Modern views on the complex therapy of vitiligo

Modern views on the complex therapy of vitiligo reflect a commitment to theories of the development of depigmentation. A number of authors argue that the systemic use of corticosteroids can inhibit the spread of depigmentation, especially in generalized forms. It is proposed to use prednisolone at a dose of 10-15 mg/day 2 times a week for 6 months. This author, summing up the results of the study, showed that none of the patients had complications after 6 months of treatment, but only 32% of patients had active repigmentation of lesions.

S. Radakovic-Fijan (2001) prescribed prednisolone at a dose of 0.3 mg/kg daily for 2 months. A pronounced effect in the form of complete repigmentation of foci was noted in 65% of patients with vitiligo, in whom the disease lasted no more than 2 years. As a result of the use of prednisolone 5 mg / day for 6 months, 90% of patients stopped the progression of the disease, restoration of pigmentation was observed in 67% of patients.

The results of these studies demonstrate the high efficiency of systemic steroid therapy, but a number of contraindications and a high risk of side effects and complications do not allow this method to be widely used, especially in pediatric practice.

In 2004, Indian investigators published the results of an open-label, multicentre study of the clinical efficacy of levamisole for the treatment of vitiligo. Levamisole was considered as a drug with antihelminthic activity and influencing certain parts of immune responses. Levamisole was used in patients aged 14 to 55 years at 150 mg/day twice a week for 12 weeks. As a result, it was concluded that levamisole is ineffective in this disease, since only 15% of patients had partial repigmentation in lesions, and in a parallel placebo-controlled study, partial repigmentation of individual lesions was also observed in 12.5% of patients taking placebo.

Cyclosporine is widely used for the treatment of immunomediated dermatological diseases. Some authors used its immunosuppressive properties in vitiligo, but the results of treatment were very doubtful. Complete repigmentation was not observed in any patient, partial repigmentation of individual foci was observed only in 8% of patients. Given the possible complications and side effects, this method has not yet found wider application.

A positive clinical effect was noted when drugs with immunomodulatory effects were included in the complex therapy. So the use of polyoxidonium caused the restoration of normal skin color in patients with common and limited forms of vitiligo. THEM. Korsunskaya (2004) successfully used the domestic drug Glutoxim, which belongs to the class of thymopetins and has an antioxidant effect, modulating the effect on intracellular processes of thiol metabolism. For several decades, complex therapy with B vitamins, folic acid in combination with microelements (zinc, copper) and ultraviolet radiation has been used and in some cases is still used. Against the background of the therapy, no pronounced clinical changes were detected. Pathogenetic justifications for the use of the patient's vitamins are also doubtful, partial repigmentation of individual foci was observed only in 8% of patients. Given the possible complications and side effects, this method has not yet found wider application.

For several decades, complex therapy with B vitamins, folic acid in combination with microelements (zinc, copper) and ultraviolet irradiation has been used and in some cases is still used. Against the background of the therapy, no pronounced clinical changes were detected. The pathogenetic justification for the use of vitamins is also doubtful.

Therapeutic Algorithms Muscalu A.S. et al. (2008) recommend using taking into account the clinical form of vitiligo, the duration of the disease and the severity of psycho-emotional changes that have developed against the background of the disease. In children, comprehensive approaches to the treatment of vitiligo include the use of topical steroids, psoralen, Vitix (an antioxidant), and ultraviolet B radiation and antidepressants. The choice of duration, dose depends on the clinical form of vitiligo.

