxsalen).
Oral PUVA treatments using 8-MOP (0.4–0.6 mg/kg) are typically administered two times weekly. For patients with vitiligo, the initial dose of UVA is usually 0.5–1.0 J/cm2, gradually increasing until minimal asymptomatic erythema of the involved skin occurs. To reduce the risk of the Koebner phenomenon, significant erythema.
(phototoxicity) is avoided.
The response rate of PUVA is variable; although most patients obtain cosmetically acceptable improvement, complete repigmentation is achieved in only a few patients. The total number of PUVA treatments required is generally between 50 and 300.
Only a few vitiligo patients with PUVA-induced cutaneous carcinomas have been reported. Although this probably reflects a smaller cumulative UVA dose than in patients treated for other disorders such as psoriasis, extensive follow-up studies have not yet been done in PUVAtreated vitiligo patients. Until more data are available, it seems wise to recommend that vitiligo patients receive a maximum cumulative UVA dose of 1000 J/cm2 and 300 treatments.
Topical (paint) PUVA is more challenging because of the high risk of phototoxicity (e.g., blistering, koebnerization) from topical psoralen formulations. Low concentrations (≤0.1%) should be used, necessitating diluting commercially available preparation.
Approximately 20–30 minutes after applying the topical preparation (cream or ointment) onto the lesions, the patient should be exposed to
initial UVA doses of no more than 0.25 J/cm2, with the same fractional increments until mild erythema is achieved in the treated sites.
PUVASOL (psoralens + natural sunlight) can be used in sunnier climates according to the same principles as PUVA. Less phototoxic oral psoralens such as 5-MOP are preferred to avoid phototoxic reactions.
Other forms of phototherapy
Concern has been raised about the hepatic toxicity of khellin. There have been conflicting reports regarding the efficacy of oral khellin plus UVA and oral phenylalanine plus UVA for vitiligo treatment. As a result, these modalities are not recommended. Topical khellin plus UVA has a relatively low risk of phototoxicity. Still, it requires a longer duration of treatment and higher UVA doses than oral PUVA to provide the same degree of repigmentation.
Focused microphototherapy has the advantage of irradiating only the affected skin. A directed beam of broadband or narrowband UVB light is applied to areas of vitiligo. Treatments are administered several times weekly to twice monthly, sometimes with an initial boost of daily treatments for five days. In one large study, 70% of patients who received a mean of 24 treatments over 12 months achieved >75% repigmentation.
Lasers and related light devices
Excimer laser and lamp
The operational wavelength of the 308 nm excimer laser and the lamp is close to that of NBUVB. The therapeutic benefit of the excimer laser for vitiligo has been investigated in multiple studies, and, overall, 20–50% of lesions achieve ≥75% repigmentation35,36; the excimer lamp appears to have similar efficacy.
Localized patches of vitiligo are treated one to three times weekly for an average of 24 to 48 sessions. The repigmentation rate depends on the total number of sessions, not their frequency. Erythema and rarely blistering represent potential side effects.
Helium-neon laser
The helium-neon laser emits a wavelength (632.8 nm) in the red visible light range that can enhance melanocyte proliferation and melanogenesis in vitro.
Surgical therapies
For vitiligo patients who fail to respond to medical therapy, surgical treatment with autologous transplantation techniques may be an option. The general selection criteria for autologous transplantation are a stable disease for at least six months, an unsatisfactory response to medical therapy, absence of the Koebner phenomenon, a positive minigrafting test (retention/spread of pigment at the recipient site, and no koebnerization at the donor site after 2–3 months), no tendency for scar or keloid formation, and age above 12 years.
Several methods of surgical repigmentation have been successfully utilized. Minigrafting is the most straightforward technique. Tiny punch grafts (1–2 mm) from uninvolved skin are implanted within achromic areas, separated from each other by 5–8 mm. Because scarring and dyspigmentation may occur at the donor sites, cosmetically insensitive areas are chosen.
A cobblestone effect, a variegated appearance of the grafts, and sinking pits represent potentially unfavorable outcomes. The advantages of suction blister epidermal grafting are the absence of scarring at the donor site and the possibility of reusing this area. However, failure of the graft to take and koebnerization may occur.
