Vitiligo

Abstracts

O vitiligo é doença de pele de causa desconhecida que acomete cerca de 1% da população, comprometendo de modo semelhante homens e mulheres, preferencialmente entre 10 e 30 anos de idade. Alguns fatores precipitantes para essa doença são: estresse físico e emocional, traumas mecânicos e substâncias químicas, como derivados do fenol. Doenças auto-imunes, principalmente as tireoidianas, podem estar associadas ao vitiligo. Novas terapias têm sido propostas, como o uso de imunomoduladores tópicos, aliadas àquelas já consolidadas, como os psoralenos e os corticosteróides; o sucesso terapêutico, entretanto, está estritamente relacionado à qualidade da relação médico/paciente.

hipopigmentação; vitiligo

REVIEW ARTICLE

Vitiligo^*

Denise Steiner^I; Valcinir Bedin^II; Mirella Brito Moraes^III; Ricardo Tadeu Villas^IV; Tatiana Steiner^V

^IAdjunct professor, Dermatology Service, School of Medicine, Jundiaí - SP

^IIM.D., Postgraduate student at UNICAMP - SP

^IIIAssistent M.D., Clínica Stöckli - SP

^IVResident, Dermatology Service, Escola Paulista de Medicina

^VProf. of Medicine, School of Medicine, Fundação ABC

^{Correspondence}

SUMMARY

Vitiligo is a skin disease of unknown etiology that affects 1% of the population. It affects both sexes equally and the mean age at onset is between 10 and 30 years. Some of the factors involved are: emotional or physical stress, mechanical trauma, chemicals such as phenol and certain diseases. Autoimmune diseases, especially of thyroid origin, may be linked to vitiligo. New and emerging therapies have been proposed such as topical immunomodulators, allied to traditional therapies with psoralen and steroids. The most important factor in the therapeutic success depends on the doctor and patient relationship.

Key-words: hypopigmentation; vitiligo.

INTRODUCTION

Vitiligo is an acquired idiopathic cutaneous disease, characterized by pearly-white patches of various sizes and shapes that have a tendency to increase in size centrifugally. It can involve both sexes of all races and appear at any age. The mean onset is around 20 years of age.^1,2

Vitiligo affects from 0.5 to 2% of the world's population.¹ The prevalence of the disease varies considerably between the various ethnic groups, estimated at 2% in Japan, 1% in the USA and 0.14% in Russia. Women are usually considered to be more affected than men, however the most recent studies have suggested there is no sex bias.²

Several factors have been associated with the etiopathogenesis of the disease. The main ones are:

- Inheritance: the genetic factor present is autosomal,³ dominant or recessive and multifactorial, or that is, with the probable engagement of several genes. Approximately 20% of the patients with vitiligo have at least one close blood relative with the disease.⁴

- Autoimmunity: vitiligo has been considered to be an autoimmune disease due to the positive association with some diseases such as thyroiditis, diabetes mellitus and alopecia areata.¹ There has also been reported a relationship with HLA – DR4; or with DW7, DR1, B13, A2, B21, CW6, DR53, A19 and DR52.^5,6

- Environmental factors: Between 10% and 76% of patients with vitiligo attribute the disease to some precipitating factor.⁷ It is probable that stress, intense solar exposure or exposure to certain pesticides may act as precipitating factors for the disease in genetically predisposed individuals.⁸

Clinically, vitiligo is characterized by initially hypochromic stains, which are usually noticed in the photoexposed areas such as the face, back of the hands and around the corporal orifices, with a tendency to symmetrical distribution. The hair may eventually be involved (leukotrichia), including eyebrows, eyelashes and pubic hair. Itching or inflammation is rarely present.

The damage to healthy skin frequently causes a depigmented area, a phenomenon that is called isomorphic or Köebner. Studies show that this phenomenon is present in 21% to 60% of the patients with vitiligo, although it is not specific to this disease.⁹

The histological alterations of vitiligo are generally not very responsive to hematoxylin and eosin stain. Electron microscopy reveals a vacuolization and degeneration of the keratinocytes, melanocytes and Langerhans' cells of the basement membrane layer. This is accompanied by a mononuclear inflammatory infiltration with small lymphocytes and histiocytes localized in the papillar dermis, mainly in the margin of the lesion. Recently, Abdel-Nasser¹⁰ demonstrated that this infiltration of lymphocytes is composed mainly of CD8 T lymphocytes and that this occurs not only in vitiligo, but also in other autoimmune diseases.

