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Systematizing two decades of global experience in the off-label use of tacrolimus ointment. Part I.

1.    Introduction
Since the introduction of topical glucocorticosteroids (TCSs) into dermatological practice, which revolutionized the treatment of a wide range of inflammatory, allergic, and autoimmune skin diseases, several new important classes of topical medications have emerged, including retinoids, vitamin D analogues, Janus kinase inhibitors, phosphodiesterase inhibitors, aryl hydrocarbon receptor agonists, etc. Among them, topical calcineurin inhibitors (TCIs) occupy an important place, becoming the first real alternative to TCSs in 50 years in terms of the potency of their anti-inflammatory and immunosuppressive effects, but without the side effects characteristic of glucocorticosteroid hormones [1-4]. The first and most active representative of the TCI class was tacrolimus in the form of an ointment (Protopic®) [5, 6], registered for the treatment of moderate to severe atopic dermatitis in 2000 in Japan, in 2001 in the US, in 2002 in the EU, and in 2011 in the Russian Federation.

To date, a vast evidence base has been accumulated on the use of tacrolimus ointment for the treatment of atopic dermatitis, including several meta-analyses summarizing data from numerous high-quality double-blind randomized controlled clinical trials involving a total of tens of thousands of patients [6-11], which provides the highest level of evidence from the perspective of evidence-based medicine; thus, it is included in the Russian federal clinical guidelines for the treatment of atopic dermatitis with a level of confidence and reliability of recommendations of 1A [12]. 

At the same time, for a number of reasons, mainly commercial in nature, the manufacturers of tacrolimus ointment and pimecrolimus cream (Astellas and Novartis, respectively) did not invest in a program of clinical trials of these drugs for the treatment of other skin diseases, which is necessary for the registration of new indications. At the same time, the mechanism of action (selective suppression of the T-cell immune response) pathogenetically justifies the use of TICs in a wide range of other dermatoses, and accumulated clinical experience, including a large number of high-quality randomized trials conducted by independent research groups, indicates the efficacy and promise of TIC use for many other indications besides atopic dermatitis.

In 2013 and 2014, Professors Olisova O.Yu. et al. [13] and Kruglova L.S. et al. [14] published two excellent literature reviews on the use of tacrolimus ointment for off-label indications; Similar works can also be found in foreign literature, for example, Hengge UR, 2013 [15]. At the same time, over the past decade, a large amount of new clinical data on this topic has been accumulated, which makes it necessary to systematize it in a new review.

2.    Tacrolimus – general information
When discussing the class of calcineurin inhibitors, it is necessary to characterize the immunophysiological role of their key target – calcineurin serine-threonine phosphatase, which is widespread in eukaryotic cells and plays an important and multifaceted biological role. Calcineurin has many substrates, including transcription factors (in particular, NFAT, FOXO, MEF2, TFEB), a number of receptors and their channels, some mitochondrial proteins, including those involved in the regulation of cell death processes, and microtubules, which determines its importance for a number of systems and their functions; These include higher nervous activity (learning, memory), the physiology of the cardiovascular system, kidneys, muscle fiber development, and, of course, the immune system [16-19]. 

The most important role of this phosphatase in terms of human physiology and the pharmacodynamics of calcineurin inhibitor drugs is its role in the immune response. Activation of the T-cell receptor after antigen presentation to a naive T-lymphocyte by an antigen-presenting cell triggers a signaling cascade that activates phospholipase C-gamma, which hydrolyzes phosphatidylinositol-4,5-bisphosphate to form secondary messengers, diacylglycerol, and inositol-1,4,5-trisphosphate; the latter binds to receptors located on the endoplasmic reticulum and causes the release of calcium ions into the cytoplasm. An increase in the cytoplasmic concentration of calcium leads to the activation of calcineurin, forming a “calcineurin + calcium + calmodulin” complex, which causes the dephosphorylation of the cytoplasmic fragment of transcription factors belonging to the NFAT family (Nuclear Factor of Activated T-cells) family. It should be noted that the NFAT family of factors in its hyperphosphorylated form is the main substrate for calcineurin in immune cells, as well as cardiomyocytes and skeletal myocytes. De-phosphorylation of NFAT causes conformational changes that enable the translocation of these factors into the cell nucleus and also increases their affinity for certain DNA sequences. This is followed by the translocation of NFAT to the nucleus, where the factor interacts with regulatory elements, stimulating the expression of genes key to the T-cell immune response of cytokines and chemokines, including IL-2,3,4,5,13,17, IFN-γ, TNF-α, etc. In order for NFAT to remain in an activated state, constant calcineurin activity is required; a decrease in cytoplasmic calcium levels (e.g., upon cessation of antigenic stimulation) or pharmacological inhibition of calcineurin leads to NFAT dephosphorylation and its removal from the cell nucleus back into the cytoplasm [19-23]. 

