Alopecia areata: treatment and prospects for new research

The urgency of the problem of treating alopecia areata at the present stage is significantly increasing, which is due not only to an increase in the incidence among young people, but also to an increase in the requirements for appearance as a factor that plays an important role in society. The multifactorial nature of the development of the disease, the clinical variety of forms of manifestation cause great difficulties in the development of effective methods of therapy.

Alopecia areata (AA) is currently regarded as a tissue-specific autoimmune disease mediated by autoactivated T-lymphocytes. Interaction of aggressive lymphocytes with hair follicle cells, abnormal expression of some tissue antigens, induction of apoptosis in the matrix contribute to the development of autoimmune inflammation.

The most important trigger factors include:

• microcirculation disorders;
• hypoxia;
• cytotoxic effect of lipid peroxidation products;
• endocrine dysfunction;
• neurotrophic and psycho-emotional disorders.

Therapy for alopecia areata

The modern arsenal of GA therapy includes both potent pathogenetic pharmacological agents and a variety of adjuvant or traditional agents. The dynamics of immune inflammation in GA and the development of the consequences of an autoimmune attack on the follicle, as well as an indefinite delay in the conversion of the follicle into a new anagen cycle, dictate the stages of therapeutic interventions. The wrong choice of therapy, not appropriate for the clinical phase, can worsen the course of the disease.

Glucocorticosteroids (GCS) remain the most widely available immunosuppressants; optimal tactics and stages of their application in GA have been developed. An indication for oral steroids may be recent alopecia with a rapidly progressive course.

Complete or cosmetically acceptable hair growth 4 months after the start of treatment was observed in 58.3% of patients receiving prednisolone pulse therapy at a dose of 300 mg orally at 4-week intervals. Some researchers report hair regrowth in 43% of patients treated with pulse therapy at a dose of 1,000 mg of prednisolone. Complete hair regrowth was observed in 71% of sick children after intravenous pulse therapy with methylprednisolone at a dose of 5 mg / kg per day for 3 days For patients weighing 60 kg or more, daily oral prednisolone at a dose of 40 mg is recommended for 1 week from subsequent weekly dose reduction by 5 mg to 20 mg per day, then – with a dose reduction of 5 mg every 3 days until the drug is completely discontinued. Recently, a long-acting steroid diprospan has been used.

Intrafocal administration of corticosteroids is the method of choice in the treatment of GA, however, with the involvement of more than 50% of the surface of the skin of the scalp, the rapid progression of the disease, and long-term forms, this method is not effective enough.

In a study involving 84 patients, hair growth in lesions on the background of such therapy resumed in 92% of patients with focal and 61% – total alopecia. Hair growth during 3 months after the treatment was observed in 71% of patients with focal and 28% – total alopecia. After the start of the introduction of corticosteroids in persons responding to this therapy, hair began to grow already within 3-4 weeks. More often, triamcinolone acetonide (kenalog) is used for this purpose, the total amount of which can be from 2.5 to 10 ml (less than 0.1 ml per 1 cm2 of affected skin).

Diprospan is prescribed at the rate of 0.1 ml per 2 cm2 of the lesion at weekly intervals. No more than 10 procedures are usually recommended for a course of treatment. When the focus is localized in the eyebrow area, the maximum dose per injection is 0.1 ml of the drug intradermally in 5 or 6 areas of each eyebrow (total 0.2 ml in both eyebrows). The most common side effects of intralesional corticosteroids are pain during injection, transient skin atrophy.

Topical corticosteroids are used in the treatment of GA. The use of fluocinolone acetonide 2% cream twice a day has a positive effect in 61% of patients. Children under the age of 10 years and patients with a disease duration of less than a year respond significantly better to this therapy. Betamethasone dipropionate 0,
A method for the treatment of extensive foci of GA with topical corticosteroid clobetasol propionate 0.05% in the form of an ointment has been proposed. A positive effect was observed in 97% of cases, of which in 63% of patients it was complete. At the same time, it is noted that combination therapy with minoxidil accelerates the restoration of hair in the foci. If in patients older than 14 years only corticosteroids with maximum activity should be used, then mometasone is preferred in children. For deeper penetration in the initial and progressive stages, elokom ointment is used, then they switch to lotion. They are applied to the foci of hair loss 1 time per day.

Treatment with topical corticosteroids should be continued for at least 3 months before hair growth resumes. Among the side effects of therapy, the most common are folliculitis, which usually develops after a few weeks. Telangiectasias and local skin atrophy have also been reported. There were no cases of systemic side effects.