The psychosocial aspect of this pathology should not be ignored. Porter et al.¹¹ showed in a study that more than 50% of the patients with vitiligo report having suffered some type of social discrimination and that of these 20% had experienced being treated rudely. Thus, the patient with vitiligo should not be approached as a subject with an organic disease, but as a person with a social and professional life in which physical appearance plays great importance.

ETIOPATHOLOGY

Several theories have been proposed to try to explain the depigmentation process that occurs in vitiligo. These theories include the presence of autoantibodies; the participation of cytotoxic T cells; the 'self-destruction' of melanocytes by intermediate products of the melanogenesis; intrinsic and extrinsic defects of the melanocytes themselves or of the melano-epidermal unit, including probable alterations in the nerve endings. These theories are described below.

Genetic theory

According to Nath et al.,¹² there is a multifactorial genetic component in certain individuals predisposing them to vitiligo. This multifactorial nature is probably responsible for the complexity of the clinical presentation of the disease. Majumder et al.¹³ postulated that at least three different allelic genes are involved in the onset of vitiligo; it should therefore be considered a polygenic disorder.

Recent studies ^13,14 have demonstrated that the culture of melanocytes from patients with active vitiligo reveals a lower c-Kit expression and stem cell factor (SCF), which are fundamental receptors in the process of differentiation of the melanocyte and subsequent melanization. Furthermore, Chen and Jimbow¹⁴ have demonstrated that in a culture of melanocytes from skin lesions there was an increase in the release of protein 1 related to tyrosinase (TRP - 1).

Genetic predisposition is also related to the development of the so-called 'occupational vitiligo'. Experiments have demonstrated that some environmental chemical substances, such as phenol derivatives, can be selectively toxic to the melanocytes, both in vitro and in vivo.¹⁵ Hydroquinone, is one of these components and is used in the topical treatment of hyperpigmented lesions, but has been shown to be poisonous to genetically susceptible individuals.

Autoimmune Theory

Several observations suggest that vitiligo is an autoimmune disease that targets the pigmentary cells.¹⁶ These findings include:

- The theory is corroborated by the relationship of vitiligo with diseases such as thyroiditis, pernicious anemia, Addison's disease, diabetes mellitus, localized scleroderma, alopecia areata, myasthenia gravis, pemphigus vulgaris and halo nevus. It has been demonstrated that patients with vitiligo have autoantibodies against the thyroid, adrenals, parietal cells, nevus cells and malignant melanoma.^17,18 Recently, Zamani et al.¹⁹ at the University of Amsterdam showed that the association of the antigens of the HLA system with vitiligo varies according to ethnic origin. In that, HLA-DR4 prevails among Caucasian Americans, HLA-DR4 and HLA-DQW3 prevails in the blacks, HLA-DR7 and DQW3 in the north of Italy, HLA-DR53 in the population of Kuwait and HLA-DRW12 in the north of Germany.

- Some treatments for vitiligo, such as PUVA, topical steroids and cytotoxic drugs, are immunosuppressors, a fact suggesting the benefits of these therapies could result in a suppression of the local immune reactions against the melanocytes.

- The autoantibodies present in vitiligo are also present in individuals with melanoma, which suggests that both pathologies have similar immunological mechanisms.²⁰

However, the most convincing factor indicating that vitiligo is an autoimmune disease is the presence of autoantibodies to melanocytes in the circulation of most of these patients. These antibodies were demonstrated initially by immunoprecipitation and by indirect immunofluorescence, but their presence has been confirmed by other techniques, including complement-dependent cytotoxicity, antibody-dependent cellular cytotoxicity, imunoblotting,²¹ and Elisa.²²

The presence of autoantibodies in vitiligo is directly related to the extension of the depigmentation and to the activity of the disease. They have been verified in approximately 50% of the patients with incipient vitiligo, while in those with the extensive form of the disease this value can reach 93%.^23,24

Theory of autotoxic melanocytes

The theory of autointoxication is based on the observation that phenol and some of its derivatives are capable of specifically harming the pigment producing cells, i.e. the melanocytes.^1,25

Bleehen et al.²⁶ suggested that the destruction of the melanocytes resulted from the action of free radicals or of exogenic components of phenol. Later, Riley ²⁷ suggested that the increase in phenol production is found more frequently in genetically susceptible individuals and that an excessive amount of toxic products in the epidermis and in the papillar dermis would necessarily damage the melanocytes, whose capacity for proliferation is limited.

