At the completion of this article, the reader should be able to improve their management of dry eye disease (DED), including:
- Understand the role of inflammation in DED and the use of topical anti-inflammatory drops like ciclosporin A (CsA) in managing the condition
- Understand the challenges in prescribing CsA, the varying formulations, dosages and treatment durations, as well as patient compliance and potential side effects.
- Be familiar with the findings from clinical trials regarding CsA dosage, treatment duration, and comparative effectiveness with other treatment options for DED.
Dr Ngozi C. Chidi-Egboka
OD MPH PhD, FNCO FAAO
Corneal Research Group
Save Sight Institute, Faculty of Medicine and Health
The University of Sydney
Professor Stephanie Watson OAM
Bsc(Med), MBBS, PhD, FRANZCO, FARVO, GAICD
Corneal Research Group
Save Sight Institute, Faculty of Medicine and Health
The University of Sydney
Despite the promise of ciclosporin A in dry eye disease, many eyecare professionals find themselves navigating a maze of varying concentrations, formulations and dosing regimens. DR NGOZI CHIDI-EGBOKA and PROF STEPHANIE WATSON examine the literature on its effectiveness in relieving symptoms and explore the best dosage and treatment duration.
Dry eye disease (DED) is a chronic inflammatory condition of the ocular surface affecting one in five people globally and increasing in incidence as the population ages and by lifestyle and environmental conditions change.
Dry eye diagnosis is based on the patient exhibiting a series of sensitive inflammatory thresholds characterised by loss of ocular surface homeostasis including symptoms and clinical signs such as ocular surface disease index (OSDI) ≥13, Schirmer < 10mm/5min, tear breakup time <10 seconds, positive corneal and/or conjunctival staining, poor meibomian gland secretion and expressibility, fast tear evaporation and increased tear osmolarity.1
Dry eye may be caused by and/or exacerbated by several factors including allergy (Figure 1), ocular rosacea, contact lens wear, pterygium, uncorrected refractive error, ocular surgery, blepharitis (Figure 2), dysregulation of the immune system [autoimmune disease], hormonal changes, medication use and other systemic disease triggers.
Dry eye and inflammation
Inhibiting the chronic inflammatory cycle and rebuilding ocular surface homeostasis imbalance is a key goal for DED treatment. A range of studies have investigated and reported the use of topical anti-inflammatory drops such as corticosteroids and/or ciclosporin A (CsA) in DED management.2,3 Long-term use of corticosteroids may lead to the risk of ocular hypertension, glaucoma, or cataract.4
Topical CsA has been widely used as an immunomodulatory therapy targeted to: inhibit apoptosis or programmed cell death in the ocular surface epithelium; prevent the activation of T-cells; and reduce the chronic cycle of inflammatory cell infiltrates in the lacrimal gland, which may increase tear production.5 CsA is recommended for long-term management of dry eye syndrome as it has no systemic adverse effect.
Topical ciclosporin
The US Food and Drug Administration (FDA) approved the first CsA ophthalmic emulsion Restasis (CsA 0.05%, Allergan Inc, Irvine, CA, USA) in 2002 and the second, Cequa (CsA 0.09%, Sun Pharma, Cranbury, NJ, USA), was approved in 2018. The indication for both emulsions was mainly for improved tear production in clinical cases of ocular surface inflammation associated with moderate to severe dry eye disease.
Apart from Restasis and Cequa, there are five other commercial CsA products available globally including Ikervis (CsA 0.1%), TJ Cyporin (CsA 0.05%), Clacier (CsA 0.05%), Zirun (CsA 0.05%) and CyclASol (CsA 0.1%) made available by new technologies and formulations to improve CsA delivery systems and partly due to the low bioavailability of Restasis.2
Treatment of ocular surface inflammatory conditions using topical ciclosporin formulations compounded by pharmacists have also proven to be therapeutically useful.6 The relatively recent emergence of these preparations in the market has led clinicians to seek evidence for their use and for researchers to understand their therapeutic potential.7
Available products in Australia are CsA 0.1% and CsA 0.09%. Topical CsA 0.1% (Ikervis, CSL Seqirus (Australia) Pty Ltd) is the first ciclosporin to be PBS-listed in Australia which became available from 1 October 2021 as prescription-only medicine, with optometrists and ophthalmologists exclusively eligible to prescribe. CsA 0.09% (Cequa, Sun Pharma ANZ Pty Ltd) became PBS-listed in Australia from 1 June 2023 also as prescription-only medicine. Both CsA 0.1% and 0.09% are approved for use in adults for treatment of moderate to severe DED and ocular surface inflammation associated with severe keratitis. Treatment may be used in combination with artificial tears.
