Tacrolimus ointment: summarizing two decades of experience in off-label use. Use in rosacea, seborrheic dermatitis, papulosquamous dermatoses, lupus erythematosus, eczematous dermatoses, alopecia, and other diseases

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Introduction

The first part of this review, published earlier, provided general information on tacrolimus ointment, including its development history, pharmacological characteristics and clinical application features, and discussed the issue of off-label drug use. The evidence base for the use of tacrolimus ointment in the treatment of vitiligo and fibrotic connective tissue diseases was analyzed.

The present, second part focuses on synthesizing the available evidence for its off-label use in rosacea, seborrheic dermatitis, papulosquamous dermatoses (including psoriasis and lichen planus), cutaneous lupus erythematosus, eczematous dermatoses other than atopic dermatitis, alopecia, various less common skin diseases, as well as ocular lesions and even applications in veterinary dermatology.

Use of tacrolimus ointment for unregistered indications (off-label)

Use of tacrolimus ointment in rosacea and perioral dermatitis

Rosacea is a chronic inflammatory dermatosis characterized by facial skin lesions in the form of erythema and papulopustular elements, phymatous and ocular lesions. From the pathogenetic point of view, a leading role is played by activation of innate immunity (in particular, via TLR2 activation) by pathogen-associated molecular patterns associated with the mite Demodex folliculorum and colonizing bacteria Bacillus oleronius; this leads to a local increase in the production of cathelicidin, metalloproteinases, chemokines, and a spectrum of pro-inflammatory cytokines, including IL-6. The latter enhances Th17 differentiation and their production of IL-17, which, in turn, activates the neutrophil response; neutrophil granulocytes and the free radicals produced by them represent an important link in the pathogenesis of the papulopustular subtype of rosacea [1, 2]. This makes treatment aimed at Th17 suppression pathogenetically justified.

Perioral dermatitis is an independent nosological entity manifested by characteristic inflammation and rashes in the perioral area; however, simultaneous occurrence of these two diseases is not uncommon.

Lesions similar to rosacea and/or perioral dermatitis may be a side effect of topical glucocorticosteroid therapy and are known as steroid-induced rosacea and steroid perioral dermatitis.

Although there have been no high-quality randomized clinical trials on the use of tacrolimus ointment for the treatment of rosacea, the literature contains a number of publications describing series of such clinical cases.

For example, Bhat YJ et al. [3] published a case series of 200 cases of severe steroidal rosacea treated with tacrolimus ointment 0.03% in combination with antibiotics or as monotherapy. Most patients showed a good response to combination therapy after approximately 2–3 months of treatment, while symptom relief with tacrolimus alone was observed within 4–6 weeks in patients with mild disease.

Bamford JT et al. investigated the efficacy of tacrolimus 0.1% ointment in an open-label study involving 24 patients (erythematous-teleangiectatic or papulopustular subtype) treated for 12 weeks. Erythema improved significantly (p < 0.05), whereas the number of papulopustular lesions did not decrease [4].

In a case series described by Garg G et al., including patients with erythematous-teleangiectatic rosacea (n = 8) and steroidal rosacea (n = 2), treatment with tacrolimus 0.1% ointment twice daily resulted in complete resolution of the disease after 6 weeks in most patients (60%) [5].

Goldman D described three clinical cases of steroidal rosacea in which erythema, pruritus, and pain completely resolved in all patients after 7–10 days of therapy with tacrolimus 0.075% ointment (not reported) applied twice daily [6].

Ollech A et al. [7] conducted a retrospective study on the use of topical calcineurin inhibitors (TCIs) for the treatment of perioral dermatitis in children. Data from 72 patients were analyzed: 53 received tacrolimus ointment 0.03%, 7 received tacrolimus ointment 0.1%, and 12 received pimecrolimus cream 1%. Forty-eight patients (67%) received TCI monotherapy, 12 (16.7%) received a combination of TCIs and topical metronidazole, 9 (12.5%) received TCIs and a systemic antibiotic, and 3 (4.2%) received all three agents. Complete response was achieved in 68.8% of patients receiving TCI monotherapy, 75% of those receiving TCIs and metronidazole, and 77.8% of those receiving TCIs and a systemic antibiotic. The median duration of treatment with tacrolimus was 30 days, and the time to achieving a partial or complete response was 14 days.

At the same time, the literature contains descriptions of clinical cases of rosacea-form dermatitis as a side effect of TCI therapy; some authors attribute this to increased proliferation of Demodex folliculorum mites due to induced local immunosuppression [8].

Use of tacrolimus ointment in seborrheic dermatitis

Seborrheic dermatitis is a chronic recurrent skin disease manifested by inflammation and desquamation of the skin in areas of sebaceous gland accumulation. A central role in its pathogenesis is attributed to lipophilic yeast fungi of the genus Malassezia, which, through mechanisms of innate immunity (in particular, TLR2, NOD-like receptors, and C-type lectins), induce an inflammatory response and differentiation of dendritic cells with the formation of inflammatory infiltrate. Subsequently, Th2 and Th17 responses are activated, with increased production of the corresponding cytokines [9, 10]. Taking into account the above-described mechanisms of action of tacrolimus, a bidirectional effect is achieved in seborrheic dermatitis—an anti-inflammatory effect and suppression of the T-cell immune response, as well as an antifungal effect against Malassezia fungi.