Based on the mechanism described above, it is clear that inhibition of calcineurin will prevent the activation of NFAT factors and, thus, the activation of T lymphocytes, preventing the development of a T-cell immune response. This premise formed the basis for the emergence of a new class of immunosuppressive agents—calcineurin inhibitors. 
The first representative of this class was cyclosporine, discovered in 1976, which has a slightly different mechanism of action from tacrolimus but leads to the same result—calcineurin inhibition. Its use in transplantology was a real game changer because it caused powerful T-cell suppression but, unlike methotrexate, azathioprine, and other drugs used before, it didn't have cytostatic properties and had almost no myelotoxic effect [20, 24, 25].

In 1983, the Japanese company Fujisawa opened a research laboratory in Tsukuba Science Park, focused on finding biologically active metabolites with immunomodulatory properties. Using a mixed lymphocyte reaction for evaluation, the laboratory screened more than 10,000 samples of metabolites produced by microorganisms obtained from soil, and in 1984, a representative of the Streptomyces genus, Streptomyces tsukubaensis (the species was named after the mountain where it was discovered), which produced a macrolide compound that demonstrated a powerful immunosuppressive effect. This compound was given the code FK506 and later the INN tacrolimus; This INN is, in fact, an abbreviation in which T is taken from the English spelling of the name of Mount Tsukuba, -acrol- from macrolide, and -imus from immunosuppressant [1, 26, 27]. In addition, two macrolide compounds produced by Streptomyces hygroscopicus strains were isolated, which also had the ability to inhibit calcineurin; however, they had much less immunosuppressive activity than tacrolimus, and therefore their development was discontinued [28, 29]. Nevertheless, this species, Streptomyces hygroscopicus, was later used to obtain a compound that was assigned the INN pimecrolimus; despite being three times less active than tacrolimus (in one publication it was called a “minor variant of tacrolimus” [4]), this agent also found its place in clinical practice [4, 30].

I would like to clarify the terminology regarding the term “macrolide,” as HCPs most often associate it with antibiotics. Macrolides are chemical compounds that have a macrocyclic ring of carbon atoms in their structure, closed by lactonization. The term “macrolides” was originally proposed by Woodward to refer to antibiotics with a macrocyclic lactone structure [31], but it later acquired a broader meaning [32-34]. At the same time, many macrolides have immunomodulatory and anti-inflammatory effects in addition to their main antibacterial or antifungal properties: for example, a wide range of such effects has been described for antibiotics such as erythromycin, clarithromycin, and roxithromycin [35].

The question also arises as to what evolutionary significance is inherent in the production of calcineurin-inhibiting compounds by prokaryotes. The fact is that these producers compete for habitat and food resources with eukaryotes—fungi that use calcineurin in their cell cycle; inhibiting fungal calcineurin hinders their growth and gives a competitive advantage [4, 36, 37]. In fact, for this reason, calcineurin inhibitor drugs demonstrate some antifungal effect as a “positive side effect”; Thus, in the early stages of tacrolimus research, it was demonstrated that it had high activity against Fusarium oxysporum and Aspergillus fumigatus, but had no activity against dermatophytes and yeasts [38]. Later, its activity against fungi of the genus Malassezia was discovered [4, 39, 40], which increases the value of tacrolimus in the off-label treatment of seborrheic dermatitis and pityriasis versicolor, as well as in the treatment of atopic dermatitis affecting the face and neck, where sensitization to these fungi plays a particularly significant role [41]. 

