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 Table of Contents  
MAJOR REVIEW
Year : 2019  |  Volume : 31  |  Issue : 3  |  Page : 182-190

Ciclosporin A in ophthalmology: A systematic review


Department of Ophthalmology, College of Medicine, King Faisal University, Al Hofuf, Saudi Arabia

Date of Web Publication31-Dec-2019

Correspondence Address:
Dr. Kaberi Biswas Feroze
Department of Ophthalmology, College of Medicine, King Faisal University, Al Hofuf
Saudi Arabia
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/kjo.kjo_80_19

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  Abstract 


Aim: To systematically analyse data from randomized controlled trials of topical Ciclosporin with the aim of assessing the uses and effectiveness of Ciclosporin in different conditions, optimal dosage and adverse effect profile. Methods: 24 RCTs that had evaluated the uses and efficacy of Ciclosporin in different ocular conditions were selected and were used in this review. Articles published upto December 2018 were identified from the following sources- Medline, Scopus, Web of science and references from relevant articles. Results: The average JADAD score was 3.16. Symptomatic relief and objective improvement of ocular signs were noted in most cases of allergic eye disease, moderate to severe dry eye disease and lid margin inflammatory disease. It was also found to accelerate post surgical corneal nerve healing and recovery of corneal sensation. It was not effective in post keratoplasty graft rejection. Adverse effects reported were minimal and included symptoms like ocular stinging. Conclusions: Even though topical Ciclosporin A is an attractive treatment option in many ocular conditions, more structured RCTs are needed to standardize the dose and provide a detailed adverse effect profile.

Keywords: Allergic eye disease, ciclosporin, dry eye disease


How to cite this article:
Feroze KB. Ciclosporin A in ophthalmology: A systematic review. Kerala J Ophthalmol 2019;31:182-90

How to cite this URL:
Feroze KB. Ciclosporin A in ophthalmology: A systematic review. Kerala J Ophthalmol [serial online] 2019 [cited 2020 Jan 23];31:182-90. Available from: http://www.kjophthal.com/text.asp?2019/31/3/182/274614




  Introduction Top


Topical ciclosporin is an extremely important pharmacological agent in the ophthalmologist's armamentarium. It is an immunosuppressive drug, which acts mainly by inhibiting the proliferation of T-helper 2 lymphocytes and reducing the production of interleukin 2,[1] which in turn reduces the production of immunoglobulin E, activation of mast cells, eosinophils and neutrophils, and numerous toxic mediators that promote inflammatory and remodeling process.[2],[3] It is obtained from the fungus, Tolypocladium inflatum, and was used originally to prevent transplantation rejections.[4] It is used in ophthalmology in a number of inflammatory diseases and immunological conditions. It is US Food and Drug Administration approved for the treatment of dry eye disease (0.05% eye drop). Ciclosporin A (CsA) is also emerging as a potent new treatment strategy in different ocular conditions.

This systematic review was conducted to systematically review the randomized control trials (RCTs) of the usefulness, optimal dosage, safety, and efficacy of topical CsA in different ocular conditions.


  Materials and Methods Top


Search strategy

The search strategy included the following key words “Ciclosporin”, “ophthalmology”, “randomized controlled trial”, either singly or variably combined. Databases searched included Pubmed, Embase, Cochrane library and Science direct. The search strategy was to identify randomized control trials (RCTs), either singly or variably combined. Databases searched included PubMed and Embase.

Inclusion and exclusion criteria

Researches were included in the study if they fulfilled all the inclusion criteria: (a) studies involve use of topical CsA; (b) studies were RCTs; and (c) treatment effects of CsA were measured.

Exclusion criteria included:

  1. Article which was not an RCT
  2. Treatment effects of CsA were not measured.


Data selection

All the obtained data were screened according to the inclusion/exclusion criteria. Only RCTs were included in this study. Fifty-three RCTs were retrieved, and after applying the exclusion and inclusion criteria, 24 articles were included in the study. An evaluation of the quality of the research was conducted using JADAD score. This score gives a weightage of the quality of the RCT out of a total of 5. One point each is assigned if the study is an RCT, is double blinded, and whether there was a description of dropouts/failures. One additional point was assigned if the method of randomization was described and appropriate and 1 point if the method of double-blinding was described and appropriate. The score ranges from 0 (bad) to 5 (excellent). In general, scores of 3 and above are considered as reflecting good reporting quality.[5] Average JADAD value of the researches was found to be 3.16.