Data from several high-quality randomized trials are available on the use of tacrolimus ointment in seborrheic dermatitis.

A single-blind randomized comparative study was conducted by Papp KA et al. [11] to evaluate the efficacy of 0.1% tacrolimus ointment (n = 16) and 1% hydrocortisone ointment (n = 14) applied twice daily for seborrheic dermatitis. The primary efficacy measure was the severity of facial seborrhea at the end of treatment (day 84). Treatment efficacy did not differ between the comparison groups (p = 0.86); however, significantly fewer days of treatment were required to achieve an effect in the tacrolimus group. The number of missed treatment days at the first and second visits was 15.6 vs. 7.6 (p < 0.05) and 13.5 vs. 7.7 (p = 0.08), respectively; the main reason for missed applications in the tacrolimus group was the absence of clinical signs of skin involvement.

Kim TW et al. [12] conducted a multicenter, double-blind, randomized, placebo-controlled study in Korea to evaluate the efficacy of 0.1% tacrolimus ointment for maintenance therapy of seborrheic dermatitis. Seventy-five patients who achieved stabilization of the facial skin process after two weeks of treatment with tacrolimus ointment were randomized into three groups receiving 0.1% tacrolimus ointment once weekly, 0.1% tacrolimus ointment twice weekly, or placebo twice weekly for 10 weeks as maintenance therapy. Both tacrolimus-treated groups showed significant improvement in erythema, flaking, and pruritus, which was maintained for 10 weeks (p < 0.001 for both groups compared with baseline), whereas no significant improvement was observed in the placebo group (p > 0.05). The mean recurrence rate in the placebo group was significantly higher than in the tacrolimus-treated groups (p < 0.005); moreover, the recurrence rate was significantly higher in the group receiving tacrolimus once weekly compared with twice-weekly administration (p < 0.005). The authors concluded that a maintenance therapy regimen with tacrolimus 0.1% ointment applied twice weekly is effective in seborrheic dermatitis.

Joly P et al. [13] conducted a comparative multicenter, double-blind, randomized, placebo-controlled study in France to evaluate the efficacy of 0.1% tacrolimus ointment and 1% ciclopiroxolamine cream for maintenance therapy of seborrheic dermatitis. After initial therapy with THX for one week, patients were randomized into groups receiving tacrolimus (n = 57) or ciclopiroxolamine (n = 57) twice weekly for 24 weeks. Relapses were observed in 12 patients receiving tacrolimus (median time to relapse, 91.5 days) and in 23 patients receiving ciclopiroxolamine (median time to relapse, 27 days). The duration of complete remission was significantly longer in the tacrolimus group (p = 0.018).

Use of tacrolimus ointment in papulosquamous dermatoses (psoriasis and lichen planus)

There are data in the literature on the use of tacrolimus ointment in psoriasis and lichen planus. The key role of the T-cell component in the pathogenesis of psoriasis has been known and experimentally confirmed since the early 1980s. Autoantigen presentation (the role of cathelicidin complexes with self-DNA, as well as the melanocytic antigen ADAMTSL5 and KRT17) by dendritic cells and their production of IL-23 lead to Th17 activation and IL-17 production; subsequently, IL-17 and IL-22 become the leading cytokines in the pathogenesis of this dermatosis [14, 15]. The pathogenesis of lichen planus (LP) is less well understood; however, characteristic lymphocytic infiltration by CD8+ and CD45RO+ cells suggests their leading pathogenetic role [16]. Thus, the use of T-cell suppressants appears pathogenetically justified in these dermatoses.

The results of the first experiments with the use of tacrolimus ointment in psoriasis seemed disappointing. After the efficacy of systemic (oral) tacrolimus in the treatment of psoriasis was confirmed in a randomized double-blind placebo-controlled study [17], a pilot randomized study evaluated the efficacy of tacrolimus ointment 0.3% (this concentration was not registered) in plaque psoriasis vulgaris compared with placebo and calcipotriol ointment [18]. At the end of this study, the efficacy of tacrolimus ointment did not differ from placebo and was significantly inferior to that of calcipotriol.

However, it was later found that the low efficacy in plaque psoriasis vulgaris was due to impaired penetration of the large (>800 Da) tacrolimus molecule into the hyperkeratotic plaque. In particular, in a study in which tacrolimus ointment was used in combination with a keratolytic agent (6% salicylic acid gel), treatment efficacy in the group receiving the keratolytic and tacrolimus ointment was significantly higher than in the group receiving the keratolytic and placebo (p < 0.05) [19]. Subsequent confirmation of this hypothesis was provided by the demonstration of much greater efficacy of tacrolimus ointment in psoriasis localized to areas without pronounced hyperkeratosis, such as inverse psoriasis and psoriasis of the face and genital area.

