Topical Tacrolimus: A New Therapy for Atopic Dermatitis

JOHN J. RUSSELL, M.D.

Atopic dermatitis is a common problem affecting up to 10 percent of all children. The mainstays of therapy have been oral antihistamines, topical emollients, topical doxepin, and topical corticosteroids. Side effects associated with higher potency topical corticosteroids have limited their use in children and for facial areas. Tacrolimus (Protopic) is an immunosuppressive agent typically used systemically in transplant patients. Used topically, it has been found to be effective in treating moderate to severe atopic dermatitis without causing the atrophy that might occur with prolonged use of topical corticosteroids. Tacrolimus works equally well in children and adults, with more than two thirds of both groups having an improvement of greater than 50 percent. Despite its potency, very little of the medication is systemically absorbed, and absorption decreases as the atopic dermatitis resolves. The main side effects are burning and itching, but these also decrease with improvement of the atopic dermatitis.

Atopic dermatitis affects up to 20 percent of Americans and is the most common chronic skin disease in children.¹ The majority of patients are younger than 30 years, with 90 percent reporting symptoms beginning by five years of age.² In this chronic condition, therapy is directed at decreasing inflammation and minimizing symptoms. Available treatments include oral antihistamines, topical emollients, topical doxepin (Zonalon), and topical corticosteroids. It may also be alleviated with attention to bathing habits and avoidance of irritants. Disease severity and location determine which therapies are used. Topical steroids are commonly used to treat moderate to severe disease, but chronic use of these agents at higher concentrations can cause skin atrophy and pigmentation changes. Chronic use of higher potency steroids can also have systemic effects on the hypothalamic/pituitary axis and inhibit growth. These adverse events may limit corticosteroid use in young children and adults in all areas, especially the face and intertriginous zones.

More has been learned over the past few years about the pathophysiology of atopic dermatitis. The recurrent itch and dermoepidermal inflammation manifests histologically as hypertrophy of the dermis and epidermis with presence of eosinophils, macrophages, and T cells. The inflammatory response in atopic dermatitis begins when an IgE-associated Langerhans’ cell in the skin binds an antigen and presents the antigen to T cells, leading to the release of numerous cytokines, including various interleukins. These mediators lead to the recruitment of more inflammatory cells, and this results in edema. Scratching causes keratinocytes to release a variety of proinflammatory cytokines, which recruits more inflammatory cells.

Acute and chronic responses in atopic dermatitis are probably caused by separate inter-leukins.^3–5 Targeting these pathophysiologic factors has led to the development of new therapies, such as tacrolimus (Protopic).

Tacrolimus is the first new topical therapy for the treatment of moderate to severe atopic dermatitis since the advent of topical corticosteroids. An immunosuppressive medication derived from macrolides, oral tacrolimus has been used since 1994 to prevent allograft rejection in liver and kidney transplants.⁶ Pimecrolimus (Elidel) 1 percent cream was recently approved by the U.S. Food and Drug Administration for short-term and intermittent long-term treatment of mild to moderateatopic dermatitis in patients two years and older who do not respond well to or have side effects with conventional treatments. ⁷

Cyclosporine (Sandimmune), another immunosuppressive agent, has also been used orally to treat psoriasis and atopic dermatitis, but its use is limited by the high incidence of side effects. Topical cyclosporine has shown inconsistent results. Tacrolimus has similar results to cyclosporine when administered systemically, but tacrolimus has better skin penetration (probably because of the smaller molecular mass of tacrolimus compared with cyclosporine), which makes it a better candidate for topical use.⁸

MECHANISM OF ACTION

Topical tacrolimus has been shown in vitro to bind to specific receptors on T cells. This leads to an increase in intracellular calcium that, in turn, causes a series of reactions inhibiting the transcription of several genes, mainly the cytokines (IL-2, IL-4, and IL-5). Tacrolimus also acts to decrease the production of IL-8 receptor genes and inhibits the production of receptors for IgE molecules.^9,10 Because it affects a variety of interleukins, it can be effective in the treatment of acute and chronic atopic dermatitis. Biopsy studies at three and seven days have shown diminished T-cell and eosinophilic infiltrates.⁵

PHARMACOKINETICS

Tacrolimus is metabolized in the liver but, with topical use, very little is absorbed. In a study of patients with moderate to severe atopic dermatitis, blood concentrations were below the detectable level in 80 percent of samples. Only 0.3 percent of samples had serum levels in the 5 to 20 ng per mL range, which is the target range for transplant patients, with the highest levels being 8.13 ng per mL.¹¹ Studies have shown that damaged skin has a sevenfold higher rate of absorption of tacrolimus.¹⁰ Healed skin regains percutaneous barrier function, preventing the large molecule of tacrolimus from being absorbed.