  Results Top


The review included 24 articles. Six articles investigated the use of ciclosporin in allergic eye diseases, 10 in dry eye disease, 4 involved eyelid diseases, 2 in corneal graft rejection, and 2 in early postoperative recovery of corneal sensation. A total of 2330 patients were included in these studies. RCTs included in the review ranged from 1999 to 2017. All the researches involved in this review were randomized and of this, 15 were double-blinded. The average JADAD score of the trials was found to be 3.16.

Ciclosporin A in allergic eye diseases

There were six RCTs which studied the effect of CsA in allergic eye diseases [Table 1]. Five hundred and forty-six participants took part in these trials. Most of the trials focused on the use of CsA in vernal keratoconjunctivitis (VKC), one study on both VKC and atopic keratoconjunctivitis (AKC) and one study on AKC alone. The various trials evaluated the efficacy of topical ciclosporin in concentrations ranging from 0.05% to 2%. The duration of the various trials ranged from 4 weeks to 4 months. Subjective relief of ocular symptoms was assessed, and the eyelid, conjunctival, and corneal signs of allergic eye disease were noted in most studies. Conjunctival biopsy was performed in one study to document conjunctival inflammation. Most of the studies showed reduction in both signs and symptoms of allergic conjunctivitis. Signs and symptoms of both AKC and VKC were found to be reduced in comparison to placebo in patients using topical CsA.[6],[7],[8] It was found to be as effective as tacrolimus and dexamethasone in VKC patients.[9],[10] In steroid-dependent allergic conjunctivitis, it was found to be as effective as a placebo.[11] Concentrations as low as 0.05% were found to be effective in moderate-to-severe VKC.[6] Histopathology showed a significant reduction in leukocyte count and other inflammatory cells.[7] These trials show that CsA is an effective alternative to steroids in allergic eye diseases without the dangers of steroid use. Minor side effects such as stinging have been noticed in these trials. As a summary, 4 out of 6 studies showed relief of symptoms and 5 out of 6 studies showed objective signs of improvement.
Table 1: Ciclosporin a in allergic eye diseases

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Ciclosporin A in dry eye disease

There were 10 RCTs with 1390 subjects studying the effect of CsA on dry eye disease [Table 2]. Majority of the studies used a concentration of 0.05% CsA. The duration of treatment in the various studies ranged from 5 weeks to 6 months. Almost all the studies evaluated the dry eye status using the Ocular surface disease index (OSDI), Tear break up time (TBUT), Schirmer's scores, and corneal staining characteristics. Two of the trials involved flow cytometry studies and monitoring of Human leukocyte antigen- DR isotype (HLD DR) expression. Most of the trials showed improvement in dry eye symptoms and signs.[12],[13],[14] Significant reduction in HLA DR-positive conjunctival cells was seen in ciclosporin users, which in turn points to its efficacy in reducing conjunctival inflammation in dry eye patients.[15],[16] However, in contact lens wearers with dry eye symptoms, there was no significant difference in symptoms and signs between CsA users and those using artificial tears in one study,[17] but there was significant symptomatic and contact lens wearing time improvement in the other.[18] CsA was found to have an additive effect with punctal occlusion and promoted long-term ocular surface health in dry eye patients.[19] Loteprednol etabonate pretreatment was found to improve response to treatment in dry eye disease patients on CsA.[20] It was also found to be as effective as Vitamin A in the treatment of dry eye disease.[21] Most of these trials showed the effectiveness of CsA in moderate and severe dry eye disease. No significant side effects of ciclosporin were noted in any of these studies.
Table 2: Ciclosporin in dry eye disease

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Ciclosporin in eyelid diseases