The compound obtained by Fujisawa scientists, tacrolimus, demonstrated very high immunosuppressive activity in vitro: when comparing its ability to suppress mixed lymphocyte reactions with cyclosporine A and prednisolone, the IC50 values (inhibitory concentration suppressing the reaction by 50%) in a mouse model were 0.32 nmol for tacrolimus, 27 nmol for cyclosporine, and 17 nmol for prednisolone, while in the human model, the values were 0.22 nmol, 14 nmol, and 80 nmol, respectively, i.e., the immunosuppressive activity of tacrolimus exceeded that of the comparators by orders of magnitude. Subsequent studies on the ability to inhibit the cytotoxic response of T lymphocytes by suppressing the expression of IL-2 and its receptor yielded IC50 values of 0.1 nmol for tacrolimus and 10 nmol for cyclosporine, i.e., the activity of tacrolimus was 100 times higher [26, 38, 42]. 

This information laid the fundamental basis for the systemic use of tacrolimus in transplantology—the main pathogenetic role in transplant rejection is played by T-cell reactions mediated by CD8+ cytotoxic lymphocytes and “conductors” - Th1 cells. In 1989, clinical trials of tacrolimus in transplantology began, and in 1993 it was first registered under the trade name Prograf®, becoming a new revolution in this field of medicine - its efficacy significantly exceeded that of its predecessor, cyclosporin A [1, 43, 44]. Subsequently, the efficacy of systemic therapy with tacrolimus was demonstrated in a wide range of autoimmune diseases, including dermatological ones — this was, in principle, expected, given their T-cell pathogenesis [1, 45, 46]. It is noteworthy that in the early stages of research on pimecrolimus, attempts were also made to use it systemically, but these were later abandoned—pimecrolimus is now used only topically [47, 48].  

A kind of “happy accident” for dermatology was the unexpected positive side effect observed in transplant patients receiving systemic therapy with tacrolimus: in the presence of background atopic dermatitis or psoriasis, a marked improvement was noted [1, 49]. Based on this observation, the concept of topical tacrolimus for the treatment of various skin diseases, while avoiding systemic side effects, was born. In 1996, clinical trials of tacrolimus in ointment formulation began, and at the beginning of the 21st century, it entered the global market under the trade name Protopic®. The trade names Prograf® and Protopic® have a specific meaning: “graf” in the name of the systemic drug Prograf® is taken from the English word “graft” (transplant), i.e. “Pro-graf” = “for graft,” and “topic” in the name Protopic® comes from the English word ‘topical’ (“local, external”), “Pro-topic” = “for topical application.”

How does tacrolimus work? In order to exhibit calcineurin-inhibiting activity, it must first bind to a protein of the FKBP (FK Binding Protein) family, also known as immunophilin-12 [4, 20, 49]. For reference, immunophilins are endogenous cytosolic peptidyl-prolyl cis/trans isomerases (PPI) involved in protein folding and many other cellular functions [20, 50]. The tacrolimus + immunophilin-12 complex inhibits calcineurin, preventing the dephosphorylation of the transcription activation factor NFAT and, thus, its translocation into the nucleus, which prevents lymphocyte activation and the expression of a wide range of pro-inflammatory cytokines (see Fig. 1b) [4, 20, 49]. This fundamentally distinguishes the mechanism of action of tacrolimus from that of glucocorticosteroids, which are non-selective immunosuppressants and also cause multiple endocrine and metabolic effects (see Fig. 1a) [51, 52].

Figure 1a. Glucocorticosteroids mode of action. Non-selective immune suppression, multiple endocrine and metabolic effects.

Figure 1b. Tacrolimus mode of action. Selective T-cell immune suppression.