CLINICAL TRIALS

Several studies have examined the efficacy of topical tacrolimus in adult patients. In a double-blind, placebo-controlled study, 215 patients with moderate to severe atopic dermatitis were randomized to receive 0. 03, 0.1, or 0.3 percent tacrolimus, or vehicle, applied twice daily. Patients were evaluated at three weeks using atopic dermatitis severity scores. The decrease in scores for the three groups was 67, 83, and 75 percent for the 0.03, 0.1, and 0.3 percent ointments, respectively. The vehicle group showed a 22 percent decrease in severity scores. No statistical difference was found among the three tacrolimus groups, which showed equal efficacy in face, neck, and trunk regions. The only statistically significant side effect in treatment versus vehicle groups was a sensation of local burning, but this effect resulted in no increase in the dropout rate.¹² [Evidence level A, randomized controlled trial (RCT)]

In another study of 632 patients with moderate to severe atopic dermatitis, patients were randomized for 12 weeks to receive vehicle, 0.03 percent tacrolimus, or 0.1 percent tacrolimus ointment applied twice daily. Physician assessment at 12 weeks showed 90 percent improvement in 6. 6 percent of the vehicle patients, 27.5 percent of the 0.03 percent tacrolimus group, and 36.8 percent of the patients using 0.1 percent tacrolimus ointment. Both treatment groups were significantly better than the vehicle group. Greater than 50 percent improvement occurred in 19.8 percent of the vehicle group, compared with 62 and 73 percent of the 0.03 and 0.1 percent tacrolimus groups, respectively. The differences between the two tacrolimus groups were most evident in patients with more severe disease and disease involving a larger surface area, and in black patients. Discontinuation of the study because of adverse events occurred twice as often in the vehicle group.¹³ [Evidence level A, RCT]

Pediatric studies also showed efficacy. In a randomized, double-blind, vehicle-controlled study, 0.03 percent, 0.1 percent, and 0.3 percent tacrolimus were compared with vehicle therapy in children seven to 16 years of age over 23 days, with twice-daily treatment. Physician assessment showed that 67 to 70 percent of patients in the three treatment groups and 38 percent in the vehicle group had greater than 75 percent improvement in their atopic dermatitis. ¹⁴ [Evidence level A, RCT]

In another study, 351 children two to 15 years of age with moderate to severe atopic dermatitis were treated for 12 weeks with 0.03 percent or 0.1 percent tacrolimus ointment, or vehicle. By physician assessment, greater than 50 percent improvement occurred in 73 and 78 percent of the tacrolimus groups, respectively, versus 27 percent in the vehicle group. A higher incidence of skin burning and varicella occurred in the two treatment groups. Side effects were not dosage dependent.¹⁵ [Evidence level A, RCT]

A study of Dermatology Quality of Life Indexes performed on 985 adult and younger patients with moderate to severe atopic dermatitis showed significant improvement in all areas over 12 weeks in patients who used tacrolimus. Patients were randomized to vehicle, 0.03 percent, or 0.1 percent tacrolimus and evaluated at the end of 12 weeks. The surveys included such aspects as itchiness, self-consciousness, relationships, and dressing. Significant differences versus vehicle were seen in every category in adults. In children, the biggest quality-of-life differences were found in itchiness, sleeping, emotions, and activities. When patients were asked if they were “very likely to continue” using the medicine, those using both strengths of tacrolimus were more likely to want to continue the medication than those who used the vehicle in all age groups.¹⁶ [Evidence level A, RCT]

SAFETY

In clinical trials, the most common side effect was a burning sensation of the skin, occurring in 46 to 58 percent of patients treated with tacrolimus. This side effect was most frequent early in the course of treatment. Pruritus was reported in 46 percent of patients, although this rate was not statistically different than that for vehicle. Local effects are more common in patients with a higher amount of body-surface area affected. Patients using tacrolimus reported a higher rate of herpes simplex and eczema herpeticum. No laboratory abnormalities were reported, and no skin atrophy was noted.¹⁰

In a one-year open-label study of children two to 15 years of age, using 0.1 percent tacrolimus ointment twice daily, the most common side effect was skin burning in 26 percent, generally early in the course of therapy. Pruritus occurred in 23 percent of patients, and there was also an increase in skin infections (11 percent), namely herpes simplex, varicella, and eczema herpeticum. No significant laboratory abnormalities were found compared with baseline.¹⁷