There were four trials which involved 170 subjects [Table 3]. All the studies used 0.05% ciclosporin topical formulation. All the studies had a treatment duration of 3 months. All of these studies assessed eyelid and corneal changes along with Schirmer's score, TBUT score, and symptoms of dry eye, either by the OSDI scores or the ocular symptoms scale. Significant subjective and objective improvement was noted in patients with meibomian gland dysfunction in the OSDI scores, the objective measurements of tear stability and volume, and the eyelid margin inflammation.[22],[23],[24] Furthermore, it was found to be more effective than dexamethasone in treating posterior blepharitis.[25] In short, it was found to be a very effective treatment option in patients with eyelid disorders, which also affect the stability of the tear film and may serve as an effective steroid-sparing agent in patients with evaporative dry eye disorders associated with eyelid pathologies.
Table 3: Ciclosporin in eyelid diseases

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Corneal graft rejection

There were two trials, involving 151 subjects [Table 4]. The concentrations of topical ciclosporin were 2% in one and 0.05% in the other, for a treatment period of 6 months. The clarity of the graft, graft thickness, and presence or absence of anterior chamber inflammation were assessed in these studies. Both of the trials showed no advantage of adding ciclosporin to steroids in patients with endothelial graft rejection and patients with previous history of graft rejection.[26],[27]
Table 4: Ciclosporin in corneal graft rejection

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Recovery of corneal sensation

There were two RCTs comparing the effect of ciclosporin versus placebo in improving corneal sensation postoperatively, one after Laser assisted insitu keratomiluesis (LASIK) and another after cataract surgery [Table 5]. Both these studies utilized the Cochet and Bonnet esthesiometer to test corneal sensation at multiple points in the central and peripheral cornea. The concentration of topical ciclosporin was 0.05%, and the treatment duration was a month in 1 and 3 months in the other.[28],[29] The number of participants were 73. Both studies showed that ciclosporin was effective in hastening recovery of corneal sensation.
Table 5: Ciclosporin and recovery of corneal sensation

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  Discussion Top


This article reviewed 24 RCTs involving various uses of topical ciclosporin in ophthalmology. It was found to be as effective as tacrolimus and dexamethasone in allergic eye diseases such as AKC and VKC.[9],[10] Concentrations as low as 0.05% were found to be effective.[6] There was also notable reduction in conjunctival inflammatory cells.[7] Thus, it is found to be an effective steroid-sparing medication with minimal adverse effects in allergic eye diseases.

Another important ophthalmological application of ciclosporin is in the field of dry eye diseases. It was found to be superior to artificial tears in moderate-to-severe dry eye,[12],[13],[14] and the mechanism of action is thought to be by reducing the accompanying inflammation seen in dry eye disease. It can be used as a supplementary management tool with punctal occlusion in severe cases.

Of the four RCTs of eyelid margin diseases, all of them showed significant improvement of tear film stability and eyelid margin inflammation with topical CsA.[22],[23],[24],[25]

There were two RCTs evaluating the effectiveness of topical ciclosporin in corneal graft rejection, but without much success.[26],[27] However, it was found to be an effective topical medication in postsurgical recovery of corneal sensation.[28],[29]


  Conclusion Top


Ciclosporin, a potent nonsteroidal immunomodulating agent, is found to be effective in the management of allergic eye diseases, dry eye disease, eyelid margin disease, and in recovery of corneal sensation. Its use in allergic eye diseases and dry eye disease, though already established, needs to be more encouraged, particularly in the severe forms of the disease as a steroid-sparing agent. However, the effect of this drug in graft failure cases is not very encouraging. The study attempted to systematically review the various commonly known and the newer uses of topical ciclosporin in the eye. Different treatment protocols and durations prevented a proper meta-analysis from being performed. Furthermore, the comparatively lesser number of trials in certain fields is a limitation in formulating the standardized dosage and a detailed analysis of the adverse effect profile. As newer RCTs emerge, a wider study in this field could be attempted and give more insight into this drug, providing the base for stronger systematic reviews.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

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Baudouin C, Figueiredo FC, Messmer EM, Ismail D, Amrane M, Garrigue JS, et al. A randomized study of the efficacy and safety of 0.1% cyclosporine A cationic emulsion in treatment of moderate to severe dry eye. Eur J Ophthalmol 2017;27:520-30.  Back to cited text no. 12
    
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    Tables

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



 

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