The use of topical steroids for vitiligo is common in Europe and the United States, however, the use of these drugs for a long time (at least 3 months) is recommended for small areas of damage and there are restrictions for certain areas of the skin (eyelids, large folds, genital area ), on which skin atrophy develops most quickly and often. Long-term use of topical steroids in the periorbital region increases the risk of glaucoma and cataracts. In studies of scientists, it was found that 0.1% hydrocortisone-butyrate cream, 0.05% clobetasol propionate cream, a cream containing 50 mg / g of calciumpotriol have a photoprotective effect, but even with prolonged external use in combination with sunlight, they do not cause carcinogenic effect,

Some authors suggest various topical regimens, including 0.05% clobetasol or a combination of 0.05% clobetasol and 0.625% estrogen cream. The results of the clinical study indicate that the combined use can reduce the risk of side effects in the form of skin atrophy and the appearance of telangiectasias.

The authors observed an increase in the action of clobetasol in combination with estrogen.

The method of topical application of prostaglandin E2 analogs involved in melanocyte proliferation is called innovative. In an experiment on mice, it was found that applying PgE2 to the skin leads to an increase in the number of melanocytes. As a result, in 62% of patients the appearance of pronounced repigmentation was observed, in 25% of patients moderately pronounced repigmentation was observed and in 12% of patients - mild changes. The study of the clinical efficacy of topical PgE2 is ongoing, as the positive effect obtained is considered significant.

At present, there are a large number of publications on the results of the use of pimecrolimus and tacrolimus — non-steroidal inhibitors of pro-inflammatory cytokines in various forms of vitiligo. Thirty-five vitiligo patients under 30 years of age were enrolled in a study to investigate the clinical efficacy of tacrolimus 0.1% ointment applied to lesions twice daily for 3-6 months. In 7 patients, brilliant results were observed and complete repigmentation in the lesions was noted, in 24 patients there was partial repigmentation of large lesions (pigmentation recovered by 50-75%) and complete restoration of normal skin color in small lesions, in three patients no positive changes were found, however, the sharp border between depigmented and normally colored skin disappeared, only one patient did not respond to treatment. The authors also noted that lesions on the face, chest, and labia repigmented most rapidly.

Win Z., Costigan J., Bhat J., Abdullah A. (2009) conducted a retrospective analysis of the results of treatment of vitiligo in children with tacrolimus ointment (protopic) in 2007-2008. 100% repigmentation of all lesions was observed in 19 of 24 patients, partial repigmentation was noted in 4 children, and only 1 child did not receive any positive results. The authors emphasize that tacrolimus therapy should be long-term, at least 4 months. This method of treatment did not involve additional medications and UV irradiation.

In 2009, MD Rooseleer N. published his own observations of a 35-year-old patient with vitiligo for more than 2 years who used a combination of calciumpotriol/betamethasone dipropionate ointment with ultraviolet irradiation for 23 months. Partial repigmentation was noted in lesions on the face and hands, while clinical signs of skin atrophy were not observed. External therapy of vitiligo with a combination ointment of calciumpotriol/betamethasone dipropionate has shown high efficacy in the treatment of facial skin lesions in vitiligo.

Currently, a combination of calcipotriol cream with sunbathing may be used. 38 patients with vitiligo, in which the area of the lesion was not more than 20% of the surface of the skin, were applied calciumpotriol cream once a day in the evening, the next day, the patients sunbathed for 10 minutes until 10 am for 6 weeks. In 12 patients, complete repigmentation in the lesions was observed, in 13 people - partial and in 13 — lack of results of combined treatment.

Phototherapy. Experimental studies in photobiology demonstrate the various effects of UV irradiation in combination with various substances, as well as their involvement in melanogenesis and the appropriateness of their use. The experiment found that procytein is a potential inhibitor of tyrosinase and a potential antioxidant, and vitamin C reduces the transport of melanin to keratinocytes.

Phototherapy is a very common treatment for vitiligo. It is used in children and adults, with limited and generalized forms of vitiligo with varying duration of the disease. The expediency of using phototherapy is due to the possible stimulation of pigment formation and some ability to reduce the activity of cells of the skin's immune system. The search for the most efficient UV irradiation technique continues. To this end, a comparative study of the effect of UV with different wavelengths is carried out, as well as the possibility of using combined approaches, including topical agents used in the treatment of vitiligo. Scientists emphasize that phototherapy should be long-term, and in some cases indefinitely long, and the treatment time can be significantly reduced by prior treatment with topical steroids, calcineurin blockers or other known methods. However, the authors draw attention to the fact that in stable vitiligo (with a disease duration of 2 years or more), the best results are achieved using surgical techniques.

