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Table of Contents
REVIEW ARTICLE
Year : 2020  |  Volume : 2  |  Issue : 1  |  Page : 36

Use of topical tacrolimus in ophthalmology: Nonsystematic review


1 Department of Ophthalmology, Paulista Ophthalmology Unit – UPO, São Paulo, Brazil
2 Department of Ophthalmology, Paulista Ophthalmology Unit – UPO, São Paulo; Department of Ophthalmology, Sorocaba Eye Banking, Banco de Olhos de Sorocaba – BOS, Sorocaba, Brazil
3 Department of Ophthalmology, Paulista Ophthalmology Unit – UPO; Department of Visual Sciences, Federal University of São Paulo, UNIFESP, São Paulo, Brazil
4 Department of Visual Sciences, Federal University of São Paulo, UNIFESP, São Paulo, Brazil

Date of Submission30-Aug-2020
Date of Acceptance27-Oct-2020
Date of Web Publication10-Dec-2020

Correspondence Address:
Dr. Morgana Arima Vedovato
Avenida Redenção, 465, Ap 113, Bairro Jardim Do Mar, São Bernardo Do Campo - São Paulo
Brazil
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/PAJO.PAJO_45_20

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  Abstract 


The two immunosuppressants most used topically in ophthalmology are cyclosporine (CS) and tacrolimus (TL). Their mechanism of action is similar, but the TL is ten to a hundred times more powerful than the CS. We reviewed the studies found in the literature on the use of topical TL and described them, as follows, divided by indication of use. Topical TL is effective and safe against inflammatory and immunological processes of the ocular surface, although it is less powerful than corticosteroids, it has fewer side effects.

Keywords: Allergy, corneal diseases, dry eye, tacrolimus


How to cite this article:
Vedovato MA, Do Carmo TQ, Rios LC, Corrêa VC, Oliveira FR, Capelanes NC, Moscovici BK. Use of topical tacrolimus in ophthalmology: Nonsystematic review. Pan Am J Ophthalmol 2020;2:36

How to cite this URL:
Vedovato MA, Do Carmo TQ, Rios LC, Corrêa VC, Oliveira FR, Capelanes NC, Moscovici BK. Use of topical tacrolimus in ophthalmology: Nonsystematic review. Pan Am J Ophthalmol [serial online] 2020 [cited 2021 Jan 25];2:36. Available from: https://www.thepajo.org/text.asp?2020/2/1/36/303002




  Introduction Top


Eye inflammation, especially in the anterior segment, is relatively common in ophthalmological practice. The topical use of anti-inflammatory drugs is frequent in the treatment of eye diseases; however, most anti-inflammatory agents have side effects if used for a long period, especially corticosteroids. Thus, the use of topical immunosuppressants, which also has anti-inflammatory activity, has obtained more indications.[1],[2],[3]

The two immunosuppressants most used topically in ophthalmology are cyclosporine (CS) and tacrolimus (TL). Their mechanism of action is similar, but the TL is ten to a hundred times more powerful than the CS. TL is a macrolide with immunomodulating activity, isolated from fermentation of Streptomyces tsukubaensis that becomes biologically active when bound to immunophilin. It inhibits calcium-dependent events, such as transcription of the interleukin 2 gene, activation of nitric oxide synthesis, apoptosis, and cell degranulation. It also inhibits B-lymphocyte activation, modulates a late stage of B lymphocyte activation, and substantially inhibits B-cell proliferation.[1],[2],[3],[4],[5],[6],[7],[8],[9],[10],[11],[12],[13],[14],[15],[16],[17],[18],[19],[20],[21],[22],[23],[24],[25],[26]

TL suppresses the immune response by inhibiting the release of some cytokines such as interleukins (3, 4, 5, and 8), alpha-interferon, and tumor necrosis factor (acts in blocking the cascade).[1],[6],[9] Therefore, he is used due to decreased mediated response activity by T lymphocytes, mainly in uveitis, ocular allergy, decreasing post-transplant rejection and graft-versus-host disease1.[1],[2],[3],[4],[5],[6],[7],[8],[9]

In the dry eye, TL acts by inhibiting the proliferation of T-lymphocytes and controlling inflammation, penetrating the lacrimal gland acini, and improving its function.[1],[3],[6]

TL can be found in the form of eye drops and ointment.[27],[28],[29],[30],[31],[32],[33],[34],[35],[36],[37],[38],[39],[40],[41],[42],[43],[44] Commercially, we found only TL in the form of dermatological ointment in concentrations of 0.03% and 0.1%. It is usually used in skin allergies, dermatitis, and rosacea. In Japan, we find 0.1% TL eye drops commercially. In Brazil, its use is off label for ophthalmology and can be manipulated in the form of eye drops and ointment. The main vehicles used are sesame oil, olive oil, linseed oil, and almond oil. The ointment uses petroleum jelly as a vehicle. New manuscripts have studied other vehicles to reduce the adverse effects of its instillation such as stinging and burning.[2]


