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

1.    Introduction

In the first part of this review, general information on tacrolimus ointment, including the history of development, pharmacologic characteristics, and clinical use, was summarized, and the problem of off-label use was discussed. The evidence base for the use of tacrolimus ointment for the treatment of vitiligo was analyzed. 

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

2.1 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, fim and eye lesions. From the point of view of pathogenesis, the leading role is played by activation of innate immunity (in particular, due to 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 proinflammatory cytokines, including IL6. The latter enhances Th17 differentiation and their production of IL17, which, in turn, activates neutrophil response, and neutrophil granulocytes and free radicals produced by them are an important link in the pathogenesis of papulo-pustular subtype of rosacea [1, 2]. This makes treatment aimed at Th17 suppression pathogenetically justified. Perioral dermatitis, manifested by characteristic inflammation and rashes in the perioral area, shares pathogenetic features with rosacea.

Both conditions can be a side effect of external glucocorticosteroid therapy - so-called steroid-induced rosacea and perioral dermatitis.
Although there have been no high-quality randomized clinical trials on the use of tacrolimus ointment for the treatment of rosacea, there are a number of publications in the literature describing a 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 in monotherapy. Most patients showed a good response to combination therapy after approximately 2-3 months of treatment, with symptom relief with tacrolimus alone being 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) for 12 weeks. Erythema improved significantly (p <0.05), while the number of papulo-pustular lesions did not decrease [4].

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

Goldman D described 3 clinical cases of steroidal rosacea where erythema, pruritus and pain completely resolved in all 3 patients after 7-10 days of therapy with tacrolimus 0.075% ointment (not reported) twice daily [6].

Ollech A et al. [7] conducted a retrospective study on the use of TIC for the treatment of perioral dermatitis in children. Data from 72 patients were analyzed, of which 53 received tacrolimus ointment 0.03%, 7 received tacrolimus ointment 0.1%, and 12 received pimecrolimus cream 1%. 48 (67%) received TIC monotherapy, 12 (16.7%) received a combination of TIC and external therapy with metronidazole, 9 (12.5%) received TIC and a systemic antibiotic, and 3 (4.2%) received all three agents. Complete response was achieved in 68.8% of patients receiving TIC alone, 75% of patients receiving TIC and metronidazole, and 77.8% of patients receiving TIC and systemic antibiotic. The median time to treatment with tacrolimus was 30 days, and the time to achieving a partial or complete response to treatment was 14 days.

At the same time, there are descriptions of clinical cases of rosacea-form dermatitis as a side effect of TIC therapy in the literature; some authors attribute it to increased reproduction of Demodex folliculorum mites due to induced local immunosuppression [8].

As an illustration, a clinical case of tacrolimus 0.1% ointment therapy for rosacea in a 30-year-old female patient is presented in Figure 1.

Figure 1. Combined therapy with tacrolimus ointment (Protopic^®) 0.1% 2 times a day for 3 weeks in a 30-year-old woman with rosacea. The case is provided and used with the permission of dermatovenerologist Morozova O.P., Penza.

2.2 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. The central role in the pathogenesis is attributed to lipophilic yeast fungi Malassezia, which due to mechanisms of innate immunity (in particular, TLR2, NOD-like receptors and C-type lectins) induce inflammatory response and differentiation of dendritic cells with the formation of inflammatory cells. Subsequently, Th2 and Th17 response is activated with increased production of relevant cytokines [9, 10]. Taking into account the above described mechanisms of action of tacrolimus, a bidirectional effect is achieved in seborrheic dermatitis - anti-inflammatory and suppressive in relation to T-cell immune response, and antifungal effect in relation to Malassezia fungi.

Data from several high-quality randomized trials are available on the use of tacrolimus ointment in seborrheic dermatitis.
A simple 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) 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), but significantly fewer days of tacrolimus treatment were required to achieve an effect (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; and the main reason for missed application in the tacrolimus group was the absence of signs of skin process).