Prescribing indications for dED
Evidence from randomised clinical trials (RCTs) on the use of topical CsA has mostly included moderate-to-severe cases of DED and has supported the US FDA’s approved indications for use.2,3,8,9,10 Some studies have shown that patients with mild DED may also benefit from early intervention with CsA treatment which may reduce the progression of DED severity.
In Australia, the current Pharmaceutical Benefits Scheme (PBS) guideline for prescribing CsA states that the patient should undergo an initial treatment phase for up to 180 days and must exhibit corneal fluorescein staining (CFS) Grade of 4 at treatment initiation using the Oxford scale or equivalent (Figure 3) and an ocular surface disease index (OSDI) score of ≥ 23. In addition, the ocular surface condition must be inadequately controlled by monotherapy with a preservative-free artificial tear substitute. Simultaneous treatment with a preservative-free artificial tear substitute is strongly indicated. The PBS recommendation for continuing treatment with CsA after the initial treatment phase is dependent on patient receiving subsidised treatment and requires an improvement in corneal fluorescein staining by ≥ 3 grades and OSDI score by ≥30% from baseline (i.e., before initial treatment).
Given that symptoms and signs of DED often do not correlate, determining severity for treatment selection based on DED subtype classification features is strongly recommended by the TFOS DEWS II management and therapy report. The features suggested to identify include deficient meibomian gland features (meibomian gland orifice plugging, lid margin vascularity, secretion Grade 8-12, expressibility Grade of 2 and a meshwork or wave flow lipid pattern) and low tear volume (between ≤ 5 mm/5min to < 10mm/5min).4 Tear film inferometry is an a supplementary test that may support a diagnosis of evaporative dry eye (Figure 4). In cases of aqueous tear deficiency, consideration should be given to whether the patient has underlying Sjogren’s disease by consulting with a rheumatologist as concurrent systemic treatments maybe indicated in such patients.
What clinical trials say about treatment dosage
Numerous clinical trials have been performed to assess the effectiveness and safety of the various CsA formulations for dry eye and other ocular surface diseases. For DED, CsA has been used in varying concentrations and dosage including 0.05%, 0.08%, 0.09%, 0.1%, 0.2%, 0.5% and 2%. The most-frequently reported dose of CsA 0.05% was one drop instilled twice a day in each eye.
Evidence from several published studies showed significant improvements in DED symptoms and signs (improved tear breakup time and reduced corneal fluorescein staining) with twice-daily drops treatment of CsA 0.05%. Treatment with twice-daily drops of CsA 0.05% was also reported to have a higher efficacy in terms of patient responder rate compared to vehicle or AT alone for DED treatment. 2,3 Other topical CsA including CsA 0.1% and CsA 0.09% have demonstrated similar treatment effect and superior responder rate compared to vehicle. 8-10 The post-surgical management of ocular surface inflammation or dry eye with twice-daily drops of CsA 0.05% also showed better efficacy for improvement in symptoms and clinical signs including, tear stability, tear secretion, and tear osmolarity compared to antibiotics and steroid twice-daily drops in post-refractive surgery.11
Conflicting evidence on CsA dosage has also been reported. Four-times-daily drops treatment with CsA has been reported to produce a more rapid clinical response, especially for patients with persistent symptoms despite prolonged treatment with twice-daily drops treatment. Though other studies reported better treatment effect with four-times-daily drop of artificial tears over twice-daily drop of CsA 0.05% treatment12 and vice versa.13
In more severe DED, frequent CsA dosing beyond twice-daily use or additional use of antihistamines, mast-cell inhibitors (artificial tears), or topical corticosteroid may provide faster relief from symptoms and clinical signs.14 Use of increased concentrations of CsA have not been proven to have any therapeutic benefits, but there is increased likelihood of stinging and other side effects when higher CsA concentrations are used. Topical CsA concentrations from 0.05% to 0.1% have yielded better balance between efficacy and side effects.15 Increasing the daily dose of topical CsA has not been linked to systemic side effects given that there is insignificant systemic adsorption of the drug after topical application to the eye.
Optimal dosing for CsA is yet to be established. Evidence from RCTs has supported the current prescribing indications for the CsA formulations. Evidence is also emerging on variations on these dosage regimes.