Thus, in an open study by Brune A et al. [20] involving 11 children aged 6–15 years with psoriasis of the face and skin folds, treatment with tacrolimus ointment 0.1% was effective in all patients without exception. Bissonnette R et al. [21] demonstrated the efficacy of tacrolimus ointment 0.1% applied in 12 men with genital psoriasis for 8 weeks: the PASI score decreased from 15.8 at baseline to 1.2 at week 8 (p < 0.001). Treatment tolerability, according to the authors’ assessment, was “very good”.

Liao YH et al. [22] conducted a double-blind, parallel-group comparative study in which 50 patients with facial or genital psoriasis were treated with tacrolimus ointment 0.03% or calcitriol ointment (unmodified vitamin D₃). Tacrolimus treatment was more effective: significantly greater improvement was observed in the Target Area Score (TAS) (67% vs. 51%; p < 0.05), and significantly more patients treated with tacrolimus achieved complete or near-complete resolution of the skin process according to the Physician’s Global Assessment (PGA) scale (60% vs. 33%; p < 0.05). Treatment was well tolerated, although calcitriol ointment was significantly more likely to cause hyperemia.

Lebwohl M et al. [23] conducted a double-blind, randomized, placebo-controlled, multicenter study to evaluate the efficacy of tacrolimus ointment in facial and intertriginous psoriasis in adult patients. The study included 167 patients who received tacrolimus ointment 0.1% twice daily or placebo for 8 weeks. As early as day 8 of treatment, significantly more patients receiving tacrolimus achieved complete or near-complete resolution of the skin process compared with placebo (24.8% vs. 5.8%, respectively; p = 0.004). After 8 weeks, this proportion reached 65.2% in the tacrolimus group and 31.5% in the placebo group (p < 0.0001); the incidence of adverse events did not differ between groups. The authors concluded that tacrolimus ointment is effective in the treatment of psoriasis at these localizations.

More recently, Wang C and Lin A, under the auspices of the Canadian Dermatological Association [24], published a literature review on the use of topical calcineurin inhibitors (TCIs) in psoriasis. This review included 9 double-blind and 13 open-label studies of tacrolimus, as well as 4 double-blind and 1 open-label study of pimecrolimus. Based on the analyzed data, the authors concluded that tacrolimus ointment, and to a lesser extent pimecrolimus cream, are effective and safe therapeutic options for the treatment of psoriasis, particularly for localizations such as the face, skin folds, and genital area.

Experience with the use of tacrolimus ointment in other clinical forms and localizations of psoriasis is also noteworthy.

Thus, De Simone C et al. [25] conducted a randomized controlled open-label trial of tacrolimus ointment 0.1% for the treatment of nail psoriasis. Twenty-one patients were included; the drug was applied to the nail plates of one hand twice daily for 12 weeks, while the other hand served as an untreated control. At week 12, a statistically significant improvement was observed in the treated nail plates (p < 0.001): the change in the NAPSI score was 13 in the treated nails versus 3 in the untreated nails.

Apalla Z et al. [26] published descriptions of two clinical cases of psoriatic cheilitis successfully treated with tacrolimus ointment 0.1% for one month.

In 2024, Bubna AK [27] published a study comparing the efficacy of tretinoin cream 0.05% and tacrolimus ointment 0.1% combined with iontophoresis (n = 60). Treatment was administered weekly during the first 4 weeks and at weeks 6 and 8. Significant improvement (p < 0.001) was achieved in both groups: disease severity (ESIF score) decreased from 8.7 to 3.2 and from 8.2 to 3.3 in groups 1 and 2, respectively. Differences between the two groups were not statistically significant.

In summary, tacrolimus ointment is an effective therapeutic option for psoriasis localized to areas without pronounced hyperkeratosis, such as the face, genital area, and inverse psoriasis. The drug is included in the joint clinical guidelines of the American Academy of Dermatology and the National Psoriasis Foundation [28], with particular emphasis on these localizations.

The main clinical form of lichen planus for which substantial clinical evidence on the use of tacrolimus ointment has been accumulated is oral lichen planus. Notably, one of the first reports of tacrolimus use for this indication involved an ex tempore preparation: investigators used a mouthwash prepared by dissolving the powder from oral tacrolimus capsules (Prograf®) in distilled water (0.1 mg per 100 ml), applied four times daily for six months in eight patients [29]. A treatment response was achieved in seven of the eight patients.

To date, data from numerous studies on the use of tacrolimus ointment in oral LP have been summarized in several meta-analyses.

In particular, Sun SL et al. [30] conducted a systematic review and meta-analysis of randomized controlled trials evaluating topical calcineurin inhibitors for the treatment of oral LP. Twenty-one studies (965 patients) were included: 12 on tacrolimus, 3 on pimecrolimus, and 6 on cyclosporine (topical dosage forms of cyclosporine are not registered in the Russian Federation). All three TCIs demonstrated efficacy that did not differ statistically from topical corticosteroids (TCSs); however, the incidence of local adverse effects was higher with tacrolimus and cyclosporine than with steroid therapy. The authors concluded that tacrolimus ointment 0.1% should be the first-line option for oral LP resistant to standard treatment regimens.