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. 75 patients who achieved stabilization of the facial skin process after 2 weeks of treatment with tacrolimus ointment were randomized into three groups treated with 0.1% tacrolimus ointment once or twice weekly or placebo twice weekly for 10 weeks (maintenance therapy). Both groups receiving tacrolimus showed significant improvement in the criteria for erythema, flaking, and pruritus, which was maintained for 10 weeks (p < 0.001 for both groups compared with baseline); no significant improvement was noted in the placebo group (p > 0.05). The mean recurrence rate in the placebo group was also significantly higher than in the tacrolimus-treated groups (p < 0.005); and the recurrence rate was significantly higher in the group receiving tacrolimus once weekly than when the drug was used twice weekly (p < 0.005). The authors concluded that a maintenance therapy regimen for seborrheic dermatitis with tacrolimus 0.1% ointment twice weekly was effective.

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

As an illustration, a clinical case of therapy with tacrolimus ointment 0.1% for seborrheic dermatitis in a 35-year-old patient (Fig. 2).

Figure 2. Combined therapy with tacrolimus ointment (Protopic^®) 0.1% once a day in a 35-year-old man with seborrheic dermatitis. The course of treatment was prescribed for a year, but resolution of the skin process was noted after 5 days. The case is provided and used with the permission of dermatovenereologist Yenokyan K.R., St. Petersburg.

2.3 Use of tacrolimus ointment in papulosquamous dermatoses

There is information in the literature about the use of tacrolimus ointment in psoriasis and lichen planus. The key role of T-cell link in the pathogenesis of psoriasis is known and experimentally confirmed since the early 80s of XX century. Autoantigen presentation (the role of cathelicidin complex with its own DNA, as well as melanocytic antigen ADAMTSL5 and KRT17) by dendritic cells and their production of IL23 leads to Th17 activation and IL17 production; further IL17 and 22 become the leading cytokines of the pathogenesis of this dermatosis [14, 15]. The pathogenesis of LP is less well understood, but the characteristic lymphocytic infiltration by CD8+ and CD45RO+ cells suggests their leading pathogenetic role [16]. Thus, the use of T-cell suppressants seems to be pathogenetically justified for these dermatoses.

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

However, it was later found that the low efficacy in plaque psoriasis vulgaris was due to impeded penetration of the large (>800 Da) tacrolimus molecule into the thickness of the hyperkeratotic plaque; in particular, in a study where tacrolimus ointment was used together with a keratolytic (6% salicylic acid gel), the efficacy of treatment in the group receiving the keratolytic and tacrolimus ointment was significantly higher than with the keratolytic and placebo (p < 0.05) [19]. Subsequently, confirmation of this hypothesis was the demonstration of much greater efficacy of tacrolimus ointment treatment of psoriasis in localizations where there is no marked hyperkeratosis - inverse psoriasis, facial and genital psoriasis.

Thus, in an open study by Brune A et al. [20] involving 11 children aged 6-15 years with psoriasis of the face and folds, treatment with 0.1% tacrolimus ointment was effective in all patients without exception. Bissonnette R et al. [21] demonstrated the efficacy of 0.1% tacrolimus ointment applied in 12 men with genital psoriasis for 8 weeks - the PASI index decreased from 15.8 baseline to 1.2 at week 8 (p < 0.001); the tolerability of the treatment, 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 0.03% tacrolimus ointment or calcitriol ointment (unmodified vitamin D3). Tacrolimus treatment was more effective: there was significantly greater improvement on the Target Area Score (TAS) (67% and 51%; P < 0.05) and significantly more patients treated with tacrolimus achieved complete or near-complete resolution of the skin process on the Physician's General Assessment (PGA) scale: (60% and 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 for facial and fold 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% and 5.8%, respectively; p = 0.004). After 8 weeks, this rate was 65.2% for tacrolimus and 31.5% for placebo (p < 0.0001); the incidence of side effects did not differ between groups. The authors concluded that tacrolimus ointment is effective in the treatment of psoriasis of these localizations.