Cyclosporin A

(sandimmune) — a specific immunosuppressive drug that inhibits the response of T-helper type 1 (Th1) of the hair follicle, acting selectively at the level of cytokines and disrupting the cooperation of immunocompetent cells. The drug is prescribed for the first 3 months at 5 mg/kg daily, then – 3 mg/kg daily followed by withdrawal. Cyclosporine A resumes hair growth, but after discontinuation of the drug, a recurrence of HA may occur. In addition, the use of cyclosporine does not fundamentally affect the prognosis of the disease and has a number of side effects (changes in the level of serum transaminases, creatinine and cholesterol in the blood, etc.). Therefore, the temporary positive effect of such therapy is more of a theoretical significance, confirming the immune mechanisms of the development of GA, and therefore the drug is not recommended for widespread use. However, in severe, refractory forms of GA, with resistance to other methods of treatment, the use of cyclosporine is indicated. The effectiveness of its topical application in the treatment of severe forms of GA has not been proven.

There are few reports in the literature of the effective use of methotrexate in patients with long-term severe GA. The possibility of a wider use of this drug in GA requires further study.

Topical immunosuppressive therapy is the most effective treatment for GA. The list of contact allergens (irritants) currently includes squaric acid dibutyl ester (SADBE) and diphenylcyclopropenone (DCP).

Although the results of the Ames test for DCP and SADBE indicate no mutagenic effect, none of these drugs have been approved by the FDA because their safety profile is not fully understood. The essence of the method consists in the artificial induction of allergic contact dermatitis on the skin of a patient with GA according to the type of delayed-type hypersensitivity. As a result, T-suppressors and macrophages are activated, which modify the immune process in the affected area of ​​the skin, which contributes to the resumption of hair growth; the expression of vascular endothelial growth factor (VEGF) in the keratinocytes of hair follicles is activated, providing the supply of nutrients and oxygen. The anti-apoptotic properties of VEGF are also manifested by the suppression of the CASP9 and BAD genes — main factors of apoptosis of follicle cells. The cosmetically acceptable hair regrowth with these drugs in patients with severe HA (more than 50% skin involvement) is 22-68%. The effectiveness of topical immunotropic therapy is influenced by the age of patients: the later they developed HA, the higher the effectiveness of treatment and the better the prognosis. However, these drugs are not available in Ukraine, which makes the use of this method impossible.

Irritating and hyperemic drugs were among the generally accepted and main appointments in the middle of the last century. These drugs are used in the stationary stage of HA after the cessation of hair loss.

Antralin

– synthetic hydroxyanthrone, which has a non-specific immunomodulatory effect, inhibiting the activity of Langerhans cells. Anthralin is most effective in the treatment of small foci of GA. The most common adverse reactions to the application are redness, peeling, itching, as well as cervical lymphadenopathy and pigmented skin disorders. A large number of studies have confirmed the effectiveness of psoralen in combination with UV-A (PUVA) in the treatment of patients with GA. The effectiveness of the method is 20 & ndash; 73%, however, the frequency of relapses, unfortunately, is high – 50–88%. In most patients, a relapse of the disease develops several (on average 4–8) months after stopping treatment. PUVA therapy can be administered both systemically and locally. The number of sessions required to restore hair growth ranges from 20 to 40. Early manifestation of HA, long duration of the disease, total and universal forms – predictors of treatment failure.

Minoxidil

is a direct treatment for hair follicles. When used systemically, the drug has a powerful vasodilating effect. The stimulating effect of minoxidil on hair growth is realized through its sulfonated metabolite, which opens potassium channels. The main key mechanisms of its action, known to date, are carried out by stimulating the synthesis of VEGF and prostaglandins, and this effect is dose-dependent. VEGF increases microvascular permeability and angiogenesis, promotes mutual adhesion of hair keratinocytes, increases hair strength, thickness and density. In the dermal papillae of hair follicles, VEGF stimulates the proliferation of matrix cells and endotheliocytes of the vasculature, the formation of extracellular matrix substance, thus maintaining the follicles in the anagen state.

The treatment regimen for alopecia with minoxidil is still being developed. Recent studies have shown that topical application of a 5% solution of minoxidil has a better effect than lower concentrations. According to clinical studies, cosmetically acceptable hair regrowth with topical use of a 5% solution of minoxidil is achieved in 45% of patients with involvement in the pathological process of 20-99% of the scalp within one year.

Minoxidil is not effective in the acute phase of the disease because it does not have an anti-inflammatory effect. The drug is often used in combination with other treatments, such as corticosteroids and substances that cause contact dermatitis.