With systemic tacrolimus, the principal adverse side effects are nephrotoxicity, neurotoxicity (especially insomnia, tremor, and headache), and gastrointestinal disturbances (e.g., diarrhea, nausea, and vomiting). With all immunosuppressive treatment regimens, there is an increased rate of malignancies, especially lymphomas.¹⁸ No topical study showed an increase in malignancy rate, but all of the studies were of short duration. Because of the increase in non-melanoma skin cancer in patients using systemic tacrolimus therapy, it would make sense to ensure good sun protection in areas treated with topical tacrolimus. The drug is listed as a pregnancy category C agent, with no adequate well-controlled studies undertaken in pregnant women.¹⁹

DOSAGE AND COST

Tacrolimus ointment is produced under the brand name Protopic. It comes in 0.03 percent and 0.1 percent formulations. Adults can use either strength, but only the 0.03 percent strength is approved for use in children, and then only in those two years or older. A thin coating should be applied twice daily. The average wholesale cost of a 30-g tube is $54.37 for the 0.03 percent ointment and $58.12 for the 0.1 percent strength. The cost of a 60-g tube is $108.75 for the 0.03 percent ointment and $116.25 for the 0.1 percent.²⁰

Topical Tacrolimus – Newcastle Hospitals NHS Foundation Trust

What is topical Tacrolimus and how does it work?

Tacrolimus ointment is not a topical steroid. It is an ointment that reduces the inflammation in affected skin and works in a completely different way to other treatments such as topical steroids.

Topical tacrolimus can be used on Adults and Children (over 2 years) for the treatment of atopic eczema. It is also sometimes prescribed to treat other skin conditions for which it is not licensed such as psoriasis and vitiligo.

How often is topical Tacrolimus treatment and how do I apply it?

Topical Tacrolimus should be applied as a thin layer to affected areas of your skin. It can be used on most parts of the body; however it tends to work best on the face and neck.

Topical Tacrolimus should be applied to clean, dry skin that has not had an emollient applied to the area within an hour (to avoid diluting the tacrolimus and making it less effective).

Topical Tacrolimus is usually applied twice a day initially, once in the morning and once in the evening, then this is reduced to once daily after 2 weeks. Your healthcare professional will advise on maintenance treatment which includes reducing the strength of the topical Tacrolimus and/or the frequency of application.

What are the possible side effects of topical Tacrolimus treatment?

Topical Tacrolimus can cause a burning sensation and itching to the affected area however this usually improves within one week of use.

Absorption through the skin is extremely low. Common side effects include redness, feeling of warmth, pain, increased skin sensitivity (especially to hot and cold), skin tingling, rash and facial flushing or skin irritation after drinking alcohol.

There is a theoretical concern about an increased risk of skin infections. If you notice the appearance of crusting or small blisters, please contact your healthcare professional.

Tacrolimus can make you burn more easily in the sun. Therefore, sunblock should be used on a regular basis to sun exposed areas that have been treated. You should not use sunbeds or receive ultraviolet phototherapy whilst using topical Tacrolimus.

When should topical Tacrolimus treatment not be used?

Topical Tacrolimus should not be used if you have a skin infection (bacterial, fungal or viral), liver failure, previous sensitivity or adverse reaction.

If you are allergic to macrolide antibiotics (e.g. Azithromycin, Clarithromycin, Erythromycin) topical Tacrolimus is not advised.

For children less than 2 year’s topical Tacrolimus treatment is not recommended.

Avoid using the ointment inside your nose or mouth or in your eyes. If the ointment gets on any of these areas, it should be thoroughly wiped off and/or rinsed off with water.

Do not cover the skin being treated with bandages or wraps.

Fire Hazard

This is a paraffin-containing product and there is a danger that smoking or being near a naked flame can cause it to catch fire. To minimize this risk do not smoke, use naked flames (or be near people who are smoking or using naked flames) or be near anything which may cause a fire whilst these products are in contact with your skin, clothes, dressings or bandages.

Ensure that your clothes and bedding are changed regularly as the paraffin soaks into the fabrics and can potentially be a fire hazard. You should also be careful to make sure that the paraffin does not soak into chairs, seating or other furniture.

Medicines Information Patient Helpline:

Tel: 0191 282 3016. Available 9am to 4pm, Monday to Friday (excluding Bank Holidays). This helpline is available for patients of the Newcastle upon Tyne Hospitals, to answer any questions they may have regarding their medicines.

Dermatology:

Tel: 0191 282 0098. Available 9:00am to 4:00pm, Monday to Friday (excluding Bank Holidays).

Out-of-hours Advice:

Contact NHS 111 or visit your nearest NHS Walk-in Centre.

Page last updated: 01/11/2022

The use of tacrolimus in the treatment of children with cancer

Supportive care

Trademarks:

Prograf®

Other names:

FK506

Often used for:

Graft-versus-host disease (GVHD) after stem cell transplant, severe aplastic anemia

Tacrolimus is a drug that works to suppress the immune system (called an immunosuppressant). It is used to reduce the body’s natural immunity in order to prevent and treat GVHD during hematopoietic cell transplantation.