More recently, Wang C and Lin A., under the auspices of the Canadian Dermatological Association [24], published a review of the literature on the use of TIC in psoriasis; this work covered 9 double-blind and 13 open-label studies on tacrolimus, and 4 double-blind and 1 open-label study on pimecrolimus. Based on analyzed data, it was concluded that tacrolimus ointment and, to a lesser extent, pimecrolimus cream, are an effective and safe therapeutic option for the treatment of psoriasis, particularly for localizations such as the face, folds, and genitalia.
The experience with tacrolimus ointment in other clinical forms and localizations of psoriasis is noteworthy.

Thus, De Simone C et al. [25] conducted a randomized controlled open trial of tacrolimus ointment 0.1% for the treatment of psoriasis of finger nail plates. Twenty-one patients were included, and the drug was applied to the nail plates of one hand twice daily for 12 weeks; the other hand was the control hand and was not subjected to any treatment. At week 12, there was a statistically significant (p < 0.001) improvement in the treated nail plates - the change in NAPSI score was 13 versus 3 for the untreated nail plates.

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

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

It can be summarized that tacrolimus ointment is an effective therapeutic option for psoriasis of localizations in which there is no marked hyperkeratosis - face, genitalia, inverse psoriasis. The drug is included in the joint clinical recommendations of the American Academy of Dermatology and the National Psoriasis Foundation [28] with a focus on these localizations.

The main clinical form of lichen planus, for which a large body of data from clinical studies on the use of tacrolimus ointment has been accumulated, is oral lichen planus. Interestingly, one of the first descriptions of tacrolimus use for this indication concerns the ex tempore preparation - researchers used a mouthwash prepared by dissolving the powder obtained from tacrolimus oral capsules (Prograf®) in distilled water (0.1 mg per 100 ml) and applied 4 times a day for 6 months in 8 patients [29]. Treatment response was achieved in 7 out of 8 patients.

To date, data from numerous studies 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 clinical trials of topical calcineurin inhibitors for the treatment of oral LP. Twenty-one studies (965 patients) were included in the analysis - 12 for tacrolimus, 3 for pimecrolimus, and 6 for cyclosporine (similar dosage forms of cyclosporine are not registered in the Russian Federation). Based on the analysis, all three TCIs demonstrated efficacy that was not statistically different from TCSs; the incidence of local side effects was higher with tacrolimus and cyclosporine than with steroid therapy. The authors concluded that tacrolimus 0.1% tacrolimus ointment should be the first choice for oral LP resistant to standard therapy regimens.

A meta-analysis by Guo CL et al. [31] specifically focused on the efficacy of tacrolimus ointment in oral LP and yielded a similar result. Nine randomized controlled clinical trials (n = 476) were included and found that the efficacy of tacrolimus ointment therapy had no statistically significant difference from TCS (OR 1.19 (95% CI 0.64-2.22)), the incidence of side effects also did not differ. In the subgroup analysis for tacrolimus ointment with 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.
Later meta-analyses by Su Z et al. [32] (9 studies) and Pinto J et al. [33] (11 studies) came to a similar conclusion - the efficacy of tacrolimus ointment and TCS in oral LP is not statistically different.

Finally, da Silva EL et al. [34] conducted a larger systematic review and meta-analysis on the efficacy of non-steroidal immunomodulatory agents in general, including 28 studies. As in previous cases, no significant differences in efficacy were found between this category of agents and TCS. The authors concluded that 0.1% tacrolimus and 1% pimecrolimus are effective and safe agents for the treatment of oral LP, demonstrating similar efficacy to TCS in terms of clinical response and symptom relief, while being more effective in preventing disease recurrence.

In the literature there are descriptions of the use of tacrolimus ointment in LP of other localizations. Thus, in 4 open-label studies involving 2 to 22 patients, efficacy was observed in vulvovaginal LP; tacrolimus ointment was also effective in 9 described clinical cases of skin LP and 5 cases of nail LP, while in 1 case of cutaneous LP treatment was ineffective [35].