The differences in the mechanism of action explain an important difference between tacrolimus and TCS – the absence of side effects characteristic of GCS, including atrophogenicity and negative effects on the morphofunctional characteristics of the epidermal barrier. Unlike the latter, tacrolimus ointment therapy improves the structure and thickness of the epidermis, does not have a negative effect on collagen synthesis, increases hydration, integrity, and cohesion of the stratum corneum, reduces protease activity and pH in it, leads to a decrease in transepidermal water loss, and has a positive effect on the length of lipid membranes in the intercellular spaces of the stratum corneum (see Table 1) [53, 54]. This valuable property makes it possible to use tacrolimus ointment for a much longer period of time than TCS, including for maintenance therapy, which is important for many dermatoses with a chronic recurrent course. 

* OCT, optical coherence tomography; ** TEM, transmission electron microscopy; *** Na-PCC, sodium pyrrolidone carbonate; **** ELISA, enzyme-linked immunosorbent assay.

At the same time, tacrolimus ointment also has some side effects specific to the TCS class; the most typical of which are burning and skin hyperemia in the first days of treatment, observed in many patients. They are associated with the release of neurotransmitters, in particular substance P, from the neurosecretory granules of sensory nerve endings in the skin—one of the proposed mechanisms is TRPV1 phosphorylation; Subsequently, as neurotransmitter reserves are depleted, the burning sensation is levelled out and an antipruritic effect is achieved [55, 56]. This side effect limits the use of tacrolimus ointment as initial therapy for acute inflammatory processes, where it may be exacerbated; in such cases, it is preferable to start treatment with TCS, with the possibility of switching to tacrolimus ointment later.

3.    Off-label use of tacrolimus ointment
Medical science knows hundreds of skin diseases whose pathogenesis is based on disorders of the T-cell immune response, in which the use of a selective T-cell immunosuppressant is scientifically sound and clinically justified. It is not surprising that the emergence of the TIC class has attracted great interest from the medical community, leading to the accumulation of experience in the use of drugs in this class that goes far beyond the approved indications. The evidence base accumulated to date has allowed tacrolimus ointment to be included in numerous clinical guidelines covering a wide range of nosological entities (see Table 2) [57-60]. 
Below is information on the accumulated experience of using tacrolimus ointment for specific skin diseases. 

Table 2. Representation of tacrolimus ointment in clinical guidelines. The GLs of the Russian Society of Dermatovenerologists and Cosmetologists, the European Academy of Dermatology and Venereology (EADV), the European Dermatology Forum (EDF) and the German Society of Dermatology (DDG) were analyzed

* Eczema of the hands

3.1    Use of tacrolimus ointment for vitiligo
Vitiligo is a chronic disease of unknown etiology characterized by the appearance of depigmented patches and discolored hair on various parts of the body due to the destruction and reduction of melanocytes in the skin. 
Although there are a number of theories regarding the pathogenesis of vitiligo, including oxidative, neurohumoral, and some others, autoimmune mechanisms are currently considered to play a leading role—about 85% of genes associated with a predisposition to vitiligo encode genes that are in one way or another related to the immune response [61]. From the point of view of pathogenesis, autoreactive CD8+ cytotoxic T lymphocytes and the key cytokine they produce, INF-γ, which induces the production of chemokines CXCL9 and CXCL10 by keratinocytes, are considered to be the main cell population. the latter being necessary for the recruitment of CD8+ lymphocytes to the lesions [62-63]. Moreover, the recurrence rate of vitiligo within a year after repigmentation is 40%; This is associated with the persistence of resident tissue CD8+ memory T cells in the skin, which reactivation leads to the resumption of the pathological process [63]. Thus, the use of calcineurin inhibitors as selective T-cell immunosuppressants in vitiligo is pathogenetically justified. In addition, vitiligo usually requires long-term treatment, so the absence of atrophogenic potential and endocrine effects in tacrolimus ointment is an undoubtful advantage.

From verbal communications with employees of the commercial departments of Astellas and LEO Pharma, the author of this review is aware that in some Central Asian CIS countries, dermatologists prescriptions of tacrolimus ointment for the treatment of vitiligo often exceeded prescriptions for the approved indication, which indicates the high demand for this therapeutic option.
There are so many clinical studies on the use of tacrolimus ointment for vitiligo that even a simple list of them would not fit into the format of a review article; therefore, the focus will be on the results of meta-analyses that systematize the accumulated clinical data.  