Tacrolimus is broken down in the body by certain enzymes. The patient may need genetic testing to determine how well the enzymes are working. If tacrolimus is broken down faster than usual, the dose of the drug may be increased.

During therapy, the patient will need regular blood tests to check blood levels of tacrolimus, potassium and magnesium, and to monitor kidney and liver function. The dosage of the drug may vary depending on its content in the blood.

Oral capsules

Oral liquid form

Administered intravenously (through a drip) in liquid form

Skin application

• Kidney disorders
• High blood pressure
• Tremor (body trembling)
  
• Numbness or tingling in hands and feet
  
• Low blood magnesium level
  
• High blood potassium
  
• Increased risk of infection
• Nausea and vomiting
• Abdominal pain
• Liver disorders
• Headache
• Sleep disorders
• Visual impairment
• Convulsions
• Low red blood cell count (anemia)
• High blood sugar (diabetes)

The listed side effects are not observed in all patients who are prescribed tacrolimus. The most common side effects are highlighted in bold, but others are not excluded. Report all possible side effects to your doctor or pharmacist.

Some patients may experience long-term side effects or long-term effects that persist from the time of taking the drug or appear only several months or years after the end of the drug. Possible long-term effects of tacrolimus:

• Secondary cancer (such as lymphoma or skin cancer)

Be sure to discuss these and other recommendations with your doctor or pharmacist.

• Medical staff will notify the patient in advance of the dates and times of testing to measure the level of tacrolimus in the blood. On the specified day, taking the drug should be postponed until blood sampling.
• Antacids (eg, ranitidine) should be avoided within 2 hours before or after tacrolimus, unless this type of drug is prescribed by your healthcare provider.
• Patients who have been prescribed this drug should not eat grapefruit or orange juice, drink their juice or drinks containing these juices.
• The drug may cause increased skin sensitivity to sunlight and the risk of burns. It is necessary to protect the skin from sunlight. Use sunscreen and wear sun protection clothing. Avoid sun exposure if possible.
• Sexually active patients should use contraceptive methods during therapy and for 6 months thereafter.
• Pregnant or breastfeeding patients should notify their physician.

Tacrolimus home use:

• Tacrolimus can be taken with or without food. If the drug causes stomach upset, it must be taken with food.
• It is important to follow the order of taking every day. Taking the drug at the same time every day in compliance with the diet (eating strictly at the same time before or after taking the drug) allows you to maintain a constant level of tacrolimus in the body.
• Capsules should be swallowed whole. Do not cut, crush or chew the capsules.
• Store at room temperature.
• If vomiting occurs within 30 minutes of taking oral tacrolimus, take another dose.
• Liquid tacrolimus must be shaken before use. To hide the taste of the drug in liquid form, it can be mixed with orange or apple juice (room temperature) in a glass and mix well. Take immediately after mixing. After that, pour some more juice into the glass, shake slightly and drink. Do not take tacrolimus with grapefruit juice.
• Take your dose as soon as possible if you miss it. Do not do this only if there are no more than 4 hours left until the next appointment. In no case do not double the dose at the next dose!
• Do not use an expired drug.
• Follow instructions for safe handling, storage and disposal.

More about tacrolimus

• Sex life on therapy
• Protecting caregivers from the adverse effects of drugs
• CYP3A5 and drugs

More about tacrolimus

Tacrolimus in the pathogenetic therapy of chronic dermatosis

At present, the results of studies have confirmed the role of immune mechanisms as the most significant in the pathogenesis of a number of chronic dermatoses, including atopic dermatitis (AtD), a genetically determined disease that is under the active influence of various endogenous and exogenous environmental factors. As is known, various kinds of environmental factors (environmental, social, etc.), dysmetabolic processes, infectious, helminthic-protozoal agents, etc. are significant in the formation of immunopathological processes.

According to the WHO [1], over the past decades, the number of patients with various clinical forms of allergy, with the most common skin manifestations, and primarily AD, has been increasing. The incidence of AD over the past 16 years has increased by 2.1 times. The prevalence of AD among children is up to 20%, among adults – 1-3%. In 60-70% of children, AD begins in the first months of life and continues for many years. Chronic staged course of dermatosis, severe itching that accompanies the disease, have an adverse effect on the emotional, mental and physical development of children. The proven influence of hereditary predisposition to the development of allergic dermatosis suggests the danger of a further increase in the number of patients.

Dermatologists, pediatricians, allergists experience significant difficulties in prescribing therapy for patients with allergic dermatosis, often receiving only a temporary improvement in the process. Treatment of AD should be strictly individualized, taking into account the duration of the disease, the phase of relapse, the degree of activity of the process and its clinical form, the constitutional features of the patient, comorbid pathological conditions, and the presence of complications.