A meta-analysis by Guo CL et al. [31] specifically focused on the efficacy of tacrolimus ointment in oral LP and yielded similar results. Nine randomized controlled trials (n = 476) were included and showed no statistically significant difference in efficacy between tacrolimus ointment and TCSs (OR 1.19; 95% CI 0.64–2.22); the incidence of adverse effects also did not differ. In subgroup analyses for tacrolimus ointment concentrations of 0.1% and 0.03%, the ORs were 1.87 (95% CI 0.60–5.82) and 1.47 (95% CI 0.14–16.04), respectively.

Subsequent meta-analyses by Su Z et al. [32] (9 studies) and Pinto J et al. [33] (11 studies) reached similar conclusions, demonstrating no statistically significant differences in efficacy between tacrolimus ointment and TCSs in oral LP.

Finally, da Silva EL et al. [34] conducted a larger systematic review and meta-analysis of non-steroidal immunomodulatory agents, including 28 studies. As in previous analyses, no significant differences in efficacy were found between these agents and TCSs. The authors concluded that tacrolimus ointment 0.1% and pimecrolimus cream 1% are effective and safe treatments for oral LP, with efficacy comparable to TCSs in terms of clinical response and symptom relief, and with greater effectiveness in preventing disease recurrence.

The literature also contains reports on the use of tacrolimus ointment in LP at other localizations. Thus, in four open-label studies involving 2–22 patients, efficacy was observed in vulvovaginal LP. Tacrolimus ointment was also effective in nine reported cases of cutaneous LP and five cases of nail LP, whereas in one case of cutaneous LP the treatment was ineffective [35].

Use of tacrolimus ointment in lupus erythematosus

Lupus erythematosus is a multifactorial autoimmune inflammatory disease of connective tissue; despite the pathogenetic importance of B cells and autoantibodies, lupus is currently considered by many authors to be an “acquired interferonopathy” [36]. After keratinocytes are damaged as a result of a triggering factor (e.g., ultraviolet irradiation), these cells produce pro-inflammatory cytokines of the early phase of inflammation, such as IL-1β, IL-6, TNF-α, and type I and III interferons (IFNs). Under the influence of these cytokines, neutrophils, macrophages, and plasmacytoid dendritic cells are activated, the latter becoming the main producers of IFN-α. This is followed by autoantigen presentation by dendritic cells, which leads to activation of CD4+ T lymphocytes producing IFN-γ and IL-17A; IFN-γ induces the production of chemokines, including CXCL10, which attracts cytotoxic CD8+ T lymphocytes expressing CXCR3 to the dermo-epidermal junction. These T lymphocytes attack keratinocytes, causing their apoptosis and the development of characteristic vacuolar dermatitis [36]. Thus, therapy aimed at suppression of the T-cell component appears pathogenetically justified.

One of the first reports on the use of tacrolimus ointment was published by Yoshimasu T et al. [37], who observed 11 patients with facial skin lesions caused by lupus erythematosus or dermatomyositis. In six patients (three with systemic lupus erythematosus, one with discoid lupus erythematosus, and two with dermatomyositis), application of tacrolimus ointment resulted in significant regression of skin lesions, whereas in four patients (three with discoid lupus erythematosus and one with dermatomyositis) no response to treatment was observed.

Tzung TY et al. [38] conducted a double-blind randomized study with bilateral comparison of tacrolimus ointment 0.1% and clobetasol propionate ointment 0.05% for the treatment of facial cutaneous lupus erythematosus. The study included 20 patients who applied tacrolimus ointment to one half of the face and clobetasol ointment to the other half for four weeks. Treatment was effective in all patients, with no statistically significant differences between tacrolimus and clobetasol. At week 8 (four weeks after discontinuation of therapy), all patients showed some worsening that did not reach baseline severity. However, 11 patients (61%) developed telangiectasias in areas treated with clobetasol, whereas no such changes were observed in areas treated with tacrolimus (p < 0.05).

In a similarly designed comparative study conducted by Pothinamthong P et al. [39] in Thailand, 21 patients with cutaneous lupus erythematosus and symmetrical bilateral lesions applied tacrolimus ointment 0.1% to one side and clobetasol ointment 0.05% to the other side for six weeks. Treatment was effective in both groups, with clobetasol demonstrating higher efficacy than tacrolimus (p < 0.05). Typical adverse effects at the tacrolimus application sites included a burning sensation, whereas clobetasol was associated with telangiectasias and acneiform eruptions.

In another comparative study [40], tacrolimus ointment 0.1% and halobetasol propionate ointment 0.05% (also belonging to class IV, super-potent topical corticosteroids) were evaluated against oral hydroxychloroquine in patients with discoid lupus erythematosus. Forty patients treated for eight weeks were included. Overall, both topical agents demonstrated comparable efficacy; however, halobetasol was significantly more effective in lesions with pronounced hyperkeratosis and desquamation.

Kuhn A et al. [41] conducted a multicenter, randomized, double-blind, placebo-controlled study involving 30 patients with various subtypes of cutaneous lupus erythematosus. Participants received tacrolimus ointment 0.1% or placebo twice daily for 12 weeks. Compared with placebo, significant improvement (p < 0.05) was observed on days 28 and 56, but not on day 84 of treatment. Edema responded most rapidly to tacrolimus therapy, with a pronounced difference compared with placebo on day 28 (p < 0.001); the treatment effect was most evident in the tumor-like form of lupus erythematosus tumidus.