2.4 Use of tacrolimus ointment in lupus erythematosus

Lupus erythematosus is a multifactorial autoimmune inflammatory disease of connective tissue; despite the pathogenetic importance of B-cell and autoantibodies, today lupus is considered by many authors to be an "acquired interferonopathy" [36]. After keratinocytes are damaged as a result of a trigger (e.g., ultraviolet irradiation), these cells produce proinflammatory cytokines of the early phase of inflammation, such as IL1β, IL6, 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 become the main producers of IFN-α. This is followed by autoantigen presentation by dendritic cells, which leads to the activation of CD4+ T-lymphocytes producing IFN-γ and IL-17a, with the former inducing the production of chemokines, including CXCL10, which attracts cytotoxic CD8+ T-lymphocytes expressing CXCR3 to the dermal-epidermal interface. These T lymphocytes attack keratinocytes, causing their apoptosis and the development of the characteristic vacuolar dermatitis [36]. Thus, therapy aimed at suppression of the T-cell link appears to be pathogenetically reasonable.

One of the first descriptions of the use of tacrolimus ointment belongs to Yoshimasu T et al. [37], who monitored 11 patients with facial skin lesions caused by lupus erythematosus or dermatomyositis. In 6 of them (3 - SLE, 1 - discoid LE and 2 - dermatomyositis) application of tacrolimus ointment resulted in significant regression of the skin process, in 4 (3 - discoid LE, 1 - dermatomyositis) there was no response to treatment.

Tzung TY et al. [38] conducted a double-blind randomized study with bilateral comparison of the use of tacrolimus 0.1% ointment and 0.05% clobetasol propionate ointment for the treatment of cutaneous facial lupus erythematosus. The study included 20 patients who applied tacrolimus ointment to one half of the face and clobetasol ointment to the other half of the face for 4 weeks. Therapy was effective in all patients, with no statistically significant differences between tacrolimus and clobetasol; at week 8 (4 weeks without treatment), all patients showed some worsening that did not reach baseline severity. However, 11 patients (61%) developed telangiectasias in the area of clobetasol application, which was not observed in any case of 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 with symmetrical bilateral lesions participated, applying tacrolimus 0.1% ointment on one side and clobetasol 0.05% ointment on the other for 6 weeks. Treatment was effective in both groups, with clobetasol outperforming tacrolimus in efficacy (p < 0.05). Typical side effects at the sites of application of tacrolimus were burning, while those of clobetasol were telangiectasias and acneiform rashes.

In another comparative study [40] 0.1% tacrolimus ointment and 0.05% halobetasol propionate ointment (also TCS IV (super potent) class of activity) against oral hydroxychloroquine in discoid lupus erythematosus. Forty patients treated for 8 weeks participated. In general, both drugs demonstrated comparable efficacy, but the efficacy of halobetasol was significantly higher in foci with marked hyperkeratosis and desquamation.

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

Wang X et al. [42] conducted a randomized controlled trial on the treatment of discoid lupus erythematosus lip lupus erythematosus. Patients were treated with 0.03% tacrolimus ointment (n = 22) and 0.1% triamcinolone acetonide cream (n = 19); the drugs were applied 3 times a day in the first week of treatment, 2 in the second week, and 1 in the third week. Treatment was effective in both groups, with complete treatment response and recurrence rates after 3 months not statistically different (p > 0.05). The authors concluded that tacrolimus ointment and triamcinolone acetonide cream were equally effective in the treatment of cutaneous lupus erythematosus of the lips.

Based on the data presented, it can be stated that tacrolimus ointment is not inferior to high potency class TCSs in the treatment of cutaneous lupus erythematosus and can be considered as a therapeutic alternative.

2.5 Use of tacrolimus ointment in eczematous dermatoses (other than atopic dermatitis)

Today there is some terminological confusion related to the term "eczema" - while in the Russian Federation it is an independent nosological entity, in foreign literature it is often interpreted as any skin inflammation accompanied by histological signs of spongiosis, in this connection atopic, allergic contact, and seborrheic dermatitis are also referred to the category of eczema. Therefore, this section will summarize the use of tacrolimus ointment in both traditional eczema and allergic contact dermatitis (ACD).