Arora CJ et al. [64] conducted a systematic review of randomized clinical trials to evaluate the efficacy and safety of tacrolimus ointment in vitiligo in mono- and combination therapy. A total of 19 studies involving 814 patients were included in the analysis. A meta-analysis of two studies using a random effects model showed that combination therapy with tacrolimus and narrowband ultraviolet B (NB-UVB) is more effective than NB-UVB alone in terms of achieving >75% repigmentation [OR 1.34 (95% CI: 01.05-1.71), P = 0.02]. Tacrolimus and steroids have similar efficacy in terms of this criterion [OR 1.02 (95% CI: 0.19-5.51), P = 0.98]. A meta-analysis of two studies showed that combination therapy with fractional laser and tacrolimus is not superior to tacrolimus monotherapy in achieving repigmentation >75% [OR 2.11 (95% CI: 0.87-5.09), P = 0.10]. The authors state that combining tacrolimus with other treatments, such as steroids, phototherapy, and laser therapy, may be more effective than using tacrolimus alone.

The meta-analysis by Chang HC et al. [65] compared the efficacy of TICS and TCS (as classes) in vitiligo; data from 11 studies involving a total of 509 patients were processed. In the pooled analysis, the efficacy of TICs in achieving repigmentation >50% was lower than that of TCS (OR 0.72; 95% CI, 0.58-0.89); however, TICs were comparable to TCS in achieving repigmentation >75% (OR 0.78; 95% CI, 0.56-1.10). In a subgroup analysis, when TCS were divided into medium-strength and ultra-strong, TIC showed a similar effect in terms of >50% repigmentation compared to medium-strength TCS. In addition, in the treatment of the pediatric group, no difference in repigmentation >50% and >75% was found between TCS and TIK. Subgroup analysis for different TIKs also yielded similar results. Extra-strong TCS showed greater efficacy than TICs in terms of >50% repigmentation, but TICs may be a safer alternative, especially for long-term use.

In a systematic review and meta-analysis by Suo DF et al. [66], the efficacy of tacrolimus ointment and 308 nm excimer laser in the treatment of facial vitiligo in monotherapy and in combination was analyzed; data from 19 studies (n=2085) were processed. It was found that combination therapy with tacrolimus ointment and excimer laser was statistically significantly superior to each of the monotherapy options (P < 0.001 according to the total response rate criterion for both comparisons).

Dong Y et al. [67] devoted their meta-analysis to the efficacy of tacrolimus ointment for vitiligo in combination with phototherapy, including 11 studies covering 588 patients. Compared with phototherapy alone, combined treatment with tacrolimus and phototherapy significantly increased the frequency of excellent response (repigmentation ≥75%) (OR = 1.40, 95% CI 1.16, 1.69; P <0.001) and reduced the frequency of poor response (repigmentation <25%) (OR = 0.37, 95% CI 0.22, 0.61; P = 0.001). However, the frequency of good response (repigmentation 50-75%) (OR = 1.00, 95% CI 0.59, 1.69, P = 1.000) and moderate response (repigmentation 25-50%) (OR = 0.91, 95% CI 0.60, 1.38; P = 0.653) did not differ significantly. Subgroup analysis showed that when lesions were located on the face and proximal extremities, combination therapy had a higher frequency of excellent responses than phototherapy alone. Both NB-UVB and excimer laser, when used in combination with tacrolimus ointment, resulted in a significantly higher frequency of excellent responses than when used as monotherapy. Meta-regression analysis showed that children had a higher frequency of excellent response to treatment. Other demographic and clinical variables, including gender, disease duration, family history, and type of vitiligo, did not influence the efficacy of therapy. The combination of tacrolimus ointment and phototherapy was more effective than phototherapy alone, especially for lesions located on the face and proximal extremities.