Wang X et al. [42] conducted a randomized controlled trial in patients with discoid lupus erythematosus of the lips. Patients were treated with tacrolimus ointment 0.03% (n = 22) or triamcinolone acetonide cream 0.1% (n = 19); the drugs were applied three times daily during the first week of treatment, twice daily during the second week, and once daily during the third week. Treatment was effective in both groups, with complete response rates and recurrence rates after three months not differing significantly (p > 0.05). The authors concluded that tacrolimus ointment and triamcinolone acetonide cream are equally effective in the treatment of cutaneous lupus erythematosus of the lips.

Based on the data presented, tacrolimus ointment is not inferior to high-potency topical corticosteroids in the treatment of cutaneous lupus erythematosus and may be considered a therapeutic alternative.

Use of tacrolimus ointment in eczema and allergic contact dermatitis

At present, there is some terminological ambiguity associated with the term “eczema”. While in the Russian Federation it represents an independent nosological entity, in foreign literature it is often interpreted as any inflammatory skin condition accompanied by histological signs of spongiosis; in this context, atopic dermatitis, allergic contact dermatitis, and seborrheic dermatitis are also classified as forms of eczema. Therefore, this section summarizes the use of tacrolimus ointment in both classical eczema and allergic contact dermatitis (ACD).

The pathogenesis of ACD is based on a delayed-type hypersensitivity reaction (Gell–Coombs type IV), mediated by an inflammatory response of hapten-specific T lymphocytes. Notably, different haptens induce different patterns of immune response: for example, nickel-induced ACD is associated predominantly with Th1 and Th17 activation, whereas rubber- and fragrance-induced ACD is associated mainly with Th2 activation [43]. The pathogenesis of various clinical forms of eczema is considered more complex and involves neuro-immune-endocrine interactions; however, the leading role of the T-cell component of the immune response is beyond doubt [44]. Thus, the use of agents that suppress the T-cell response is pathogenetically justified.

Belsito D et al. [45] conducted a multicenter, randomized, double-blind, placebo-controlled study to evaluate the efficacy of tacrolimus ointment 0.1% in patients with nickel-induced ACD. Ninety-eight patients were enrolled, in whom nickel patches were applied to the skin of the forearms for 4–8 hours per day over 8 weeks; tacrolimus ointment was applied twice daily to one forearm and placebo ointment to the contralateral forearm. After 8 weeks, complete or near-complete resolution of the skin process was achieved in 45% of cases treated with tacrolimus ointment and in only 1% of placebo-treated cases (p < 0.001). Tacrolimus also demonstrated superior efficacy in reducing ACD symptoms and pruritus (p < 0.001), with statistically significant differences observed as early as day 8 of treatment.

Earlier, similar results were obtained in a randomized double-blind comparative study by Alomar A et al. [46]. The study included 28 patients with nickel-induced ACD, in whom tacrolimus ointment 0.1%, mometasone furoate ointment 0.1%, and petroleum jelly were applied under occlusion for 48 hours. Sites treated with tacrolimus and mometasone showed significant improvement on days 4 and 7 (p < 0.001 versus petroleum jelly for both). Despite a trend toward greater efficacy of tacrolimus, differences between topical glucocorticosteroids and TCIs did not reach statistical significance (p = 0.084).

Similar results confirming the superiority of tacrolimus ointment 0.1% over placebo in the treatment of nickel-induced ACD were obtained in a double-blind, randomized, placebo-controlled trial with bilateral comparison (n = 20) conducted by Saripalli YV et al. [47].

More recently, Han JS et al. [48] conducted an open prospective study of tacrolimus ointment 0.1% in the treatment of ACD, including 82 patients who applied the drug twice daily for four weeks. The main sensitizers were nickel sulfate (56.1%), balsam of Peru (14.6%), a mixture of fragrances (12.1%), tolu balsam (9.8%), and cobalt chloride (15.9%). A complete response was achieved in 14 patients (17.1%), a marked response in 37 (45.1%), a weak response in 24 (29.3%), and no response in 7 patients (8.5%).

Overall, the data presented confirm the efficacy of tacrolimus ointment in ACD and support its use as an alternative to topical corticosteroids in cases where steroid therapy is undesirable for one reason or another.

Clinical data are also available on the use of tacrolimus ointment in various forms of eczema.

Thus, Schnopp C et al. [49] conducted a single-blind randomized study comparing tacrolimus ointment 0.1% and mometasone furoate ointment 0.1% in 16 patients with dyshidrotic eczema of the palms. The drugs were applied to contralateral palms twice daily for four weeks, followed by a two-week observation period; use of emollients was permitted. After two weeks of treatment, a reduction in disease severity of 50% or more was observed with both drugs (p = 0.003 for tacrolimus and p = 0.022 for mometasone). Interestingly, in patients who also had foot involvement, no positive dynamics were observed with tacrolimus ointment at this localization, whereas mometasone ointment demonstrated weak improvement that did not reach statistical significance (p = 0.068). This difference may be related to more pronounced hyperkeratosis in this area, which impairs penetration of the active substance. The authors concluded that tacrolimus and mometasone furoate ointments have comparable efficacy in the treatment of dyshidrotic eczema of the palms and that tacrolimus ointment may be used in alternating regimens with topical corticosteroids when prolonged therapy is required.