The pathogenesis of ACD is based on a delayed-type hypersensitivity reaction (Jell-coombs type IV) mediated by an inflammatory response of hapten-specific T lymphocytes; interestingly, different types of haptens elicit different patterns of immune response - for example, nickel ACD is associated predominantly with Th1 and Th17 activation, whereas rubber and fragrance ACD is associated with Th2 activation [43]. The pathogenesis of various clinical forms of eczema is considered to be more complex and includes complex neuro-immune-endocrine interactions, but the leading role of the T-cell link of the immune response is not in doubt [44]. Thus, the use of drugs that induce suppression of the T-cell response is pathogenetically justified.

Belsito D et al. [45] conducted a multicenter randomized, double-blind, placebo-controlled study of the efficacy of 0.1% tacrolimus ointment in patients with nickel-induced ACD. Ninety-eight patients were included who had nickel patches applied to the skin of the forearms for 4-8 hours per day for 8 weeks, and tacrolimus ointment was applied twice to one forearm and placebo ointment to the opposite forearm. After 8 weeks, complete or near-complete resolution of the skin process was achieved in 45% of tacrolimus ointment cases and only 1% of placebo cases (P<0.001), and there was also superiority of tacrolimus in terms of efficacy in eliminating ACD symptoms and pruritus (P<0.001), with statistically significant differences observed after 8 days of treatment.

Previously, similar results were obtained in a randomized double-blind comparative study conducted 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 the occlusion for 48 hours. The sites on which tacrolimus and mometasone were applied showed significant benefit on days 4 and 7 (P<0.001 versus petroleum jelly for both), and despite a trend toward greater efficacy of tacrolimus, the differences between TCS and TCI did not reach statistical significance (P=0.084).

Similar results supporting the superior placebo efficacy of 0.1% tacrolimus ointment in the treatment of nickel 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 the use of 0.1% tacrolimus ointment for the treatment of ACD involving 82 patients who applied it twice daily for 4 weeks. The main sensitizers were nickel sulfate (56.1%), Peruvian balsam (14.6%), a mixture of perfumes (12.1%), Toluan balsam (9.8%), and cobalt chloride (15.9%). A complete response to treatment was achieved in 14 (17.1%) patients, a marked response in 37 (45.1%), a weak response in 24 (29.3%) and no response in 7 (8.5%).

In general, the above data confirm the efficacy of tacrolimus ointment in ACD and make it an alternative to TCS in cases when the use of steroids is undesirable for one reason or another.

There are clinical data on the use of tacrolimus ointment in various types of eczema.

Thus, Schnopp C et al. [49] conducted a simple blind randomized study of the use of 0.1% tacrolimus ointment and 0.1% mometasone furoate ointment in 16 patients with dyshidrotic eczema of the palms. The drugs were applied to the contralateral palms twice a day for 4 weeks, followed by a 2-week observation period; emollients were allowed. Already after 2 weeks of treatment, a reduction in skin process severity of 50% or more was observed for both drugs (P=0.003 for tacrolimus and P=0.022 for mometasone). Interestingly, in patients who also had foot lesions, no positive dynamics were observed with tacrolimus ointment in this localization, while mometasone ointment showed a weak positive dynamics that did not reach statistical significance (P=0.068); this may be due to more pronounced hyperkeratosis, which is characteristic of this localization and makes penetration of the active substance more difficult. The authors concluded that tacrolimus and mometasone furoate ointments have equal efficacy in the treatment of dyshidrotic eczema of the palms; tacrolimus ointment can be used in an alternating regimen with TCS if prolonged therapy is necessary.

In a randomized prospective study by Katsarou A et al. [50] involving 30 patients with eczema of the hands also did not observe statistically significant differences between ointments 0.1% tacrolimus and 0.1% mometasone furoate, and both drugs demonstrated clinical efficacy.

Schliemann S et al. [51] evaluated the efficacy of 0.1% tacrolimus ointment in the treatment of occupational hand eczema in an open-label, multicenter, prospective study (n = 29). Patients received treatment twice daily for 4 weeks, followed by for another two months on an as-needed basis. At the final visit, >50% improvement was recorded in 19 (70%) patients, with 12 (44%) achieving complete resolution of the skin process; worsening was noted in 2 (7%) patients. As in the previous case, the authors suggested that tacrolimus may be considered as a therapeutic option in alternating regimens of long-term treatment of occupational eczema with TCS.