Summarizing the results of a long-term clinical study of the effectiveness of various modifications of phototherapy (UVA and UVB), M.E. Whitton et al. (2008) conclude that the effectiveness of the selected methods of phototherapy is approximately the same. Hartmann A. et al. (2002) conducted a comparative analysis of the effectiveness of UV-B with a wavelength of 311 nm and polychromatic UVB rays. The authors showed that UVB with a wavelength of 311 nm has a pronounced effect in the treatment of patients with vitiligo, while polychromatic rays of this spectrum turned out to be absolutely ineffective. The same author believes that by combining ultraviolet irradiation with topical application of calcipotriol, a reduction in radiation power can be achieved.

PUVA therapy is still widely used for the treatment of vitiligo. Various photosensitizers are used: puvalen, methoxsalen, oxorolene, ammifurin. In their work, scientists have shown that against the background of PUVA therapy, repigmentation is observed due to increased mitosis in melanocytes through the release of endothelin-1 into the bloodstream. Scientists using PUVA therapy observed rapid (1-2 months) repigmentation in 50-75% of patients.

On the other hand, comparing UV irradiation with PUVA therapy, scientists note that the effectiveness of these methods is significantly comparable. More than 70% repigmentation was observed in 30% of patients treated with UVR and in 24% of patients treated with PUVA, and no effect from UVR was shown in 4.5% and 7% — with PUVA therapy. However, the author emphasizes that when using any method of phototherapy, the quality of life of patients with vitiligo increases, their mood improves. Various studies have shown the immunosuppressive effect of PUVA therapy on activated tissue macrophages, cytotoxic T-lymphocytes and Langerhans cells. An inducing effect of UV on T-lymphocyte apoptosis in depigmented lesions has been demonstrated.

Despite the wide popularity of PUVA therapy in various modifications, side effects and contraindications are well known, limiting the use of UVR and PUVA. Most often, among the side effects of UVR, itching, persistent erythema, severe dry skin, as well as cataracts and carcinogenic effects are noted. With PUVA therapy, headaches, dyspepsia, palpitations, dry skin, photodermatitis and long-term side effects are observed - uneven skin pigmentation, lentigo, hypertrichosis, epidermal dystrophy, onychodystrophy, up to onycholysis, keratosis, skin cancer, cataracts, liver dysfunction and kidneys, induction of autoimmune processes, manifestations of immunosuppressive action. At the same time, there are clear limitations for PUVA therapy —

In modern practice, laser radiation of various sources with different power, effect on the skin and underlying tissues is increasingly used. In modern therapy for vitiligo, an excimer laser is used, its stimulating effect on melanogenesis and its corrective effect on cells of the immune system are being studied. In a large number of foreign publications, a rather high efficiency and a smaller number of side effects are noted compared to PUVA. This method finds application in segmental vitiligo, since it is possible to selectively irradiate without affecting normally pigmented skin. According to various authors, the effectiveness of this method is different and varies from repigmentation in 95% of patients to a complete lack of effect in almost 20% of patients.

Other authors are more reserved about the high clinical results of the excimer laser. SV Mulekar et al. (2005) observed repigmentation of more than 75% in only 15% of the observed patients and 19% did not have any positive changes during excimer laser therapy. In the same period of time, M. Esposito (2005) observed complete or partial repigmentation in 29% of patients after laser therapy. Subsequent work demonstrates better results — repigmentation was observed in 55-78% of patients when combined with tacrolimus or calcipotriol.