The treatment of AD is almost always complex, and one of the leading places in it is occupied by local therapy. At all stages of the complex therapy of AD patients, it is necessary to take into account not only the local effect of external therapy, but also their resorptive effect. Modern methods of therapy for AD patients are aimed at suppressing the inflammatory response in the skin caused by disorders of T-cell immunity and cytokine production characteristic of AD. Timely rational administration of topical glucocorticosteroids (GCS) is a significant moment in the relief of skin manifestations of allergies and the transformation of an acute form of the disease into a chronic one. However, do not forget about the phenomenon of “steroidophobia”, which is associated with the occurrence of side effects from the improper use of topical corticosteroids. For effective topical therapy of AD, it is recommended to shorten the duration of GCS prescription as much as possible and, at the same time, lengthen the remission period, which is possible when prescribing a modern, effective and safe drug for external use. Such an important class of drugs are topical calcineurin inhibitors, non-steroidal cell-selective inhibitors. S. Reitamo et al. [2] showed that the efficacy of tacrolimus is comparable to that of class III topical corticosteroids.

Immunotherapy is a variety of ways to influence the immune system in order to stop the pathological process. Immunosuppressants are classified as clinical immunosuppressants. These are drugs that suppress the immune response, including drugs, various agents of a biological or chemical nature that suppress immune processes. A significant achievement in the process of improving immunosuppressants was the creation of the drug cyclosporine A. Further from Streptomyces inflatum , the substance FK506 was isolated with a different structure, but a very similar mechanism of action. Once in the cell, FK506 binds to its receptor, the FKBP protein, and affinity for calcineurin arises. As a result of complex biochemical processes, an active dimer is formed – a transcription factor capable of interacting with the DNA of regulatory regions of the IL-2 gene and a number of other cytokines. When binding the complex of immunophyllin and FK506 with calcineurin, the latter loses the ability to be activated and dephosphorylate NF-AT _c (transcription factor subunit), which leads to blockade of the entire further chain of processes, including the expression of the IL-2 gene. Thus, FK506 blocks the activation of T-lymphocytes and the production of IL-2, which suggests the use of the drug in the treatment of autoimmune pathology [3–5, 8–10]. In experiments in vitro, factor suppressed the proliferation of T-lymphocytes, the synthesis of pro-inflammatory cytokines interleukins 2, 3, and interferon-gamma [4].

The development of topical calcineurin inhibitors (TCIs) began after the proven positive anti-inflammatory effect of the systemic drug cyclosporine A, a highly active T-cell inhibitor, in the treatment of eczematized dermatitis and psoriasis at the end of 90s of the XX century [1]. Based on FK-506, topical drugs have been developed – tacrolimus and pimecrolimus.

Tacrolimus is a macrolide lactone isolated from Streptomyces tsukubaensis [9]. Tacrolimus inhibits a number of key cells involved in the development of AD — T-cells, Langerhans cells, mast cells, keratinocytes, it has a selective immunomodulatory effect and a pronounced anti-inflammatory activity comparable to that of medium-strength glucocorticosteroids [2, 6, 10].

The immunotropic effect of tacrolimus is due to its effect on signal transduction pathways and inhibition of gene transcription. In fact, tacrolimus is a prodrug, causing inhibition of gene transcription and, as a result, a reduced T-cell response to antigens [10]. Tacrolimus has a wide spectrum of immunotropic action in various skin diseases due to binding to surface cellular glucocorticoid receptors and inhibiting mast cell adhesion, suppressing the release of inflammatory mediators from mast cells and basophils, reducing the expression of the intercellular adhesion molecule ICAM-1 and E-selectin, as well as inhibiting the expression of the IL-8 receptor and the high-affinity surface receptor for immunoglobulin E on Langerhans cells [11].

Despite the relatively large molecular weight (822 D), the absorption rate of tacrolimus when applied to intact skin is 3.1; 4.9 and 6.8 ng/cm ² /h for an ointment with an active substance concentration of 0.03, 0.1 and 0.3%, respectively [7]. It should be noted that the absorption of tacrolimus does not depend on occlusion and is significantly higher when it is applied to damaged skin – 40 ng / cm ² / h. Thus, in the course of topical therapy, the patient’s skin will absorb less and less tacrolimus as he recovers. This ability to self-regulate is a clear advantage of tacrolimus, as it reduces the risk of adverse reactions during the course of treatment [12].

Moderate to severe AD is the main indication for the use of tacrolimus in dermatology. The clinical efficacy of the drug has been demonstrated in a significant number of clinical trials and wide clinical use. Also, long-term use (up to 4 years) shows a high level of safety and high clinical efficacy of tacrolimus, in particular, in AD without the risk of skin atrophy and other side effects [13].