In a randomized prospective study by Katsarou A et al. [50] involving 30 patients with hand eczema, no statistically significant differences were observed between tacrolimus ointment 0.1% and mometasone furoate ointment 0.1%, with both treatments demonstrating clinical efficacy.

Schliemann S et al. [51] evaluated the efficacy of tacrolimus ointment 0.1% in the treatment of occupational hand eczema in an open-label, multicenter, prospective study (n = 29). Patients received treatment twice daily for four weeks, followed by an additional two months on an as-needed basis. At the final visit, improvement of more than 50% was recorded in 19 patients (70%), with 12 patients (44%) achieving complete resolution of skin lesions; worsening was noted in two patients (7%). As in previous studies, the authors suggested that tacrolimus may be considered a therapeutic option in alternating long-term treatment regimens for occupational eczema in combination with topical corticosteroids.

Earlier, Thelmo MC et al. [52] conducted an open pilot study evaluating tacrolimus ointment 0.1% in the treatment of hand and foot eczema (n = 25). The drug was applied three times daily for eight weeks, followed by a two-week observation period. At the end of therapy, significant improvement was observed in nearly all assessed parameters (p < 0.007). Two weeks after discontinuation of treatment, improvement in overall disease severity was maintained (p < 0.03), although several symptoms returned to baseline levels.

Use of tacrolimus ointment for eye lesions

The instructions for the medical use of tacrolimus ointment include the instruction “avoid contact of the ointment with the eyes and mucous membranes”. At the same time, there is a considerable amount of clinical data in the literature on the use of tacrolimus ointment in various inflammatory and autoimmune eye lesions; typical cases were treated by applying the ointment behind the eyelid.

A simple prospective study by Al-Amri AM [53] enrolled 11 patients with atopic keratoconjunctivitis, and all were steroid-dependent at the time of inclusion. Treatment with tacrolimus ointment 0.1% was performed once a day with application of the ointment behind the lower eyelid with subsequent reduction of the frequency of applications and withdrawal of the drug. In a week of treatment a marked improvement was observed, and in 6 weeks almost in all patients there was a complete resolution of the pathologic process.

Similar results demonstrating the effectiveness of TIC in the treatment of atopic blepharoconjunctivitis were obtained by Kiiski V et al. [54]. The authors analyzed medical records for the period 2001-2011; 297 cases of tacrolimus ointment (predominantly 0.03%) and 33 - 1% of pimecrolimus cream were identified. The response rate to blepharitis treatment was 78.8% with pimecrolimus and 89.9% with tacrolimus (P = 0.06). In multivariate logistic regression analysis of treatment response adjusted for mixed factors, tacrolimus appeared to be more effective, with an odds ratio of 2.37 (95% CI, 0.90-6.22) for blepharitis and 2.34 (95% CI, 1.02-5.40) for conjunctivitis compared with pimecrolimus. The overall discontinuation rate was 56.1% in the pimecrolimus group and 11.0% in the tacrolimus group: 33.3% of pimecrolimus courses and 9.1% of tacrolimus courses were discontinued due to patient-reported side effects, and lack of response to treatment led to discontinuation of 22.8% of initiated courses in the pimecrolimus group compared with 1.6% in the tacrolimus group. Previously, the same team from Finland demonstrated the lack of potential for tacrolimus ointment to increase intraocular pressure [55] and positive cytologic changes in conjunctiva in patients with atopic blepharoconjunctivitis: the median reduction was 85% (p =0.01) for conjunctival eosinophils, 50% (p = 0.01) for neutrophils, and 58% (p = 0.02) for lymphocytes [56].

Similar results confirming the absence of tacrolimus ointment effect on intraocular pressure were obtained by a team from Sweden [57]. A double-blind study with a cross-over design (n = 20) was conducted to evaluate the use of tacrolimus ointment 0.1% and TCS (clobetasone butyrate 0.05%) for the treatment of eyelid lesions in patients with atopic blepharoconjunctivitis. In terms of efficacy, both treatment options resulted in a reduction in blepharitis symptoms, with a trend toward greater efficacy of tacrolimus ointment at the threshold of statistical significance (P = 0.05).

There are descriptions in the literature of the use of tacrolimus ointment in other ophthalmologic diseases.

Thus, Saha BC et al. [58] conducted a retrospective observational study on the use of tacrolimus ointment 0.1% and 0.03% for the treatment of spring keratoconjunctivitis in 39 patients who did not respond to standard therapy (eye drops with corticosteroids or cyclosporine) for 12 weeks. Both groups showed a pronounced positive trend (p = 0.001), with a more pronounced effect on the papillary component when the ointment with a concentration of 0.1% was applied.

In the same year (2023) Ali W et al. [59] published the results of long-term follow-up of 70 patients with vernal keratoconjunctivitis treated with 0.03% tacrolimus ointment for 12 months with follow-up for another 12 months. After three months there was a marked response to treatment (reduction from 203.17±102.05 points initially to 69.94±70.54 points), after one year this index was close to complete remission (11.59±32.25). After treatment discontinuation, relapses were noted in 5.71% of patients.