In the future, the excimer laser as a monotherapy was used less frequently. A new combined method was developed by K. Fitz and T. Hunziker (2009), who propose to transplant uncultivated melanocytes (source - hair follicles in the anagen phase) in stable vitiligo and then stimulate melanogenesis using an excimer laser. Although these authors in their work noted high efficiency (repigmentation of more than 50%) when using pimecrolimus or tacrolimus and further phototherapy. IM Sheikh (2009) showed that in stable vitiligo, any transplantation of autologous (both cultured and non-cultured) melanocytes followed by irradiation leads to complete repigmentation in 90% of patients. The author emphasizes that in this way it is possible to reduce the time and radiation power,

Korean investigators show positive results with both UVB and excimer laser (perifollicular repigmentation was seen in 42.2% and 51.3% respectively) 12 weeks after starting treatment. In conclusion, they conclude that successful treatment to a certain extent depends on the location of the rash, the age of the patient, the duration of the disease, the rate of response to radiation, i.e. if signs of repigmentation appear in the early stages of phototherapy, then one can expect a complete restoration of normal skin color in the irradiated depigmentation foci. A group of other researchers used an excimer laser twice a week, a total of 30 procedures per course, irradiated depigmented lesions on the head and chest in patients from 0 to 60 years old. The authors believe that the best results were obtained in younger patients, however, apart from hyperpigmentation around the irradiation zones, no other side effects were noted. Laser phototherapy, and in particular the excimer laser with a wavelength of 308 nm, has a number of advantages over other methods. The possibility of clear dosing, fewer contraindications opens up prospects and requires further study.

High efficiency of combined phototherapy is noted by many researchers. When choosing a method of phototherapy and combined modifications, an individual approach is required, taking into account the prevalence, duration of the disease, age, and possible side effects. In all cases, a long — more than 3-6 months expensive treatment.

Surgical treatments for vitiligo

In the late 1950s, the results of surgical treatment of vitiligo were first published. Back in 1947, N. Haxthausen used full-thickness flaps of healthy skin to replace depigmented skin. It seemed that this method would gain acceptance. But in the future, in addition to rejection of autografts, other complications were observed in the form of cicatricial changes, infection, uneven pigmentation, and the appearance of the Koebner phenomenon. The search and development of various techniques and modifications continued and the next step was the technique of thin epidermal flaps according to the Thiersch method. R. Falabella (1971) suggested using thin covers of the epidermal bladder as an autotransplant (epidermal transplantation with suction effect). Available methods for obtaining thin epidermal flaps are: bubble formation with a vacuum extractor or liquid nitrogen. On the one hand, these techniques are performed without much difficulty, on the other hand, they are traumatic and leave cicatricial changes of varying severity after exposure. Some researchers transplanted pigmented hair into depigmentation foci, since melanocytes of hair follicles are a reserve source of autologous melanocytes. At present, when techniques are known and developed that allow transplantation of single hair follicles with pigmented hair, it is possible to avoid scarring both in the donor area and in the focus of depigmentation.

on the other hand, they are traumatic and leave cicatricial changes of varying severity after exposure. Some researchers transplanted pigmented hair into depigmentation foci, since melanocytes of hair follicles are a reserve source of autologous melanocytes. At present, when techniques are known and developed that allow transplantation of single hair follicles with pigmented hair, it is possible to avoid scarring both in the donor area and in the focus of depigmentation.

on the other hand, they are traumatic and leave cicatricial changes of varying severity after exposure. Some researchers transplanted pigmented hair into depigmentation foci, since melanocytes of hair follicles are a reserve source of autologous melanocytes. At present, when techniques are known and developed that allow transplantation of single hair follicles with pigmented hair, it is possible to avoid scarring both in the donor area and in the focus of depigmentation.