The efficacy and safety of tacrolimus has been proven by many randomized controlled clinical trials [13-17]. The results of a number of pharmacokinetic studies of tacrolimus in children and adults indicate its minimal absorption into the systemic circulation, no effect on the hypothalamic-pituitary-adrenal system. With long-term use in the treatment of adult patients for up to 1 year, there was no accumulation of tacrolimus in the skin and blood serum, no effect on the content of ceramides in the stratum corneum, and no atrophogenic effect [15]. The use of tacrolimus ointment (0.1 and 0.03%) for 12 weeks of therapy led to a significant improvement in the clinical symptoms of the disease in 351 children aged 2–15 years with moderate to severe AD: improvement was observed at the end of treatment in 72.6% of patients who used tacrolimus ointment 0.03%, in 78% of patients in the treatment of which 0.1% tacrolimus ointment was used, compared with 26.7 % of patients in the placebo group [15]. The results of a comparative study of the efficacy and safety of long-term use of tacrolimus in 568 adult patients showed a pronounced regression of AD symptoms after 6 weeks of therapy in 85% of cases, after 26 and 52 weeks – in 91% of cases, while maintaining high efficacy of the drug for 2 years of observation [14].

Comparative studies have been conducted on the efficacy and safety of tacrolimus and pimecrolimus in children and adults with AD [15]. In randomized, double-blind trials, 1065 patients with AD of varying severity took part, who used 0.1% (adults) and 0.03% (children) tacrolimus ointment versus 1% pimecrolimus cream 2 times a day for no more than 6 weeks. Tacrolimus treatment resulted in a greater reduction in EASI than pimecrolimus in all groups, with significant differences for adults and children with moderate to severe AD. Clinical efficacy (disappearance or almost complete disappearance of manifestations of dermatosis) was observed in 45.7% of adults using tacrolimus ointment, compared with 27. 1% of patients using pimecrolimus cream (p p

One of the significant properties of topical calcineurin inhibitors is their antipruritic effect, which prevents or minimizes scratching of the skin, which in turn leads to increased inflammation, secondary infection of the skin and progression of the severity of AD. Adult patients with AD noted a decrease in the severity of itching in the tacrolimus group on the 3rd day from the start of treatment [19].

Topical calcineurin inhibitors are especially important in the treatment of AD with localization in the periorbital region, where the absorption of topical corticosteroids is the highest and there is a risk of increasing intraocular pressure during long-term therapy. Researchers have shown colonization of the skin Staphylococcus aureus in 80-100% of patients with AD, in addition, a significant decrease in the degree of colonization St was found. aureus by prescribing tacrolimus as early as the 1st week of therapy [20]. It has been noted that tacrolimus has an antifungal effect against Malassezia f urfur [6, 20–22].

Short-term therapy with 0.1% tacrolimus ointment (for 3 weeks) has been shown by SCORAD and immunohistochemical studies [23] to improve the clinical course and reduce the expression of Toll-like receptors (TLR) in the skin, which can inhibit the antimicrobial potential of TLR-2 in AD foci.

The discussion on the increased risk of malignancy as a result of systemic and possibly topical use of calcineurin inhibitors has ended. Independent American and European experts specializing in dermatology, epidemiology, and oncology (post-transplantation and pediatrics) have proven that there is no association between the use of tacrolimus and an increased risk of tumor development [23, 24].

Foreign clinical guidelines [25] indicate possible options for the combined use of topical corticosteroids (TGCS) and TECs, both sequentially and in combination for external therapy of AD. There are a number of comparative trials [26] on the effectiveness of the combination of TECs and TGCS, in which the drugs were used sequentially or in parallel. The simultaneous use of 0.1% tacrolimus ointment with dexamethasone ointment achieved a better effect compared to that with tacrolimus monotherapy or with a combination of 0.1% clocortolone cream and 0.1% tacrolimus ointment [27, 28]. However, J. Spergel et al. [29] conducted a 2-week study of the comparative efficacy of fluticasone propionate 0.05% cream in combination with pimecrolimus and TGCS alone in exacerbations of AD. The authors found no benefit from the addition of pimecrolimus to the treatment regimen, which may be due to the short course of therapy and the lower efficacy of the drug than tacrolimus.

Tacrolimus is the only topical drug from the TEC group recommended in the Russian Federation for maintenance therapy [1]. During proactive therapy with 0.03% tacrolimus, 257 (54%) children had no exacerbations requiring treatment for 12 months, against 29. 6% with placebo. The result of maintenance therapy with high reliability ( p ppp Results of the CONTROL study on the use of tacrolimus in the proactive regimen.