Lerner²⁸ postulated that melanocytes have a 'protection' mechanism capable of eliminating any poisonous product, such as dopa, dopa quinone and ^5,6 -diidroxindol produced during the synthesis of melanin. In individuals in whom this protection system is deficient there is an accumulation of melanotoxic products, causing destruction of the pigmentary cells and, clinically, the depigmentation of the skin.

Neural theory

Melanocytes are cells derived from the same embryological lineage as that of the nervous system, or that is, of the neural crest.²⁹ Thus, it may be considered that any process which destroys the melanocytes of the skin can also affect the melanocytes and other related cells in the central nervous system (CNS).³⁰

Arguments in favor of this hypothesis are as follows:

a) some disorders of the CNS, such as neurofibromatosis and tuberous sclerosis may present hypopigmentation or cutaneous hyperpigmentation;

b) bacteria that cause diseases such as syphilis and leprosy affect both the skin and the nervous system;

c) occasionally vitiligo creates one or more dermatomas when in the segmentary form of the disease; ^28,30

d) vitiligo has been associated with viral encephalitis³¹ and to multiple sclerosis.

Biochemical Theory

Schallreuter et al.³² demonstrated that the characteristic fluorescence of vitiligo under Wood's light may be the result of the accumulation of two different so-called pteridine substances in an oxidized form. One is 6-biopterine with a rosy fluorescence, and the other is its isomer, 7-biopterine, with a yellow-greenish fluorescence. It is known that (6R) - L - erythro ^5,6,7,8 tetra hydropterine (6BH4) is an essential co-factor in several stages of intracellular metabolism, including the hydroxylation of aromatic amino acids such as L-phenylalanine, L-tyrosine and L-tryptophan.²⁴ Furthermore, there is evidence that the pteridines are synthesized during the activation of cellular immunity and hematopoiesis.²⁴

In 1997, Lei et al.³⁴ demonstrated the presence of 4a-OH-tetra-hydropterine-deshydratase in the epidermic keratinocytes. Based on this observation they concluded that in physiologic conditions the presence of the co-factor 6BH4 is crucial in melanocytes and in keratinocytes for the activation of the enzyme phenylalanine-hydroxylase and for the synthesis of L-tyrosine by L-phenylalanine. In those suffering from vitiligo, it is observed however, that an overproduction of 6BH4 is related to the accumulation of its isomer 7BH4.

Recently, two possible causes were established for this increase in the production of the tetra-hydropterines. One might be the increase in the activity of the GTP-cycle-hydrolase I, the 'key enzyme' in the synthesis of 6BH4. The other cause might be a defect in the 'recycling' of 6BH4 associated with a reduction in the activity of 4a-OH tetra-hydropterine.³³

This hypothesis has been tested by using a noninvasive spectroscope in 23 vitiligo patients. The results showed that all the patients had high levels of phenylalanine in the areas of the lesions in comparison with normal skin. Later, Cormane et al.³⁵ found that there was no evidence of a peripheral accumulation of this essential amino acid in those patients, which is to say that further studies are necessary into the quantitative and qualitative alterations of this amino acid in patients with vitiligo.

DISCUSSION

Clinically vitiligo is characterized by pearly-white maculae of variable size and, depending on their extension and distribution on the skin, the disease may be classified as 'localized' or 'generalized', with some subtypes.

Localized vitiligo

• Focal: presence of one or more achromatic maculae in a single area, without specific distribution.

• Segmented: presence of one or more achromatic maculae involving a unilateral segment of the body, frequently following the distribution of a dermatoma.

Generalized vitiligo

• Acrofacial: presence of typical lesions in the distal part of the extremities and face.

• Vulgar: achromatic maculae with a random distribution

• Mixed: acrofacial and vulgar, segmentary and acrofacial and/or vulgar

Universal vitiligo: depigmentation of more than 50% of the skin and/or mucous membranes.

Segmentary vitiligo appears early in life, between five and 30 years of age, and is not related to the autoimmune diseases. While the vulgar form may appear at any age and usually develops with outbreaks often associated with the occurrence of autoimmune diseases, specially of the thyroid.

The segmentary form mainly affects the face in the area of innervation of the trigeminal nerve, following this in terms of frequency, the thoracic, cervical, lumbar and sacral innervated areas. Thus, it is common to observe poliosis of eyelashes and hair in this form of the disease. It presents a single lesion in 75% of the patients, and in 11.5% of them there is a positive family history, a fact that also occurs in the nonsegmentary form.³⁶

In relation to the therapeutics, the segmentary form of vitiligo is in general more resistant to treatment than the nonsegmentary form.