The search continues for possible surgical treatments for vitiligo with the least complications. Observations show that surgical methods have the highest efficiency rates compared to others, reaching 92% restoration of normal skin color. It is recommended to resort to surgical methods in cases of stable vitiligo, including segmental, vulgar, generalized, acrofacial, refractory to traditional methods of treatment. It is proposed to evaluate the stability of the process according to the following criteria:

no new foci of depigmentation or an increase in the area of existing foci over a period of time from one to 3 years;

no Koebner phenomenon;
trial transplant — the gold standard for determining process stability and treatment efficacy: the test is considered positive if repigmentation extends beyond the autograft by 1 mm or more over a period of 3 months.

A new and promising area of surgical treatment is autotransplantation of cultured melanocytes. When using the "blister" transplantation, the culture of melanocytes grown from the patient's own pigment cells is transferred to a special carrier, after which it is applied to a pre-macerated area of depigmented skin. A. Andreassi et al. (2001) noted the restoration of normal skin color in 40-100% of cases using this technique. The disadvantages of this method are maceration of the skin, marble coloring of the area, uneven repigmentation of the affected areas. In the same period, other scientists suggested applying a suspension of melanocyte culture to depigmented skin that had previously undergone dermabrasion and showed the highest efficiency of the developed technique — repigmentation was observed in 84-100% of cases, especially in combination with PUVA therapy to restore pigmentation in large areas of depigmentation. However, the authors warn about the possibility of a Koebner phenomenon. In order to reduce the risk of its development, SV Mulekar et al. (2004) proposed the use of prednisolone at a dose of 0.5 mg/kg 1 week before transplantation and 1 week after it. The authors emphasize that the immunosuppressive effect of prednisolone not only prevents the development of the Koebner phenomenon and rejection reaction, but has a pathogenetic basis for its use in vitiligo.

repigmentation was observed in 84-100% of cases, especially in combination with PUVA therapy to restore pigmentation in large areas of depigmentation. However, the authors warn about the possibility of a Koebner phenomenon. In order to reduce the risk of its development, SV Mulekar et al. (2004) proposed the use of prednisolone at a dose of 0.5 mg/kg 1 week before transplantation and 1 week after it. The authors emphasize that the immunosuppressive effect of prednisolone not only prevents the development of the Koebner phenomenon and rejection reaction, but has a pathogenetic basis for its use in vitiligo.

Mulekar et al. (2004) proposed the use of prednisolone at a dose of 0.5 mg/kg 1 week before transplantation and 1 week after it. The authors emphasize that the immunosuppressive effect of prednisolone not only prevents the development of the Koebner phenomenon and rejection reaction, but has a pathogenetic basis for its use in vitiligo.

Until now, transplantation of a suspension of cultured melanocytes and keratinocytes has not been used in Russia, although this surgical method is the most promising and effective. The suspension obtained after the joint cultivation of keratinocytes and melanocytes is injected into the depigmentation foci. The advantage of the culture approach is that cell expansion in vitro can significantly reduce the area of the skin flap used for graft preparation.

There are some other options that make life easier for a vitiligo patient — it is a decorative masking cosmetics and micropigmentation (tattoo). The complexity of these methods lies in the selection of the required tone of the pigment, the constant use of cosmetics, anxiety when the cosmetic ends and seek, try and experience innovative developments in this area. Micropigmentation is an invasive method of introducing pigment, the tone of which can also be difficult to match. In addition, the pigment fades after some time and it becomes necessary to correct / defective areas.

Thus, studying the literature data, it becomes clear why there are still no clear algorithms for the treatment of various forms of vitiligo and many of the proposed methods are aimed only at eliminating a cosmetic defect, that there are a large number of treatment options for vitiligo, many of which have serious limitations for use, high risk of complications and side effects.

Despite the opening up new opportunities for studying impaired pigment formation, a unified view of the causes and mechanisms of depigmentation development has not yet been formed. Why do some patients have 1-2 stable foci of depigmentation for decades, while others, against the background of visible well-being and well-being, have fresh depigmented areas.