There is evidence of a reduction in the number of exacerbations of AD with long-term use of tacrolimus. The study was conducted over 2 years in 19 US medical centers. It involved 206 patients aged 2 to 15 years. The main aim of the study was to evaluate the efficacy and safety of intermittent administration of tacrolimus to reduce and prevent recurrence of AD. Based on the data obtained, it was concluded that long-term intermittent (3 times a week) administration of tacrolimus ointment to children suffering from moderate to severe AD is a new way to control the course of this disease. Long-term follow-up of more than 5000 children has shown that tacrolimus is effective, absolutely safe and has minimal systemic absorption [32].

A very wide range of application of tacrolimus ointment in chronic dermatoses, which is proved by the results of the work of domestic and foreign dermatologists. The immunotropic drug tacrolimus is highly effective and safe, comparable in strength to strong TGCS. The clinical efficacy of the drug has been proven in the course of course and maintenance therapy with an increase in the period of remission. The diverse immunotropic effect of tacrolimus suggests its topical use in various dermatoses. Foreign dermatologists [33, 34] effectively prescribed tacrolimus in the treatment of not only AD and other allergic dermatosis, but also in the topical therapy of autoimmune diseases — various clinical forms of psoriasis.

E. Martin et al. [35] used tacrolimus ointment (0.03 and 0.1%) in the topical treatment of psoriasis of the skin of the face, folds, and trunk. O.Yu. Olisova et al. [36] studied the nature and degree of topical application of 0.1% tacrolimus ointment on the dynamics of morphological and functional changes in the skin in patients with limited forms of psoriasis using non-invasive diagnostic methods. As a result of observation of 30 patients with psoriasis, the authors noted the restoration of the normal morphological structure of the skin, clinical efficacy and an increase in remission by 1. 8 months.

O.Yu. Olisova, N.G. Kochergin et al. [37] used 0.1% tacrolimus ointment in monotherapy in patients with AD, limited forms of psoriasis, seborrheic dermatitis, and in combination therapy of vitiligo and rosacea. The authors noted the effect of the treatment of all diseases with good tolerability of tacrolimus, improving the quality of life of patients.

N.N. Potekaev et al. [38] found a significant decrease in scleroderma activity in patients with limited forms and complete remission with an erythematous stage of plaque formation as a result of topical application of 0.1% tacrolimus ointment.

It was clinically effective and safe to use tacrolimus in the treatment of manifestations of lichen planus on the skin and mucous membranes, vitiligo, as an alternative treatment for persistent cutaneous erythematosis, alopecia areata, rosacea, skin lymphoma and sarcoidosis, and other dermatoses [39–46].

The general recommendations for prescribing TECs [1] indicate the method of using tacrolimus: for adults, 0. 03 and 0.1% ointment, and for children aged 2 years and older, apply 0.03% ointment in a thin layer on the affected surface 2 times a day; when the skin condition improves, it is possible to reduce the frequency of applying 0.1% ointment or switch to 0.03% ointment; in case of recurrence of symptoms of the disease, treatment with tacrolimus 0.1% ointment 2 times a day should be resumed.

Tacrolimus is recommended for the maintenance treatment of AD (moderate and severe) 2 times a week, applied to the most recurrent skin areas, in patients with exacerbations of more than four episodes per year in order to prevent new exacerbations and prolong the period of remission. This therapy is indicated only in patients in whom prior treatment with tacrolimus has resulted in complete or near-complete resolution of the skin process when using the drug on a twice daily regimen for no more than 6 weeks. There are no data on the similar use of pimecrolimus.

After 12 months of maintenance therapy, it is necessary to evaluate the dynamics of clinical manifestations and decide on the advisability of continuing the use of tacrolimus.

There are few studies in the literature evaluating the efficacy of tacrolimus ointment in patients with perianal manifestations of Crohn’s disease (CD). S. Rice et al. [47] conducted a randomized trial to evaluate the efficacy of 0.1% tacrolimus ointment in perianal CD lesions. The study included men and women aged 18 to 66 years with a diagnosis of CD confirmed by clinical, radiological, and endoscopic methods. At the time of the study, patients received therapy with drugs of the 5-ASA group, oral steroids, methotrexate, imuran, antibiotics, and biological therapy. The study included 19patients who were divided into two groups. In patients of the 1st group, perianal lesions were in the form of fistulas, those of the 2nd group were ulcers and fissures. The duration of treatment was 12 weeks. The pain syndrome, the depth of cracks, and the quality of life of patients were assessed using the IBDQ questionnaire. Of the 12 patients in Group 1, 6 received topical tacrolimus therapy and 6 received placebo. Of the 7 patients in Group 2, 4 received tacrolimus ointment and 3 received placebo. In the 1st group, by the end of the study, of the patients who received tacrolimus, only 1 patient had CD remission, another 1 showed clinical improvement. In the 2nd group, with the local use of tacrolimus ointment, the pain syndrome disappeared, the depth and area of ​​the lesion decreased, and the quality of life improved in 3 out of 4 patients. Thus, based on the results of this study, it can be assumed that the use of tacrolimus ointment is an effective therapy for such perianal CD lesions as fissures and ulcers.