In children, vitiligo has several peculiarities. The cutaneous involvement varies from 1% to 80%, and the areas most frequently affected are the face and the neck, followed by the inferior portion of the extremities, the trunk, the superior extremities and the perineal area. The mean duration of the disease is three years, and the conditions most often associated are the diseases of the thyroid and alopecia areata.³⁷

The importance should be underscored of the so-called 'occupational vitiligo' which is a type of acquired 'vitiligo-like' leukoderma associated to contact with substances that can present a toxic action to the melanocytes of genetically susceptible individuals. Examples of such substances include the phenolic compounds and catechols used in germicides, insecticides and resins, and monobenzyl hydroquinone ether, used in the rubber industry.

The course of the disease is normally unpredictable. Its natural course is usually a slow progression, nevertheless it is capable of rapid exacerbation. Spontaneous repigmentation of the lesions is generally observed in 10 to 20% of the patients with vitiligo, occurring most frequently in photoexposed areas and in lesions of small extension.

The diagnosis of vitiligo is essentially clinical with achromatic maculae and normal skin coexisting in the same individual. Wood's light is a lamp of 351nm which causes a bluish white fluorescence in the affected skin, due to the accumulation of 6-biopterine and 7-biopterine. This lamp is an important tool in that it allows the diagnosis of lesions that are barely visible to the naked eye and permits an ongoing therapeutic follow-up of the patient.

The laboratory evaluation of the thyroid is relevant in cases of vitiligo. In a study of 460 vitiligo cases, 14% of the patients presented thyroid alterations.² Other authors have also observed a greater prevalence of thyroid alterations in those with vitiligo compared to the normal population.^38,39,40

Biopsy is little used for diagnosis of the disease since the histopathological alterations are of little significance.⁴¹ In relation to the presence or absence of melanocytes in the lesions of the skin there is as yet no agreement. Le Poole et al.,⁴² using a panel of 16 monoclonal antibodies, concluded that there were no melanocytes in the affected skin. However, others have observed that melanocytes were not completely absent in the lesional skin and that these cells retain the capacity to return to function even after a prolonged duration of the disease.

In relation to the culture of the melanocytes of patients with vitiligo, several studies show that these have an abnormal behavior in the medium, demonstrating that these cells are intrinsically altered. In the testing with dopa, at first it was found that the areas with vitiligo were dopa-negative, however, occasionally, some "islets" of dopa-positive cells were observed. These were smaller and less dendritic than the normal melanocytes, which probably corresponds to what had been considered 'inactive' melanocytes.⁴³

The main diseases that are part of the differential diagnosis of vitiligo are as follows:

1. Genetic alterations: piebaldism, hypomelanosis of Ito and tuberous sclerosis. Piebaldism is a genetic autosomal dominant alteration characterized by hypochromatic patches that are generally not found on the hands and feet. In contrast with vitiligo, Wood's light reveals 'islets' of normal pigmentation or hyperpigmention in the interior or in the periphery of the lesion. Hypomelanosis of Ito usually has a linear distribution (Blashcko lines). Tuberous sclerosis is usually accompanied by other cutaneous signs, such as angiofibromas and periungual fibromas.⁴⁴

2. Inflammatory diseases such as erythematous lupus, sarcoidosis and lichen sclerosus. The typical lesions of lupus are easily clinically differentiated by the presence of atrophy and scar tissue; but with lichen sclerosus the diagnosis is usually histological.

3. Halo nevus: occurs frequently in the trunk, generally around a junctional or compound nevus.

4. Malignant diseases such as mycosis fungoides: the diagnosis is usually histological, by finding an infiltrate of mononuclear cells in the epidermis.

5. Infectious diseases such as pityriasis versicolor, syphilis and leprosy. In pityriasis versicolor Wood's light reveals a yellow-gold fluorescence, and, under the microscope, hyphas and spores are observed. Differential diagnosis of syphilis is based on the history of a previous genital ulcer and positive serology for treponemal reaction.

6. Idiopathic disorders such as idiopathic guttate hypomelanosis (IGH) and post-inflammatory hypopigmentation. IGH does not usually occur before the third decade of life. It presents small lesions of slow evolution. The differential diagnosis of post-inflammatory hypopigmentation with vitiligo is done mainly by anamnesis.