Rivkin AC et al. [60] described two cases of successful treatment of conjunctival lymphoid hyperplasia with tacrolimus 0.03% ointment applied behind the lower eyelid; the effect was achieved in 6 and 2 months of treatment, respectively.

Sivanandam A et al. [61] presented a clinical case of complete response to treatment with 0.03% tacrolimus ointment in a 15-year-old atopic patient with ectropion and tear duct stenosis induced by dupilumab. Symptoms resolved after 4 weeks of treatment with application of ointment to the eyelid margin; concomitantly, relief of atopic blepharoconjunctivitis manifestations was achieved.

Kymionis GD et al. [62] described two cases of successful treatment of refractory phlyctenular keratoconjunctivitis in children 5 and 6 years old with tacrolimus 0.03% ointment.

Authors from Japan [63] described an observed response to treatment with 0.1% tacrolimus ointment (in a combination regimen) in a 12-year-old boy with refractory interstitial keratitis who had not previously responded to topical cyclosporine therapy.

A team from Spain [64] presented a description of 4 clinical cases of successful treatment of psoriasis with eye lesions with 0.03% tacrolimus ointment.

It can be stated that high anti-inflammatory and immunosuppressive activity of tacrolimus together with the absence of ophthalmologic side effects typical for corticosteroids (increased intraocular pressure with the risk of glaucoma and cataract development) make tacrolimus ointment a valuable therapeutic option for the treatment of various inflammatory, allergic and autoimmune eye lesions, including those associated with skin diseases. Specialized ophthalmic dosage forms of tacrolimus (eye ointment, eye drops) have been developed and are used in a number of countries, which, unfortunately, are not registered in the Russian Federation at the time of preparation of this review.

Use of tacrolimus ointment in alopecia areata

Nested alopecia (alopecia areata) is a non-scarring autoimmune form of alopecia, the central mechanism of its immunopathogenesis being disruption of the immune privilege of the hair follicle and the appearance of autoreactive intrafollicular CD8+ and perifollicular CD4+ T lymphocytes that cause follicular damage [65, 66]. A key pathogenetic mechanism in frontal fibrosing alopecia, a disorder of epithelial–mesenchymal transition, is Th1-lymphocyte-mediated inflammation [67]. Thus, therapeutic T-cell immunosuppression appears pathogenetically justified.

At the same time, data on the efficacy of tacrolimus ointment in alopecia are predominantly negative. Following several animal experiments demonstrating favorable responses, a number of case-control studies in humans failed to confirm efficacy. Thus, in a study by Price VH et al. [68], treatment with tacrolimus ointment 0.1% applied twice daily for 24 weeks in 11 patients with alopecia and a mean disease duration of six years did not result in terminal hair regrowth. Park SW et al. [69] reported unsuccessful treatment with tacrolimus ointment in four patients with alopecia universalis. Similar negative results were obtained by Rigopoulos D et al. [70] using pimecrolimus cream 1% in 12 patients with alopecia areata.

The authors attributed treatment failure to insufficient penetration of topical calcineurin inhibitors into the hair follicle, as well as to suboptimal patient selection (long disease duration and lack of response to previous therapies).

Similar findings were reported in a later comparative randomized study conducted by Kuldeep C et al. [71], in which 78 patients with alopecia were divided into three groups treated with intralesional injections of triamcinolone acetonide, betamethasone valerate foam, or tacrolimus ointment. Intralesional triamcinolone acetonide was the most effective treatment, whereas tacrolimus ointment demonstrated the lowest efficacy.

These results were consistent with those obtained by Nassar A et al. [72], who conducted a comparative randomized study involving 60 patients with chronic (> 1 year) localized alopecia areata (SALT score < 25%). Patients were divided into three groups: the first received tacrolimus ointment 0.03%, the second received a combination of calcipotriol and betamethasone dipropionate ointment, and the third received the ultra-potent topical corticosteroid clobetasol propionate. Although statistically significant improvement was observed in all three groups at the end of treatment, the tacrolimus group showed the least pronounced effect: improvement according to the SALT scale was 24.16%, 53.57%, and 48.57% in groups 1, 2, and 3, respectively.

More favorable outcomes were reported by Rizzetto G et al. [73], who observed positive effects in three patients with steroid-resistant alopecia areata treated with combination therapy consisting of tacrolimus ointment 0.1% and fractional laser therapy.

Rokni GR et al. [74] and Mahmoudi H et al. [75] demonstrated the efficacy of combination regimens including tacrolimus ointment with systemic isotretinoin or finasteride in frontal fibrosing alopecia. In these studies, the combination of tacrolimus and isotretinoin was more effective than tacrolimus combined with finasteride, and isotretinoin combined with topical tacrolimus and clobetasol was superior to topical therapy with the two agents alone.

Based on the available data, tacrolimus ointment cannot currently be considered an effective therapeutic option for alopecia areata.