Previously, Thelmo MC et al. [52] conducted an open pilot study of the use of 0.1% tacrolimus ointment for the treatment of hand and foot eczema (n = 25). The drug was applied three times daily for 8 weeks, followed by observation for another 2 weeks. At the end of therapy, significant improvement was noted in almost all parameters assessed (p<0.007); after 2 weeks without treatment, improvement in the overall severity criterion was maintained (p<0.03), while a number of symptoms returned to baseline.

Figure 3 shows a clinical case of facial allergic dermatitis caused by vitamin-mineral complex supplementation.

Figure 3. Therapy with tacrolimus ointment (Protopic^®) 0.1% once a day (at night) in a 17-year-old girl with allergic dermatitis of the face caused by taking a vitamin and mineral complex. After 7 days of therapy, complete regression of rashes was noted. The case is provided and used with the permission of dermatovenereologist Schepleva N.P., Moscow.

2.6 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.

2.7 Use of tacrolimus ointment in alopecia areata

Nest alopecia is a non-rubbing form of autoimmune alopecia, the central link in the immunopathogenesis of which is the disruption of immune privilege of the hair follicle and the appearance of autoreactive intrafollicular CD8+ and perifollicular CD4+ T-lymphocytes causing its damage [65, 66]. A key link in the pathogenesis of frontal fibrosing alopecia, a disorder of epithelial-mesenchymal transformation, is associated with Th1-lymphocyte-mediated inflammation [67]. Thus, T-cell immunosuppression for therapeutic purposes seems to be pathogenetically justified.

At the same time, data on the efficacy of tacrolimus ointment in alopecia are predominantly negative. After several animal experiments showing a good response, several case-control studies in humans have failed. Thus, in the study by Price VH et al. [68] treatment with tacrolimus ointment 0.1% twice daily for 24 weeks in 11 patients with nested alopecia with a mean disease course duration of 6 years did not result in terminal hair growth.

Park SW et al. [69] described an unsuccessful experience of treatment with tacrolimus ointment in 4 patients with alopecia universalis. Similar negative results were obtained by Rigopoulos D. et al. [70] when using 1% pimecrolimus cream in 12 patients with nested alopecia areata.
The authors attributed the treatment failure to the insufficient ability of TCI to penetrate into the hair follicle and suboptimal patient selection (long disease course, lack of response to other therapeutic options).

The later conducted by Kuldeep C et al. [71], a comparative randomized study in which 78 patients with nested alopecia were divided into 3 groups treated with intraocular injections of triamcinolone acetonide, betamethasone valerate foam, or tacrolimus ointment, showed similar results. Intraocular application of triamcinolone acetonide was the most effective, and treatment with tacrolimus ointment was the least effective.

The results echoed those obtained by Nassar A et al. [72]. They conducted a comparative randomized study involving 60 patients with chronic (> 1 year) localized (SALT lesions < 25%) nested alopecia areata. Patients were divided into 3 groups, the first receiving 0.03% tacrolimus ointment, the second receiving a combination of calcipotriol and betamethasone dipropionate in ointment form, and the third receiving the ultra-strong GCS clobetasol propionate. Although statistically significant positive dynamics were observed in all three groups at the end of treatment, the group receiving tacrolimus showed the least pronounced improvement: the improvement in SALT scale was 24.16%, 53.57% and 48.57% in groups 1, 2 and 3, respectively.

More positive results were obtained by Rizzetto G et al. [73], who noted a positive effect in three patients with steroid-resistant nested alopecia areata who received complex therapy with 0.1% tacrolimus ointment and fractional laser.

Rokni GR et al. [74] and Mahmoudi H et al. [75] demonstrated the efficacy of combination therapy, including tacrolimus ointment and systemic isotretinoin or finasteride, in frontal fibrosing alopecia. In this case, therapy with the combination of tacrolimus and isotretinoin was more effective than tacrolimus and finasteride, and the combination of isotretinoin with external therapy with tacrolimus and clobetasol outperformed external therapy with the two drugs alone.