The treatment of vitiligo is still a great challenge, since many theories have been put forward that attempt to explain this disease, and no doubt many more will be proposed. The main line of treatment for vitiligo consists of stimulating the production of pigment in the affected skin areas. In 1959, Starricco⁴⁵ demonstrated that the melanocytes in the lesions did not synthesize melanin under normal conditions, however they became active when stimulated by ultraviolet light or by dermabrasion. This author concluded that melanocytes were capable of moving along the epidermis and to become morphologically and functionally mature. Later, Cui et al.⁴⁶ studied the successive stages of repigmentation and confirmed the existence of a reserve of melanocytes in the hair follicles.

The main forms of treatment described in the literature are:

STEROIDS

Topical corticosteroid constitutes one of the first treatment options for individuals with vitiligo and is, eventually, the first choice for those with the localized form of the disease and/or those that have an inflammatory component, even if at a subclinical level.

Kandil⁴⁷ studied the effectiveness of topical steroids in the treatment of vitiligo. Lesions on the face and on the extremities best responded to this therapy. Kandil demonstrated that on the face a diffuse increase of pigmentation occurred before the normal skin was involved.

Skin color also seems to be an important factor in the repigmentation process. Thus, vitiligo lesions on the face of dark-skinned patients respond better than among those with light skin.⁴¹

The clinical type of vitiligo was also reported to be an important factor in the effectiveness of treatment with topical steroids.⁴⁸ With the choice of more potent corticoids generally a better response is observed in patients with the vulgar form of the disease, whether localized or generalized.

Finally, the duration of the disease can also influence repigmentation. The more recent lesions in general respond better.

Intralesional application of corticosteroid may be a possibility that, so far is little used because of the pain involved and of the possible inherent side effects of the drug, such as atrophy of the skin, telangiectasis and intradermic hemorrhages.^47,48

The use of a systemic corticoid is based on the possibility that the activity of the disease is associated to autoimmunity against the melanocytes. There has been observed in patients who received oral corticosteroids a reduction in the complement that is mediated by the cytotoxicity of autoantibodies against melanocytes and in the titers of antibodies against the melanocytes.⁴⁹ However, treatment with such drugs can produce undesirable side effects, such as epigastralgia, weight gain, acneiform eruptions, striae, insomnia, osteoporosis and, albeit more rarely, aseptic necrosis of the bones.^50,51

In order to minimize those effects, an alternative is therapy with an oral minipulse of betamethasone or dexamethasone. In a study by Pasricha and Kaitan ⁵² on 40 patients with vitiligo, five milligrams of dexamethasone were administered in a single dose in the mornings of two consecutive days per week. An arrest in the progress of the disease was observed in the first one to three months in 32/36 patients (89%) and signs of repigmentation within two to four months in 32 patients (80%). Kim et al.⁵³ also treated active vitiligo with a low steroid dosage (prednisolone, 0.3mg/kg) to minimize the side effects. After four months of treatment, 57/81 patients (70.4%) presented some repigmentation. The clinical course of the disease was controlled in 71 (87.6%) of the 81 patients.

PUVA

Photochemotherapy with psoralen components and subsequent exposure to ultraviolet A (UVA) (320-400nm) radiation is commonly known as PUVA therapy. The psoralens are compounds formed by the fusion of tricyclic hydrocarbon components with benzopyrene to furocoumarin. They are metabolized in the liver, with a half-life in the bloodstream of approximately one hour. Their elimination is rapid, mainly through the urine, which helps to avoid a greater risk of photosensitivity inherent in this group of drugs.

It has been determined that repigmentation occurs by the stimulation of immunocytokines and inflammatory mediators that act as 'signals' for the migration of melanocytes from the hair follicles of healthy skin. However, the combination of 8-methoxypsoralen with UVA seems to neither alter the size nor the distribution of the melanosomes.

Some important considerations should be made before suggesting this therapy: ^54,55

1 - Segmental vitiligo does not respond as well to PUVA therapy as generalized vitiligo.⁵⁶

2 - The response to PUVA depends on the anatomical location of the lesion. The face is the area that best responds to this therapy, while the distal areas of the extremities and the genitalia rarely respond. This is because they are areas of glabrous skin, or in other words, areas in which there are no hair follicles.

3 - Rapidly progressive vitiligo generally does not respond to this therapy.

