Cyclosporine A eye drops for the treatment of dry eye

What is the aim of this review?
The aim of this Cochrane Review was to find out if cyclosporine A (CsA) eye drops are helpful in the treatment of dry eye. Cochrane researchers collected and analyzed all relevant studies to answer this question and found 30 studies.

What is the key message of this review?
It is unclear whether CsA eyedrops reduce the symptoms and signs of dry eye. People using CsA drops may experience adverse effects, such as burning or stinging.

What was studied in the review?
The surface of the eye is moist and covered with a thin layer of tears. When there are problems with this layer of tears, people can develop a common condition called dry eye. People with dry eye may feel discomfort, as though they have something in their eye, they may have burning sensations, or be sensitive to light. They can also have blurred vision and fluctuating vision which can affect driving and reading.

Dry eye may develop because of underlying health problems, eye treatment or for no apparent reason. One potential underlying cause of dry eye may be inflammation. CsA drops (marketed as Restasis or Cequa) aim to improve tear production by treating this inflammation.

What are the main results of the review?
Cochrane researchers found 30 relevant studies. These studies took place in many different countries (Austria, Belgium, Brazil, China, Czech Republic, France, Germany, Italy, South Korea, Spain, Sweden, Thailand, Turkey, the United Kingdom, and the United States). Twelve studies were funded by the manufacturer, one was funded by a government agency, and the remaining studies did not report funding.

Eighteen studies compared CsA combined with artificial tears versus artificial tears alone. At 6 months:

⇨ There was only low-certainty evidence on whether or not CsA combined with artificial tears may help to reduce the symptoms and signs of dry eye compared with artificial tears alone.
⇨ There was inconsistent low-certainty evidence as to whether or not CsA provides any benefit for tear production and stability.
⇨ People using CsA may have more conjunctival goblet cells (low-certainty evidence). Conjunctival goblet cells may have a role in protecting the eye by secreting mucus (a lubricant).
⇨ People using CsA drops may have more treatment-related adverse events, in particular, "burning and stinging" eyes (low-certainty evidence).

The remaining studies made several other comparisons of CsA in different concentrations with either placebo or artificial tears. The reporting of these studies did not allow us to understand the magnitude of effect.

How up-to-date is this review?
Cochrane researchers searched for studies that had been published up to 16 February 2018.

Authors' conclusions: 

Despite the widespread use of topical CsA to treat dry eye, we found that evidence on the effect of CsA on ocular discomfort and ocular surface and tear film parameters such as corneal fluorescein staining, Schirmer's test, and TBUT is inconsistent and sometimes may not be different from vehicle or artificial tears for the time periods reported in the trials. There may be an increase in non-serious, treatment-related adverse effects (particularly burning) in the CsA group. Topical CsA may increase the number of conjunctival goblet cells. However, current evidence does not support that improvements in conjunctival mucus production (through increased conjunctival goblet cells) translate to improved symptoms or ocular surface and tear film parameters. All published trials were short term and did not assess whether CsA has longer-term disease-modifying effects. Well-planned, long-term, large clinical trials are needed to better assess CsA on long-term dry eye-modifying effects. A core outcome set, which ideally includes both biomarkers and patient-reported outcomes in the field of dry eye, is needed.

Read the full abstract...
Background: 

Topical cyclosporine A (also known as ciclosporin A) (CsA) is an anti-inflammatory that has been widely used to treat inflammatory ocular surface diseases. Two CsA eyedrops have been approved by US Food and Drug Administration for managing dry eye: Restasis (CsA 0.05%, Allergan Inc, Irvine, CA, USA), approved in 2002, and Cequa (CsA 0.09%, Sun Pharma, Cranbury, NJ, USA), approved in 2018. Numerous clinical trials have been performed to assess the effectiveness and safety of CsA for dry eye; however, there is no universal consensus with regard to its effect.

Objectives: 

To assess the effectiveness and safety of topical CsA in the treatment of dry eye.