In addition to the above data, interesting experimental work demonstrating histological differences in patients receiving narrowband ultraviolet monotherapy and combined NB-UVB and tacrolimus ointment therapy was performed by Gauthier Y et al. [68]. Clinically, in the combination therapy group, in addition to the perifollicular and marginal pattern, intrafollicular repigmentation was observed. Histologically, in the combination therapy group, in addition to the migration of melanocytes from the hair follicle bulb observed in the monotherapy group, dermal melanocyte precursors located in the middle and superficial dermis were detected for the first time. The authors note that tacrolimus may not only potentiate the activation of hair follicles and dermal melanocyte precursors by NB-UVB, but also protect them from autoimmune destruction during migration from the dermis to the epidermis. 

Another systematic review and meta-analysis of the outcomes of vitiligo TIC treatment was conducted by Lee JH et al. [69]. The evaluation criteria were to achieve a weak (≥25% repigmentation), moderate (≥50%), or strong (≥75%) response to treatment. Forty-six studies with a total sample of 1499 patients were included in the analysis. With TIC monotherapy, at least a mild response was achieved in 55.0% (95% CI, 42.2%-67.8%) of 560 patients in 21 studies, at least a moderate response in 38.5% (95% CI, 28.2%-48.8%) of 619 patients in 23 studies, and a marked response in 18.1% (95% CI, 13.2%-23.1%) of 520 patients in 19 studies at a median treatment duration of 3 months (range 2-7 months). In a subgroup analysis for face and neck lesions, at least a weak response was observed in 73.1% (95% CI, 32.6%-83.5%) of patients and a marked response in 35.4% (95% CI, 24.9%-46.0%) of patients. When TIC was used in combination with phototherapy, at least a mild response was achieved in 89.5% (95% CI, 81.1-97.9%) of patients, and a marked response was achieved in 47.5% (95% CI, 30.6-64.4%) of patients. The authors conclude that TIC should be actively used for the treatment of vitiligo, both in monotherapy and in combination with phototherapy.

There are also data on maintenance therapy of vitiligo with tacrolimus ointment on the scheme 2 times a week. Cavalié M et al. [70] conducted a double-blind, randomized, placebo-controlled study that included patients with vitiligo who had previously achieved ≥75% repigmentation. They received therapy with 0.1% tacrolimus ointment (n = 19) or placebo (n = 16) twice weekly for 24 weeks. When analyzing a sample of patients who completed treatment according to the protocol, it was found that re-depigmentation was observed in 40% of foci in patients receiving placebo and only 9.7% in patients receiving tacrolimus ointment (P=0.0075), indicating the efficacy of this approach.

As an illustration, a clinical case of combination therapy with tacrolimus ointment 0.1% and narrowband ultraviolet vitiligo in a 7-year-old boy is presented at Figure 2. 
Figure 2. Combined therapy with tacrolimus ointment (Protopic^® ) 0.1% 2 times a day for 3 weeks, then once a day for 3 weeks, and a course of phototherapy Nb UVB 311 nm 2-3 times a week, 15 sessions, in a 7-year-old child with vitiligo. The case is provided and used with the permission of dermatovenerologist Zelyanina M.I., St. Petersburg.

3.2         Application of tacrolimus ointment in fibrosing connective tissue diseases

 Among dermatoses of this category, the greatest amount of clinical data on the use of tacrolimus ointment was obtained for scleroatrophic lichen and localized scleroderma.

The pathogenesis of localized scleroderma is multifactorial: the main role is attributed to autoimmune disorders, excessive collagen deposition in the skin and subcutaneous tissue, microcirculatory disorders. As a result of trigger factors, T-cells are activated and produce key profibrotic mediators, including transforming growth factor-β, platelet-derived growth factor, connective tissue growth factor, interleukins (IL-4, 6, 8, 17, IFN-γ), and some chemokines. This leads to increased synthesis and deposition of collagen and other connective tissue components in the skin and subcutaneous tissue, impaired regulation of matrix metalloproteinases (MMPs) responsible for collagen degradation, impaired microcirculation. Characteristic histopathologic picture with predominance of lymphocytic infiltrate from CD4+ T-cells and predisposition of scleroderma patients to other autoimmune diseases [71, 72]. Scleroatrophic lichen is considered by many authors as a type of localized scleroderma with predominantly genital skin lesions and has a similar pathogenesis [71, 72]. Thus, drug-induced suppression of the T-cell link corresponds to the pathogenetic features of this pathology.