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

2.8 Use of tacrolimus ointment in other skin diseases

There are reports in the literature on the use of tacrolimus ointment for a wide range of other dermatoses, which is expected as the T-cell immune response is a key pathogenetic link for many of them. For example, a 2019 review [76] cites randomized clinical trials of tacrolimus ointment for the treatment of vesicular vesicles and follicular keratosis, as well as lower level evidence (open studies and clinical cases) for skin diseases such as nodular prurigo, dermatomyositis, cutaneous manifestations of graft-versus-host reactions, Vidal's lichen planus, linear lichen, paronychia, cutaneous manifestations of Crohn's disease, gangrenous pyoderma, amyloidosis, mastocytosis, Darier's disease, eosinophilic pustular folliculitis, erosive pustular dermatosis, ring-shaped granuloma, Haley-Haley disease, juvenile plantar dermatosis, shiny lichen, Arndt-Gottron scleromyxedema, lymphocytoma, lipoid necrobiosis, Mooch-Habermann disease, sarcoidosis. Diseases not included in the above review [76] include mycosis fungoides (retrospective study of 2022, n=13) [77], undermining folliculitis (series of 4 clinical cases) [78], improved efficacy of treatment of purulent hidradenitis in patients with inadequate response to adalimumab (n = 5) [79], lower extremity ulcers in patients with rheumatoid arthritis (n = 5) [80], erythema dyschromica persistent [81], nodular form of scabies (double-blind randomized comparative trial of tacrolimus ointment with triamcinolone acetonide 0.03%, n = 50); both drugs produced a satisfactory response to treatment with, in general, greater efficacy in TCS [82], and goldenseal [83].

2.9 Use of tacrolimus ointment in veterinary dermatology

It deserves a brief mention that tacrolimus ointment is widely used for the treatment of skin diseases not only in humans but also in pets. The efficacy and safety of tacrolimus ointment in the treatment of atopic dermatitis in dogs have been studied in several randomized clinical trials [84, 85], and there are descriptions of its use in other (e.g., erythematous vesicular and discoid lupus erythematosus) dermatoses in dogs [86], as well as clinical cases in cats [87] and monkeys [88]. Tacrolimus ointment is included in the clinical guidelines of the International Working Group on the Treatment of Atopic Dermatitis in Dogs [89]. Small pets may be more vulnerable to the side effects of TCSs, making tacrolimus ointment a valuable alternative for the treatment of chronic inflammatory dermatoses in them.

3.    Conclusion

The second part of the 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 and vitiligo. This section focuses on dermatoses for which tacrolimus ointment is used off-label, including rosacea, perioral and seborrheic dermatitis, papulosquamous dermatoses, lupus erythematosus, various forms of eczema, alopecia, and several other dermatologic pathologies. Generalization of the results of numerous clinical studies, including randomized controlled trials and meta-analyses, allowed us to evaluate the therapeutic efficacy of the drug, as well as its safety profile in 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 marked inflammation and impaired skin barrier function. Unlike glucocorticosteroids, the drug does not cause skin atrophy, withdrawal syndrome and other side effects characteristic of TCS, which is especially important when long-term therapy is necessary. Inclusion of tacrolimus ointment in international and Russian clinical recommendations for treatment of a number of skin diseases confirms its recognition by the expert community and its demand in real clinical practice.

Among the available and developing means of external therapy, tacrolimus ointment retains a unique position due to the extensive evidence base accumulated over the years of use. This ensures a high level of confidence on the part of doctors and patients, as well as a stable place of the drug in the treatment algorithms of various dermatoses. In the future, further expansion of indications for the use of tacrolimus ointment is possible, as well as the integration of new data on its efficacy and safety into clinical recommendations.

Thus, the second part of the review emphasizes the importance of tacrolimus ointment as a universal means of external therapy for a wide range of skin diseases, far beyond the registered indication. Systematization and analysis of modern clinical data allow not only to substantiate the expediency of its off-label use, but also to define directions for further research and improvement of dermatological care.

Funding source
The manuscript was prepared and published at the expense of funding at the author's place of work.

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

MD, Cand. Sci. (Med.)

References

Supplementary files