4 - Patients that are young and brown skinned are usually more responsive to treatment than are older persons with light skin.

The psoralens can be administered by three methods: oral, topical or combined.

Oral Therapy

This is the type of therapy that offers the best results with the least side effects.⁵⁵ The psoralen of choice is methoxypsoralen at a dosage of 0.4mg/kg of body weight administered one or two hours before the exposure to radiation. The treatment with radiation should be done with an initial level of 1J/cm², two to three times per week with at least 48 hours between applications.⁵⁶

It is essential to protect the eyes with lenses that filter UVA radiation starting from the moment that psoralen is ingested.

The main side effect of the psoralens is the erythema produced by the UVA. This may occur from 24 to 36 hours later and may vary from a reddening of the skin to the formation of blisters and necrosis of the skin. Other side effects include pruritus, nausea and vomiting. The pruritus is frequently controlled with emollients and eventually with topical steroids, and the nausea with a fractionation of the treatment.

The main contraindications for the use of this therapy are: hepatic and renal diseases, photosensitive diseases, cataracts, glaucoma and skin cancer. The risk of skin carcinoma is, on average, 2.6 times greater than that of the general population, with prevalence in the areas that are not photoexposed.

New treatments using 5-methoxypsoralen instead of 8-methoxypsoralen and using phototherapy with narrow band UVB have been showing good results, with less phototoxicity and fewer side effects.

Topical therapy

Methoxypsoralen in a concentration of 0.1% is the psoralen most frequently used in the treatment of vitiligo.^56,57 It should be applied on the affected areas 30 to 60 minutes before exposure to radiation. The initial level of UVA should be 0.25J/cm² with an increase of 0.12 the 0.25J/cm² until the onset of erythema.

The main complication of this therapy is the emergence of a phototoxic reaction of blistering. For which, the patient should be well informed regarding the importance of the use of a wide spectrum sunscreen as soon as the psoralen is applied.

Combined therapy

The separating of the epidermis associated with the inducing of blistering for the purpose of introducing a graft is often associated with PUVA therapy. Another therapy adjunctive to PUVA is the application of topical corticoids.^58,59

Approximately 20% of the patients treated achieve very significant repigmentation, and around 50% have partial but satisfactory repigmentation. These results are obtained after a number of 'sessions' which varies from 100 to 300. A general rule indicates that, if there is no relevant sign of repigmentation after 30 UV exposures, then it probably is not going to occur.

SURGICAL THERAPY

In spite of the broad variety of clinical therapies for vitiligo, a great many of these patients do not respond well. This may be because the method chosen was not adequate in inducing repigmentation or because the reserve of melanocytes in the local follicles was depleted, or even because the melanocytes in the borders of the lesions were not stimulated sufficiently.^47,54 Thus, a graft or melanocyte transplant may be a treatment alternative for these cases by the deposition of clusters of functioning cells in the affected locus. This therapeutic modality, however, is only valid when the disease is stable, which can be defined as follows:

• Absence of an area of new depigmentation, or growth of the current lesions for the previous two years;

• Absence of the phenomenon of Köebner during the same period;

• Spontaneous repigmentation around or in the achromatic lesions;

• Positive minigraft test with a repigmentation halo of 1mm to 2mm around the transplanted area.

  ⁶⁰

The best indications for the method include:

1- stable unilateral vitiligo, either segmental or focal. In which case a success rate of 95% can be expected;

2 - vitiligo that is bilateral, when stable, can respond in 48% of the patients involved;

3 - the selection of patients is also extremely important for the success of the therapeutics.

Surgical procedures are preferable after adolescence in emotionally stable patients who are aware of the inherent risks of any surgical technique, such as incomplete repigmentation or scars.⁶¹

The absolute contraindications are: vitiligo that is still progressing, a tendency to form keloid scars or a tendency to hyperpigmentation even after minimal trauma.

MICROPIGMENTATION

The techniques of permanent dermal micropigmentation utilizing a pigment of oxidized iron can be used to cover areas of recalcitrant vitiligo.⁶² Basically this is an adaptation of the technique of eyelid tattooing. Generally there are few complications, but among them is infection by the virus of herpes simplex in predisposed individuals. In the long run, a possible complication includes köebnerization in the area of micropigmentation, with subsequent augmentation of the margin of the treated area.