Grafting of cultured autologous melanocytes is an expensive technique that requires specialized laboratory expertise; grafts consist of pure melanocytes or melanocytes admixed with keratinocytes. To avoid the need for in vitro culture (which involves mitogens to enhance cell growth), the grafting of non-cultured epidermal cell suspensions that include melanocytes has been advocated. Grafting of individual hairs to repigment vitiligo leukotrichia has also been successfully performed. Most of these techniques require clinical expertise, and candidates should be carefully selected.
Combination therapy
Combination therapy may produce higher rates of repigmentation compared to traditional monotherapies. Examples include phototherapy following surgical procedures and TCIs or topical corticosteroids together with each other, NB-UVB, or excimer laser therapy44-48. Although topical vitamin D derivatives are relatively ineffective as monotherapy, these agents may result in additional repigmentation when used in conjunction with phototherapy.
Micropigmentation
The permanent dermal micropigmentation utilizes a non-allergenic iron oxide pigment to camouflage recalcitrant areas of vitiligo. Although the color may not perfectly match the normal surrounding skin, the result is immediate and can represent a dramatic aesthetic improvement. However, the color may fade slightly over the years. This tattooing method is beneficial for sites with currently available treatments with poor repigmentation rates (e.g., the lips, nipples, and distal fingers).
Depigmentation
Depigmentation represents a treatment option for patients with widespread vitiligo with only a few areas of customarily pigmented skin in exposed sites. The patients must be carefully chosen, i.e., adults who recognize that It will significantly alter their appearance and understand that depigmentation requires lifelong strict photoprotection (e.g., sunscreens, clothing, umbrellas).
The most commonly used agent is 20% monobenzyl ether of hydroquinone (MBEH), applied once to twice daily to the affected areas for 9–12 months or longer49. It typically takes 1–3 months to initiate a response, and a loss of pigment can occur at distant sites. MBEH is a potent irritant and allergen, and an open use test should be performed before more widespread application.
Although depigmentation from MBEH is considered permanent, repigmentation (especially perifollicular in areas with pigmented hairs) can be seen following sunburn or even intense sun exposure. Side effects include contact dermatitis, exogenous ochronosis, and leukomelanoderma en confetti. Monomethyl ether of hydroquinone in a 20% cream can be used as an alternative to MBEH50.
Depigmentation via Q-switched ruby laser therapy achieved faster depigmentation than a bleaching agent. This laser has also been combined with topical 4- methoxyphenol to induce depigmentation51. Depigmentation with the Q-switched alexandrite laser has also been described.
Psychological support
The impact of vitiligo on quality of life is severe in many affected individuals. Physicians must recognize this aspect of the condition and address their patients’ psychological needs. Although a “magic” treatment is not yet available, there is always something beneficial that I can do for vitiligo patients. They first need to know what their skin disorder is.
Explaining the nature of the disease process and the potential and limits of available therapies is important and more productive than a fatalistic attitude that there is no cure and vitiligo is “only” a cosmetic disorder. Helping patients conceal the condition so that it is not visible can be part of the
management plan. The use of support groups and, if indicated, psychological counseling are important supplementary therapies.
Additional controversial therapies
Pseudocatalase with narrowband UVB
This treatment is based on the hypothesis that accumulation of hydrogen peroxide leads to pathogenic inactivation of catalase in the skin of patients with vitiligo.
Systemic antioxidant therapy
The rationale for this approach rests on the hypothesis that vitiligo results from a deficiency of natural antioxidant mechanisms. Although to date, not validated by a controlled clinical trial, selenium, methionine, tocopherols, ascorbic acid, and ubiquinone are prescribed by some physicians.
Potential emerging treatments
Dermabrasion followed by topical 5-fluorouracil and narrowband UVB Erbium: YAG laser ablation of vitiligo lesions followed by topical application of 5- fluorouracil and NB-UVB therapy twice weekly for four months was found to lead to ≥75% repigmentation in ~45% of patients, compared with a rate of 8% for lesions on the opposite side of the body that were treated with NB-UVB alone.
Topical prostaglandins A preliminary study suggested the utility of topical prostaglandin E2 in vitiligo treatment. Although interesting, these results require confirmation.
The Outcome
It is not possible to predict how a patient will respond to treatment. It is crucial to remember that no one treatment works for everyone. Results can vary from one part of the body to another. Combining two or more treatments often gives the best results.