Use of tacrolimus ointment in other skin diseases

The literature contains reports on the use of tacrolimus ointment in a wide range of other dermatoses, which is expected given that the T-cell immune response represents a key pathogenetic mechanism in many of these conditions. For example, a 2019 review [76] cites randomized clinical trials of tacrolimus ointment for the treatment of vesicular eczema and follicular keratosis, as well as lower-level evidence (open studies and clinical case reports) for skin diseases such as nodular prurigo, dermatomyositis, cutaneous manifestations of graft-versus-host disease, lichen simplex chronicus, linear lichen, paronychia, cutaneous manifestations of Crohn’s disease, pyoderma gangrenosum, amyloidosis, mastocytosis, Darier’s disease, eosinophilic pustular folliculitis, erosive pustular dermatosis, granuloma annulare, Hailey–Hailey disease, juvenile plantar dermatosis, lichen nitidus, Arndt–Gottron scleromyxedema, lymphocytoma, necrobiosis lipoidica, Mucha–Habermann disease, and sarcoidosis.

Diseases not included in the above review [76] but reported in later publications include mycosis fungoides (retrospective study, 2022, n = 13) [77], folliculitis decalvans (series of four clinical cases) [78], increased efficacy of treatment of hidradenitis suppurativa in patients with inadequate response to adalimumab (n = 5) [79], lower-extremity ulcers in patients with rheumatoid arthritis (n = 5) [80], erythema dyschromicum perstans [81], nodular scabies (double-blind randomized comparative trial of tacrolimus ointment versus triamcinolone acetonide 0.03%, n = 50), in which both drugs demonstrated satisfactory efficacy, with overall greater efficacy of topical corticosteroids [82], and lichen aureus [83].

Table 1 systematizes off-label indications for which experience with the use of tacrolimus ointment has been reported, according to levels of evidence.

Table 1. Current levels of evidence* for indications for which tacrolimus ointment has been used, in Alphabetical order. Based on Guenther L et al., 2019 [76], with modifications and additions

Таблица 1. Текущие уровни доказательств* для показаний, по которым применялась мазь такролимуса, в алфавитном порядке (на основании L. Guenther et al., 2019 [76], с изменениями и дополнениями)

* A simplified hierarchical scheme of levels of evidence is used:

• Level 1: Meta-analyses and randomized controlled trials (RCTs)
• Level 2: Non-analytical studies (e.g., open, uncontrolled studies, retrospective chart reviews)
• Level 3: Case series and case reports

** Data indicate ineffectiveness

Use of tacrolimus ointment in veterinary dermatology

It is worth briefly noting that tacrolimus ointment is widely used for the treatment of skin diseases not only in humans but also in companion animals. The efficacy and safety of tacrolimus ointment in the treatment of atopic dermatitis in dogs have been evaluated in several randomized clinical trials [84, 85]. There are also reports describing its use in other dermatoses in dogs, including erythematous pemphigus and discoid lupus erythematosus [86], as well as individual clinical cases in cats [87] and non-human primates [88].

Tacrolimus ointment is included in the clinical guidelines of the International Working Group on the Treatment of Atopic Dermatitis in Dogs [89]. Small companion animals may be more susceptible to adverse effects of topical corticosteroids, which makes tacrolimus ointment a valuable alternative for the long-term treatment of chronic inflammatory dermatoses in this population.

Conclusion

The second part of this review was devoted to a comprehensive analysis and systematization of clinical data on the use of tacrolimus ointment in various skin diseases beyond atopic dermatitis. This section focused on dermatoses in which tacrolimus ointment is used off-label, including rosacea, perioral and seborrheic dermatitis, papulosquamous dermatoses, lupus erythematosus, various forms of eczema, alopecia, and a number of other dermatological conditions. Generalization of the results of numerous clinical studies, including randomized controlled trials and meta-analyses, made it possible to evaluate both the therapeutic efficacy of the drug and its safety profile during long-term use.

Of particular importance is the fact that tacrolimus ointment, in most cases, demonstrates sustained efficacy in the treatment of chronic and recurrent dermatoses, often accompanied by pronounced inflammation and impairment of the skin barrier function. Unlike topical glucocorticosteroids, the drug does not cause skin atrophy, withdrawal syndrome, or other adverse effects characteristic of topical corticosteroids, which is especially relevant when long-term therapy is required. Inclusion of tacrolimus ointment in international and Russian clinical guidelines for the treatment of a number of skin diseases confirms its recognition by the expert community and its relevance in real-world clinical practice.

Among the available and emerging topical therapeutic agents, tacrolimus ointment retains a unique position due to the extensive evidence base accumulated over many years of use. This ensures a high level of confidence among both physicians and patients and secures a stable place for the drug in treatment algorithms for various dermatoses. In the future, further expansion of indications for the use of tacrolimus ointment is possible, as well as integration of new data on its efficacy and safety into clinical recommendations.

Thus, the second part of this review emphasizes the importance of tacrolimus ointment as a versatile topical therapeutic agent for a wide range of skin diseases far beyond its approved indication. Systematization and analysis of contemporary clinical data make it possible not only to substantiate the rationale for its off-label use, but also to identify directions for further research and improvement of dermatological care.

About the authors

Dmitry D. Petrunin

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

MD, Cand. Sci. (Med.)

References

Supplementary files