OTHER THERAPIES

Besides the conventional therapies, there are other therapies that are earning considerable space in studies into the treatment of pathologies such as vitiligo. It is known that approximately one third of the patients treated achieve satisfactory results, but for most of them this took a long time and was relatively expensive. Thus, the alternative therapies constitute a new option for these patients. They include pseudocatalase, heliotherapy, UVB, extract from human placenta, KUVA, topical and systemic phenylalanine, and antioxidants.

Pseudocatalase

It is known now that there is a tendency to accumulate oxidative substances in the epidermis of patients with vitiligo. Several studies have shown that there is early oxidative harm done both to melanocytes and to keratinocytes of the skin, characterized by vacuolar degeneration and granular deposit in normal and diseased skin.^63,64

The discovery of the low catalase level in both the healthy and the diseased epidermis of patients with vitiligo suggested a greater 'stress' originating from the accumulation of H2O2 in the epidermis. Recently, Maresca et al.⁶⁵ also reported finding a low activity of catalase in the melanocytes of patients with vitiligo. However, the expression of RNAm-catalase in the melanocytes and keratinocytes of these patients is normal when compared to that of the control group.

A pilot study was done with 33 patients with vitiligo (12 men and 21 women), with a mean age of 41 years, and with active disease. They were treated with topical pseudocatalase, calcium and exposure to UVB. The study reported that the depigmentation process was stabilized in all the patients and that in most of the patients the first signs of repigmentation were observed after a period of treatment that varied from two to four months.⁶⁴

Heliotherapy

Heliotherapy is the simplest and oldest way to treat vitiligo. The specific action of this therapy is unknown, but it has been demonstrated that light stimulates the proliferation of melanocytes in normal skin and therefore probably also does so in diseased skin. This therapy is easily acceptable to adults and children. It costs little and is relatively safe because there is no significant risk of actinic damage and few cases of skin cancer in patients with vitiligo have been reported.⁶⁶

The affected areas should be exposed to the sun until an asymptomatic erythema is noticed. The areas of healthy skin should be protected with a sunscreen of broad spectrum.

UVB

Ultraviolet B radiation is known to be an important factor in the stimulation of the synthesis of melanin in the skin by increasing the activity of tyrosinase, and in the stimulation of the proliferation of melanocytes. With the objective of reducing the carcinogenic action and the aging effects of radiation, some researchers have proposed the use of a monochromatic band of 311nm in the treatment of psoriasis. Early experiments have shown promising results.⁶⁷

The advantages of monochromatic light include: less photoalergic dermatitis, decreased phototoxicity, pruritus and xerosis, and shorter sessions (usually less than five minutes) of exposure to ultraviolet radiation.

Extract of human placenta

Melagenin was first used in Cuba in 1970, for the treatment of vitiligo, psoriasis and alopecia. It is a hydroalcoholic extract from human placenta whose active agent is the a fetoprotein produced by the cotyledons of the placenta, along with 95% ethanol.^68,69

The first study, on 732 patients with vitiligo, showed that 84% obtained total repigmentation. These results, however, could not be repeated, thus raising doubts about their scientific validity. In a second study, only 31% of 200 patients repigmented totally. Studies accomplished in other parts of the world, such as in the United States, could not confirm in animals or in vitro the benefits demonstrated by the Cuban researchers.

Khellin (KUVA)

Khellin is the extract of a plant denominated Ammi visnaga. Recent studies have shown that this substance seems to have a chemical structure very similar to that of the psoralens. Its photobiological and photochemical properties and even its phototherapeutics are quite similar to those of the psoralen group. The oral use of khellin is recommended in doses from 50 to 100mg two and a half hours before the solar exposure or UVA radiation which should start at 15J/cm² of energy.⁷⁰

Topical and systemic phenylalanine

Phenylalanine is a natural essential amino acid and a precursor of the tyrosine that participates in the synthesis of melanin. It was proposed for use in photochemotherapy by Cormane et al.,³⁵ who demonstrated dense follicular repigmentation in 26.3% of their patients and scattered repigmentation in the others with phenylalanine applied topically, followed by UVB or by 8-MOP. Promising results have been seen using this therapy with children, however with some recurrences after the suspension of treatment, varying from 12% to 64%.^71,72

The main contraindications include phenylketonuria, skin cancer, hepatic or renal dysfunction, pregnancy, nursing, radiotherapy or exposure to arsenic.