Auxiliary therapy for alopecia areata

In the staged therapy of GA, especially in the stationary stage, adjuvant agents are no less important, which are successfully used with a differentiated approach.

Given the presence of psycho-emotional disorders, various nootropic and sedative agents (persen, trivalumen, sibazon, pantogam, phenibut, glycine, piracetam) are included in the complex therapy of GA. Shown are drugs that normalize disorders of the macro- and microcirculatory bed, tissue metabolism (xanthinol nicotinate, pentoxifylline, actovegin, oxybral). In HA, zinc preparations (zincteral), copper (copper sulfate) are prescribed, octamine plus is used to restore the amino acid balance. Multivitamin preparations are recommended, preferably with microelements (pantogar, fitoval, revalid, tri-vi plus, okuvayt lutein). Given the importance of the immune link in the pathogenesis of GA,

The group of irritating agents includes 10% red pepper tincture, bodyaga, fresh garlic juice, 30% propolis ointment, etc. Drugs that improve tissue trophism (bepanten, actovegin, solcoseryl) and microcirculation in the skin have a non-specific stimulating effect on hair growth (hepatrombin, heparin ointment). With rapid hair loss, a promising group of compounds are silatranes (Mival, Mival K).

In the complex therapy of HA, physiotherapeutic procedures are widely used. In recent years, a fundamentally new type of light therapy has appeared – narrow-band phototherapy using an excimer XeCl laser with a wavelength of 308 nm. The success of the excimer laser in this disease is associated with its immunosuppressive effect.

Cosmetic correction of hairless areas is important for achieving psychological comfort. The method of non-surgical replacement is a complex of cosmetic procedures using a hair system, which ensures complete restoration of the lost hair volume. Hair system – This is an individual piece of hair, created from a cast of the head, with a special, very secure method of fixation.

There are treatments for GA that have been studied in small trials. Thus, prostaglandin analogues are currently a promising class of drugs under development. Latanoprost, Travoprost, Bimatoprost – synthetic analogues of prostaglandin F2α, used in ophthalmology in the treatment of glaucoma; their side effect is a change in eyelashes: an increase in length, thickness, pigmentation and quantity. Anecdotal reports indicate the effectiveness of bimatoprost in GA.

Capsaicin

(8-methyl-6-nonenoic acid vanillamide) — an alkaloid found in various types of Capsicum capsicum. A recent study showed the effectiveness of capsaicin in the treatment of GA, comparable to the activity of a strong corticosteroid clobetasol 0.5%.

There are data on the use of calcitriol for the treatment of GA. It is believed that the use of this drug in the form of ointment applications for 4 months can be effective; it is recommended as an alternative method for severe alopecia. By the mechanism of reverse negative regulation, calcitriol has a powerful inhibitory effect on Th. This effect can probably serve as one of the pathways for switching the immune response from Th1 to Th2. The study of the use of vitamin D3 derivatives in GA is considered one of the promising areas.

The ability

of tacrolimus

to inhibit the production of key cytokines for the T-cell immune response and to have a local immunosuppressive effect justifies its use in the treatment of GA. Resurgence of hair growth on the skin of animals after topical application of tacrolimus has been established. Oral administration of the drug was ineffective. The topical use of tacrolimus in patients with GA requires further study.

Bexarotene

is a retinoid that selectively activates retinoid X receptors and is approved for the treatment of cutaneous T-cell lymphomas. Studies are underway to study the use of 1% bexarotene gel (Targetin) in patients with various forms of GA.

Anticytokine therapy is one of the modern methods of treating autoimmune diseases. There are reports of the effective use of antibodies to INF-.gamma. at GA.

Recent studies have shown that nitric oxide acts as a mediator in various physiological and pathophysiological processes occurring in the skin, plays an important role in molecular signaling, vasodilation, and the functioning of the hair follicle. It is of interest to study the possibility of using drugs that modulate the production of nitric oxide in various forms of GA.

Thus, the modern arsenal of drugs for the treatment of GA, including both potent pathogenetic drugs and a diverse adjuvant group, is quite wide. A differentiated approach in the choice of methods of therapy in accordance with the phase of immune inflammation, the elimination of possible triggers are the fundamental principles of the treatment of dermatosis. However, the development of complications and severe side effects, insufficient study of the effectiveness and safety of individual drugs limit the possibility of a wide range of therapeutic effects and predetermine interest in the search for new opportunities in the treatment of the disease.

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