The first description of clinical study of tacrolimus ointment application in localized scleroderma belongs to Mancuso G and Berdondini RM [73]. There were 7 patients under observation, who for 3 months applied tacrolimus ointment 0.1% twice a day on some foci of scleroderma, and on others - vaseline ointment (control). Three months later, all 7 patients showed complete resolution of early foci and significant improvement of late foci (the latter softened, but atrophic and scarring changes remained) treated with tacrolimus; no dynamics was observed in the foci on which vaseline was applied.

The results were further confirmed in a double-blind randomized controlled trial by Kroft EB et al. [74] with a similar design, where 10 patients with plaque form of localized scleroderma were treated with tacrolimus ointment and vaseline (control) for 4 months. The foci on which tacrolimus was applied showed a positive trend, and the differences with Vaseline were statistically significant based on the assessment of clinical signs (p = 0.019) and on durometry data (p < 0.005).

Finally, Stefanaki C et al. [75] conducted an open trial (n = 13) of external therapy for localized scleroderma with 0.1% tacrolimus twice daily; an immunohistochemical study was additionally performed. Four patients improved less than 25%, two patients improved 50-70%, and the remaining seven patients improved more than 70%. Patients with dense stale lesions responded worse to treatment than patients with less dense and more erythematous lesions. Patients with mild to moderate fibrosis were histologically more likely to improve after treatment, and the lymphocytic infiltrate decreased regardless of the initial degree before treatment. It was concluded that topical tacrolimus therapy can be used in patients with localized scleroderma, especially those with early inflammatory lesions, even as first-line therapy.

Significantly more clinical data have been accumulated on the use of tacrolimus ointment for the treatment of scleroatrophic lichen planus.

Hengge UR et al. [76] conducted a multicenter (10 centers) phase II study of the efficacy and safety of tacrolimus ointment in the treatment of long-term active scleroatrophic lichen planus. Eighty-four patients aged 5 to 85 years with histologically confirmed disease were included; all received treatment with tacrolimus ointment 0.1% twice daily for 16 weeks. The primary endpoint (complete resolution of symptoms) was achieved in 43% of patients after 24 weeks of treatment; partial resolution was achieved in 34% of patients. The maximum effect occurred between weeks 10 and 24 of therapy. Treatment resulted in a significant reduction in total lesion area (P < 0.01) and a significant reduction in total symptom score (P < 0.005). No serious adverse events were observed. Three (9%) relapses were noted during the follow-up period. The authors concluded that tacrolimus ointment is an effective and safe therapeutic option for the treatment of scleroatrophic lichen planus.

Another prospective phase II study by Ebert AK et al. [77], investigated the use of tacrolimus ointment as adjuvant therapy in 20 boys (mean age 9.7 years) with histologically confirmed scleroatrophic lichen, who had undergone penile surgery (complete excision of the foreskin). Tacrolimus 0.1% ointment was applied postoperatively to the penile head and meatus twice daily for 3 weeks. During follow-up of a median duration of 13 months, 2 recurrences were recorded, which were completely resolved after a second 3-week course of tacrolimus ointment.

Two studies by Mazzilli S et al. [78] and Li Y et al. [79] were devoted to the use of 0.03% tacrolimus ointment for the treatment of scleroatrophic vulvar lichen in children (girls aged 4-9 years (n=10) and 4-11 years (n=14), respectively). Both publications noted the efficacy and safety of the treatment.

Funaro D et al. [80] published the results of a randomized double-blind prospective study involving 55 women with scleroatrophic vulvar lichen, who were treated with 0.1% tacrolimus ointment or 0.05% clobetasol propionate for 3 months. Meaningful improvement was noted in both groups, but efficacy was greater in the clobetasol group (P < 0.002). Previously, similar results were obtained by Goldstein AT et al. [81] when comparing clobetasol with pimecrolimus cream - the efficacy of clobetasol was also higher than TIC. At the same time, the question of safety of TCAs of activity class IV remains open, especially in long-term treatment.