Antioxidants

Montes and col.⁷³ investigated 15 patients with vitiligo and observed that there was a reduction in the levels of folic acid in 11 patients, vitamin B12 in five patients and ascorbic acid in the plasma of four patients. These patients were treated with 2mg of folic acid and 500mg of vitamin C twice a day, also 100mg of vitamin B12 was administered by intramuscular injection for two weeks. The result showed significant repigmentation in eight of the 15 patients after several years of therapy.

More recently folic acid used in conjunction with vitamin B12 before solar exposure or UVB gave better results than when used separately.

Vitamins C and E, with antioxidant properties, are used in vitiligo based on the theory that the formation of free radicals could be related to cutaneous depigmentation. Vitamin C has also been used topically with the objective of reducing erythema caused by ultraviolet radiation and to combat the harmful effects of radiation B on cutaneous immunity.^75,76

IMMUNOMODULATORS

A new perspective in the treatment of some skin diseases including vitiligo is the use of immunomodulators. Several studies have already proved their effectiveness in the treatment of atopic dermatitis and psoriasis, and there are also great perspectives for success with vitiligo.⁷⁷

One of the theories that attempt to explain the cause of vitiligo is that it occurs as an autoimmune aggression against the melanocytes. Therefore, the use of immunomodulators and immunosuppressors would appear quite promising within the therapeutic armamentarium discussed above.

Cyclophosphamide was used by Gokhale⁷⁸ in 1979, at a dosage of 100mg/day in 33 patients. There was improvement in 82% of the patients, with repigmentation even in areas such as the back of the feet, heels and lips, where repigmentation is usually difficult. Also levamisole, an anthelminthic drug, was used due to its activity as an immunomodulator, at a dosage of 150mg on two consecutive days per week with 64 patients, obtaining good results. It was effective when used alone and even more so when associated with topical corticosteroids.⁷⁷

The new generation of immunomodulating drugs, such as imiquimod, tacrolimus and pimecrolimus, has already been shown to be effective in two studies presented in the last meeting of the American Academy of Dermatology in 2002. Two papers were presented regarding the use of tacrolimus on vitiligo patients. Pearl E. Grimes et al.⁷⁹ reported promising results in five patients treated with tacrolimus (four of them with a concentration of 0.03%, and one with 0.1%). One patient achieved a total repigmentation of the lesions, three obtained from 50 to 75% repigmentation, and one 25 to 50%. In another preliminary study, Emil A. Tanghetti⁸⁰ described five cases of vitiligo treated with tacrolimus 0.1% for six weeks with partial repigmentation in all cases.

In spite of the limited amount of scientific literature available at this time, immunomodulators appear to constitute an important therapeutic option with a tendency to gain importance as more is discovered regarding the physiopathology of the disease.

DEPIGMENTATION

There are two ways to treat patients with vitiligo. The best is to restore the 'lost' melanocytes with techniques that stimulate the local and neighboring melanocytes; however, this is not always possible, because areas exist in which there is no reserve of these cells, such as in glabrous skin. Thus, there is a second line of treatment in which healthy melanocytes are destroyed with the application of a chemical product, monobenzyl hydroquinone ether. This is a simple technique, but which requires the use of the product for prolonged periods.

The main indication is for adults with involvement of more than 50% of the body surface and, above all, those capable of recognizing that this process will considerably alter their physiognomy and will demand special care in relation to solar exposure for the rest of their life.

CONCLUSION

Vitiligo is an acquired idiopathic cutaneous disorder, characterized by achromatic patches in any part of the skin and/or mucous membranes. The etiopathology is unknown, however of the proposed theories that of the immune mechanisms is underscored, mainly in the vulgar form of the disease. The importance of the immune mechanisms can be seen in the association of vitiligo with autoimmune diseases such as thyroiditis. Some precipitating factors are stress, intense solar exposure, physical trauma and exposure to some chemicals such as those used in the rubber industry and phenol derivatives. The presence or not of melanocytes in the affected skin remains controversial; it is believed that they are present, but smaller and less active in relation to normal skin. New drugs have been appearing, such as the topical immunomodulators which, allied to conventional therapies along with a good doctor/patient relationship, have been producing great successes in the therapeutics of this disease.

REFERENCES

Received in October, 03^rd of 2002.

Approved by the Consultive Council and accepted for publication in April, 24^th of 2003.

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*

Work done at "Centro de Estudos da Clinica Stockli e na Faculdade de Medicina de Jundiaí."

Publication Dates

• Publication in this collection
  05 Aug 2004
• Date of issue
  May 2004

History

• Accepted
  24 Apr 2003
• Received
  03 Oct 2002