  Literature Review Top


We reviewed the studies found in the literature on the use of topical TL and described them, as follows, divided by indication of use:

Eye allergy

TL most common indication is for the treatment of ocular allergies, mainly in atopic conjunctivitis and more severe forms of vertebral conjunctivitis. The results from the literature are shown in [Table 1], all with positive results.
Table 1: Resume of studies showing the results of using tacrolimus for allergic eye disease

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Erdinest et al. also reviewed the use of TL for allergic eye disease and found out that the molecular mechanisms of action of TL in T-cells involve inhibition of critical signaling pathways that regulate T-cell activation. TL inhibits CaN–CaM complex phosphatase activity and, as a result, inhibits activation of the transcription factor nuclear factor of activated T-cells. This inhibits the production of the major inflammatory cytokines, which play a role in allergic inflammation. Their review pointed that TL is an effective steroid-sparing agent, and in low doses, it usually controls allergic eye disease. It also showed that early treatment should prevent ocular surface complications and TL is more effective than CS A and found that the topical TL use seems to be safe.[4]

Dry eye

Another use of TL found in the literature is to treat dry eye since its mechanism of action is similar to that of CS.[1],[2],[3],[4],[5],[6]

As a definition of dry eye disease, we have a multifactorial disease of the lacrimal and ocular surface, which results in discomfort, visual disturbance, and instability of the tear film, inflammation being identified as the main associated factor.[1],[2]

The usual treatment for dry eye consists of ocular lubricants with or without preservatives, topical corticosteroid therapy, topical immunosuppressive agents, and tear point occlusion.

TL suppresses the expression of inflammatory mediators on the ocular surface. Having as benefits the restoration of secretion of a healthy lacrimal film and reduction of the signs and symptoms associated with dry eye.[1],[3]

Moscovici et al., in a double-blind randomized study using TL 0.03% eye drops (vehicle almond oil) with patients with Sjogren's syndrome, found improvement in the TL treatment group, with the results shown in [Table 2].[1],[25]
Table 2: Results from Moscovici et al. study[1]

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All patients in the treatment group complained of burning and reported improvement after treatment.

Another study compared TL 0.03% ointment with 0.5% CS eye drops in 57 patients with complaints of dry eye (ocular surface disease index [OSDI] scores >12) and signs (break up time [BUT] <10 s or Schirmer <5 mm), with the results shown in [Table 3].[8]
Table 3: Results from Fatima et al. study[8]

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  • BUT improved in both the groups, with similar values
  • Both the groups had similar complaints of irritation.


In a study on dry eye treatment with 0.03% TL eye drops, as in reports mentioned above, many patients complained of mild discomfort after using it. However, when asked whether to keep using eye drops or to discontinue due to irritation, all patients decided to maintain use due to significant clinical improvement demonstrating the effectiveness in the treatment of dry eye.[3]

Sakassegawa-Naves et al. studied the use of 0.03% TL for the treatment of blepharitis in 40 eyes for 1 month with a statistically significant improvement only in the fluorescein scores (from 1.83 to 0.44) and a decrease in telangiectasis in the upper eyelid margin.[9]

Adenoviral infiltrates

Another indication is for the treatment of adenoviral infiltrates resistant to conventional treatment.

Subepithelial corneal infiltrates (SCI) after adenoviral infections are difficult to resolve, the main treatment is performed with topical corticosteroids, but this can cause serious side effects such as glaucoma and cataracts, besides not being effective in some cases, being a possible alternative to phototherapeutic keratectomy. Some studies have used TL as an alternative to this treatment, and the results are listed in [Table 4].
Table 4: Studies analyzing tacrolimus use in adenoviral subepithelial infiltrates

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Ghanem et al. described the use of 0.03% topical TL in patients with SCI resistant to topical corticosteroid treatment. This study analyzed 7 patients (10 eyes) for an average period of 8 months, and showed success with the use of TL in 8 eyes (6 patients) , demonstrating the efficacy of TL i the treatment SCI by adenovirus.[12]

Berisa Prado et al. used TL for the treatment of SCI caused by adenoviral keratoconjunctivitis. Fifty-five patients were treated (85 eyes), 31 eyes were treated with 0.02% ointment one time daily and 55 with 0.03% eye drops two times daily, treatment lasted 185 days, and patients were followed up for 363 days. Previous treatments included the use of corticosteroids in 58 eyes and CS in 22 eyes, without satisfactory results. The use of TL ointment 0.02% and eye drops 0.03% is effective in the treatment of SCI after adenoviral keratoconjunctivitis, it was well tolerated in patients without significant adverse effects. There was a decrease, and in some cases, elimination of infiltrates. An improvement in visual acuity was observed at the end of the treatment, there was no increase in intraocular pressure (IOP) before and after treatment, and tolerance to TL formulations was good, being better in the form of eye drops.[11]