Search strategy: 

We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (which contains the Cochrane Eyes and Vision Trials Register) (2018, Issue 2); Ovid MEDLINE; Embase.com; PubMed; Latin American and Caribbean Health Sciences Literature Database (LILACS); ClinicalTrials.gov; and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP). We did not use any date or language restrictions in the electronic search for trials. We last searched the electronic databases on 16 February 2018.

Selection criteria: 

We included randomized controlled trials (RCTs) of people with dry eye regardless of age, sex, severity, etiology, or classification of dry eye. We included RCTs in which different concentrations of topical CsA were compared with one another or with artificial tears, placebo, or vehicle. We also included RCTs in which CsA in combination with artificial tears was compared to artificial tears alone.

Data collection and analysis: 

We followed the standard Cochrane methodology and assessed the certainty of the evidence using GRADE.

Main results: 

We included 30 RCTs (4009 participants) with follow-up periods ranging from 6 weeks to 12 months. We studied dry eye of various severity and underlying causes. The interventions investigated also varied across RCTs: CsA versus artificial tears; CsA with artificial tears versus artificial tears alone; and in some studies, more than one concentration of CsA. Artificial tears were used as adjunctive to study medication in all but five trials. Almost all trials had deficiencies in the reporting of results (e.g. reporting P values or direction only), precluding the calculation of between-group estimates of effect or meta-analysis.

Eighteen trials compared topical CsA 0.05% plus artificial tears versus vehicle plus artificial tears or artificial tears alone. One trial reported subjective symptoms of dry eye at 6 months and the results were in favor of CsA (mean difference (MD) -4.80, 95% confidence interval (CI) -6.41 to -3.19; low-certainty evidence). Two trials reported MD in ocular surface dye staining at 6 months, but the results were inconsistent in these two trials (MD −0.35, 95% CI −0.69 to −0.01 in one and MD 0.58, 95% CI 0.06 to 1.10 in the other; low-certainty evidence). Four trials reported MD in Schirmer test scores at 6 months and the estimates ranged from -4.05 (95% CI -6.67 to -1.73) to 3.26 (95% CI -1.52 to 5.00) (low-certainty evidence). Three trials reported risk ratio (RR) of improved Schirmer test scores at 6 months; estimates ranged from 0.98 (95% CI 0.83 to 1.17) to 3.50 (95% CI 2.09 to 5.85) (low-certainty evidence). Four trials reported MD in tear film stability measured by tear break-up time at 6 months and the estimates ranged from -1.98 (95% CI -3.59 to -0.37) to 1.90 (95% CI 1.44 to 2.36) (low-certainty evidence). Three trials reported RR of improved tear break-up time at 6 months and the estimates ranged from 0.90 (95% CI 0.77 to 1.04) to 4.00 (95% CI 2.25 to 7.12) (low-certainty evidence). Three trials reported frequency of artificial tear usage at 6 months without providing any estimates of effect; the direction of effect seem to be in favor of CsA (low-certainty evidence). Because of incomplete reporting of the results data or considerable statistical heterogeneity, we were only able to perform a meta-analysis on mean conjunctival goblet cell density. Mean conjunctival goblet cell density in the CsA treated group may be greater than that in the control group at the end of follow-up at four and 12 months (MD 22.5 cells per unit, 95% CI 16.3 to 28.8; low-certainty evidence). All but two trials reported adverse events that included burning and stinging. Participants treated with CsA may be more likely to have treatment-related adverse events than those who treated with vehicle (RR 1.33, 95% CI 1.00 to 1.78; low-certainty evidence).

Other comparisons evaluated were CsA 0.05% plus artificial tears versus higher concentrations of CsA plus artificial tears (4 trials); CsA 0.05% versus placebo or vehicle (4 trials); CsA 0.1% plus artificial tears versus placebo or vehicle plus artificial tears (2 trials);
CsA 0.1% cationic emulsion plus artificial tears versus vehicle plus artificial tears (2 trials); CsA 1% plus artificial tears versus placebo plus artificial tears (3 trials); and CsA 2% plus artificial tears versus placebo plus artificial tears (3 trials). Almost all of these trials reported P value or direction of effect only (mostly in favor of CsA), precluding calculation of between-group effect estimates or meta-analyses.

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