Skin manifestations are noted in 44% of CD patients; they significantly affect the quality of life of patients. There are three most common skin manifestations of CD: perianal lesions with the development of fissures and fistulas, peristomal pyoderma gangrenosum, and granulomatous cheilitis [48]. Granulomatous cheilitis is characterized by slowly developing swelling of one or both lips, the upper lip being more commonly affected. Other areas of the face and gums may also be involved in the process. The lips acquire a doughy texture, their edges turn inside out and protrude, when pressed on them, there is no fossa. Scales and cracks appear on the surface. These lesions are early extraintestinal manifestations of B.C. Thus, granulomatous cheilitis may coincide with or precede the onset of CD [48]. Peristomal pyoderma gangrenosum manifests as painful erythematous macules or nodules, pustules, or vesicles, followed by the formation of ulcers in the peristomal region [48]. In this regard, S. Rice et al. [47] investigated the effectiveness of tacrolimus ointment in various skin manifestations of B.K. This was an open study that included 20 patients with cutaneous manifestations of CD. 9(45%) of them had perianal lesions, 5 (25%) had granulomatous cheilitis, 2 (10%) had pyoderma gangrenosum, and 1 (5%) had peristomal pyoderma gangrenosum. Three (15%) patients had perianal lesions in combination with peristomal pyoderma gangrenosum. The age of the patients ranged from 12 to 66 years, among the participants were 12 men and 8 women. Patients used 0.1% tacrolimus ointment daily for 12 weeks. After 12 weeks, the effectiveness of the therapy was evaluated. In total, therapy was carried out for 12 months. The evaluation was performed according to the BC activity index (IABI). Adverse reactions from therapy were also evaluated. Of the 20 patients, 17 (85%) during 12 weeks of treatment showed an improvement in 4 points out of 6 according to IABA, 3 (15%) patients did not have an effect from the therapy, 5 (25%) patients had a relapse of the disease after discontinuation of the drug after 12 weeks, 1 (5%) patient withdrew from the study due to the development of side effects. In 3 (15%) patients with granulomatous cheilitis, the disease relapsed after discontinuation of the drug after 12 weeks, 2 (10%) patients withdrew from the study due to the development of adverse reactions. Patients with pyoderma gangrenosum and peristomal pyoderma gangrenosum experienced a relapse of the disease after discontinuation of the drug after 12 weeks. The results of the study showed that tacrolimus ointment in perianal manifestations of CD is effective only with long-term use. With the abolition of the drug, a relapse of the disease occurs. The effect of therapy was obtained in patients with pyoderma gangrenosum, in which a decrease in inflammation and healing of ulcers was noted. In perianal lesions of CD, long-term use of tacrolimus ointment is necessary as maintenance therapy after a positive result is obtained. The use of tacrolimus in pyoderma gangrenosum for 12 weeks gives a positive result, but its long-term use is also required [48]. These data indicate that tacrolimus ointment, when used at low concentrations, is effective in the treatment of perianal CD lesions and peristomal pyoderma gangrenosum. However, the use of tacrolimus ointment is not effective for fistulas. Patients with granulomatous cheilitis showed an improvement in clinical symptoms and a decrease in the frequency of relapses [48]. The effectiveness of topical application of tacrolimus ointment was noted in 85% of patients with skin manifestations of CD [48]. However, detailed studies of the effectiveness of this type of treatment in patients with CD are needed.

The pharmaceutical company Akrikhin JSC has released a new drug Tacropic from the TEC group with the active ingredient tacrolimus. Tacropic is used as 0.03% and 0.1% ointment in adults and 0.03% ointment in children aged 2 years and over for the treatment of moderate to severe forms of AD.

Tacropic differs from other tacrolimus preparations by the introduction of a patented hydrophilic base into its composition (patent No. 2538680 C2). The hydrophilic dosage form allows the drug to be used in acute and subacute inflammatory processes, on foci of inflammatory infiltration, hyperemia and edema. Tacropic , due to the effect of additional moisturizing, has advantages in long-term use of the drug, it can be used on any part of the skin, which increases the adherence of patients to treatment.

Tacrolimus is a highly effective and safe drug from the TEC group in the treatment of AD in children and adults [1, 12, 18].