Levinger et al. demonstrated the efficacy and safety of TL, using patients with SCI who were previously treated with topical corticosteroids without improvement or with medication suspension due to the increase in IOP. Patients were treated with 0.03% TL ointment twice daily for 22 weeks (including 1-month washout). All patients showed significant clinical improvement, and none had a severe degree of infiltrate at the end of treatment. Patients reported a significant decrease in the severity of symptoms. Demonstrating that 0.03% topical TL is a safe and effective alternative treatment for patients with SCI that are unresponsive to other types of treatment or have undesirable side effects from topical steroids.

Reviewing these studies, we conclude the efficacy and safety of using topical TL for the treatment of SCI after adenoviral conjunctivitis.[27]

Graft versus host disease

Another possible indication is for patients with graft versus host disease (GVHD). Working with 0.03% eye drops improved the OSDI questionnaire, staining with vital dyes, BUT in 28 days. Another study with 24 eyes treated for a long period (20 months) with TL showing an improvement in the inflammation score from 2.8 to 0.6 (P = 0.01), showing improvement normally after 2–8 weeks of treatment.[22] This study with 40 GVHD patients studied 0.5% TL and CS in treating the disease. After 10 weeks, there was an improvement in both the groups, but more marked in the staining scores, BUT and OSDI in the TL group. However, there was a greater complaint of burning and burning in the TL group.[25]

Corneal transplantation

For patients undergoing corneal transplant (TX), there are two possible indications: decreased rejection due to the immunosuppressive effect and possible decrease in neovascularization and anti-inflammatory effect to improve the ocular surface, some results from the literature are listed in [Table 5].
Table 5: Studies showing the use of tacrolimus in corneal transplantation

Click here to view


Besides, there are studies to develop TL nanoparticles to decrease rejection after TX.[16]

Superficial Thygeson keratitis

TL was effective in the treatment of superficial Thygeson keratitis in the treatment of 10 patients: After 72 h, they had improved ophthalmic symptoms and signs with 0.02% TL. Treatment ranged from 1 to 42 weeks, with an average of 10 weeks.[13]

Phlyctenule

A study evaluated the efficacy in six patients with recurrent phlyctenule with TL 0.03%. They were treated with CS and TL in the acute phase and after initial remission for another 10 months (approximately) to prevent a recurrence. Treatment was effective in all cases.[19]

Eye burn

Another researcher promoted alkali burns in rats and compared subconjunctival anti-vascular endothelial growth factor (VGF) injection and 0.05% TL for corneal neovascularization and fights inflammation and found better results in the TL-treated group with less opacity and less expression of inflammatory cytokines.[20] Another study also compared both the substances in neovascularization and had similar results.[21]


  Systemic Absorption and Safety Top


Although safe, its use in patients with ocular herpes or other situations that can be activated with a decrease in local immunity, the cost–benefit of the medication, and the necessary close monitoring must be evaluated. There is a report of cancer and lymphoma with topical dermatological use. It should not be used in children under 2 years and risk category for pregnancy C.

TL has limited ocular penetration due to its hydrophobic nature and relatively high molecular weight.

In an experiment with pig eyes, Siegl et al. showed a new aqueous formulation Marinosolv used to completely solubilize × 200 higher effective therapeutic doses compared to water solubility. Significantly higher concentrations were found in the cornea, choroid, sclera, and retina when compared to another commercialized product. However, the topical ocular application of TL did not result in relevant systemic exposure in this experiment.

In a study to assess the aqueous penetration of topical TL, Shoughy et al. evaluated the concentrations in aqueous humor after the installation of 0.05% topical TL in four patients who would undergo cataract surgery. TL was detected in the aqueous humor of all patients. Its concentration ranged from 2.6 to 5.6 ng/ml, a concentration higher than the minimum-recommended therapeutic level.

In another study, comparing the efficacy and adverse effects of TL × CS in patients with dry eye, Fátima et al. report that the most common adverse effects presented after using TL ointment 0.03% two times daily for 3 months were burning in the instillation of eye drops, eye irritation, and pain. No serious adverse effects justifying treatment discontinuation have been reported.


  Conclusion Top


Topical TL is effective and safe against inflammatory and immunological processes of the ocular surface; although it is less powerful than corticosteroids, it has fewer side effects. TL can be used in concentrations of 0.02%–0.1% in the form of eye drops and/or ointment (less burning in ointment presentation) 12/12 h for an indefinite time to decrease ocular inflammation, allergic, and immunological processes. Some restrictions are being off label and eye drops formulations have not yet found a better vehicle that could reduce ocular burning complaints.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5]



 

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