In this context, the works devoted to the use of tacrolimus ointment for long-term maintenance therapy of scleroatrophic lichen planus are of interest. Thus, in the above-mentioned study by Li Y et al. [79], after a basic 16-week course of treatment, 9 out of 14 patients continued to receive tacrolimus ointment 0.03% twice a week for 6 months. During follow-up, relapses were noted in 4 of 5 patients who received only the main course of treatment and in only 2 of 9 (22%) who received maintenance therapy. In another study by Kyriakou A et al. [82], men with scleroatrophic genital lichen planus who responded to starting therapy with clobetasol propionate for 8 weeks received maintenance therapy with 0.1% methylprednisolone aceponate cream twice weekly (n = 17) or 0.1% tacrolimus ointment once daily (n = 20) until week 20. By the end of treatment, both groups showed a significant decrease in DLQI and mean visual analog scale score, mean IGA score remained 0; there were no significant differences between the comparison groups.

A noteworthy study on the efficacy of 0.1% tacrolimus ointment in scleroatrophic lichen planus of anogenital and extragenital localization was conducted by Kim GW et al. [83]; 10 and 6 patients were included, respectively. Objective response to treatment was achieved in 9 of 10 patients with genital localization, and only 1 of 6 (partial) with extragenital localization. The authors concluded that tacrolimus ointment is an effective treatment for genital scleroatrophic lichen planus, but cannot be recommended for extragenital localization.

Thus, the data available to date suggest that tacrolimus ointment is a valuable therapeutic option for the treatment of scleroatrophic lichen with anogenital localization in children and adults, including long-term maintenance therapy; the effect of treatment in extragenital localization seems unlikely.

4.      Conclusion

Over the past twenty-five years since the introduction of tacrolimus ointment into clinical practice, the drug has firmly taken its place in the arsenal of dermatologists and related specialists. In the first part of the review the history and stages of development of tacrolimus ointment were considered in detail, which allowed to trace the evolution of views on the possibilities and limitations of topical calcineurin inhibitors. Particular attention is paid to the pharmacological characteristics of the drug, including its mechanism of action, pharmacokinetics and interaction with target cells.

The mechanism of action of TCI - selective immunosuppression of T-cell immune response - determines its efficacy in the treatment of a wide range of dermatoses, the pathogenesis of which is based on the activation of certain subpopulations of T-lymphocytes.

An important part of the first part of the review was the discussion of the problem of off-label use of drugs in dermatology, which reflects the current trends of personalized medicine and the desire to expand therapeutic options for patients with chronic and recurrent skin diseases. Using vitiligo as an example, an in-depth evaluation of the evidence base for the use of tacrolimus ointment outside of its registered indications was performed. The analysis of numerous clinical studies, including randomized controlled trials, confirms the efficacy of the drug in pigmentation restoration, as well as its favorable safety profile in long-term use in adults and children. This allows us to consider tacrolimus ointment as one of the important alternative options for vitiligo therapy, especially in cases when standard therapies prove insufficiently effective or carry a risk of adverse events.

In the future, we can expect a significant expansion of the arsenal of external immunosuppressive therapies - topical inhibitors of Janus kinases, phosphodiesterase-4, aryl hydrocarbon receptor agonists, etc. are undergoing clinical trials and are being introduced into practice, demonstrating similar clinical efficacy, but the important role of tacrolimus ointment will remain for a long time, as the huge evidence base accumulated over 25 years for this drug makes achieving a comparable amount of clinical data a difficult task requiring large-scale investments and many years of study.

Funding source

The manuscript was prepared and published with funding from the author's place of employment.

Authors' participation

D.D. Petrunin is responsible for the search and analysis work and the preparation of the review, as well as for the content and integrity of the entire article.

Conflict of interest

D.D. Petrunin is an employee of LEO Pharmaceutical Products, LLC.

About the authors

Dmitry D. Petrunin

Author for correspondence.
Email: prof.preobrazhenskii@gmail.com
ORCID iD: 0000-0002-6309-7044
SPIN-code: 1315-4785
Scopus Author ID: 7004119209

MD, Cand. Sci. (Med.)

References

Supplementary files