The appropriate length of treatment
Improvement in outcome following twice-daily drops with CsA 0.05% for patients with moderate DED usually occurs in four to 12 weeks following the start of treatment and may take three to six months to effectively relieve symptoms. Once daily drops of CsA 0.1% also showed similar timeline to improvement effect in particular reduced ocular surface staining within four weeks and maintained up to 24-weeks treatment duration. 8,9 The delay in symptom relief is thought to occur because CsA does not deactivate previously activated T-cells, but rather prevents new T-cell activation.
After treatment has been commenced, there is evidence that relapse of DED may occur following 12-months of treatment cessation.16 In some severe cases of DED or Sjögren’s syndrome associated DED, treatment may be continued for an extended period of time, or sometimes indefinite to prevent relapse.
Overall, there is no universal consensus with regard to CsA treatment effect timeline. Evidence based on clinical studies was that CsA of different concentrations may require several weeks of treatment to show an effect. Further studies are needed to confirm if there is added advantage of indefinite treatment.
Evidence on treatment outcomes
Randomised clinical trials have compared the efficacy of CsA with no treatment, placebo or with other topical treatment options including artificial tears, and other topical anti-inflammatory eye drops. The treatment effect of commercially-available CsA formulations globally was compared by meta-analysis and CsA 0.05% concentration (Restasis) was ranked most effective for reduced DED symptoms.2 Other formulations of CsA 0.05% (Zirun and TJ Cyporin) also demonstrated higher efficacy in improving tear secretion and tear breakup time compared to CsA 0.1% or placebo.2 The risk of reporting bias in the studies included in the meta-analysis was considered low.
A Cochrane review reported inconsistent results on the effect of different CsA concentrations on DED symptoms and clinical sign changes including on tear secretion, tear breakup time and corneal fluorescein staining.3 Although the Cochrane review reported greater improvement in conjunctival goblet cell density with CsA 0.05% compared to artificial tears or vehicle as demonstrated by two studies, the certainty of evidence was low.
In other studies, more frequent dosing of artificial tears – up to four or five times daily drops – was reported to have a better effect over CsA 0.05% in improving tear film function.2,3 One study also reported better treatment effect with topical steroid drops over CsA 0.05% in improving tear film function. Studies that compared CsA 0.05% to CsA 0.1%, CsA 0.08% or 0.1% to fluorometholone, reported no difference in treatment effect on symptoms.
Overall, the majority of studies have reported better effect of reduced DED symptoms and ocular surface inflammation staining scores with CsA treatment compared to artificial tears (AT) alone or vehicle.2,3
Challenges in prescribing
A low risk of poor patient compliance is evident in the literature. Discontinuation or dropout from the clinical trials due to treatment related adverse events, especially stinging, upon CsA drop instillation was low in published studies. No serious side effects from topical CsA were found in most of the existing studies.
The common treatment-related complaints of side effects were mild-to-moderate ocular stinging, ocular burning and blurred vision. These adverse events were not significantly different between CsA treatment and other treatment comparators. The events were mostly found to have resolved within the clinical trial period, requiring no further observation beyond the trial duration.
Upon CsA prescription, patients should be warned about the possibility of side effects such as burning, stinging upon instillation, and conjunctival redness. They should also be re-assured that there are no threats to vision if side effects are encountered, since they typically resolve as the ocular surface improves. Clinical guideline recommendations are that prescribing short-term topical steroids, not more than two to four weeks prior to starting CsA 0.05% (Restasis Allergan, Irvine, CA) may decrease the associated burning and stinging associated with the drops.17 Caution must be exercised when using topical steroids due to potential adverse effect of raising intraocular pressure, causing cataracts and the risk of infection.
The big-picture
Prescribing trends based on evidence from published clinical studies show that twice-daily drops of CsA is likely to be effective for DED treatment. Significant changes from baseline have been seen on outcomes within 12-weeks of initiating treatment. Most studies found CsA 0.05% to be effective and with higher responder rates compared to other CsA concentrations or topical treatment alternatives.
CsA 0.05% demonstrated consistent improvement in treatment effect on DED symptoms and ocular surface staining. Frequent CsA dosing of more than twice-daily drops or concomitant use with antihistamines, mast-cell inhibitors (artificial tears), or topical corticosteroid may not show more efficacy of faster symptoms and clinical signs relief. Topical CsA may be better than vehicle or AT alone for managing symptoms and common clinical signs of DED. The effect of CsA treatment on tear function and other DED clinical signs may be somewhat disproportionate. Treatment-related adverse events with CsA treatment are mostly mild. There is relatively low risk of lack of patient compliance to treatment.
There was low-to-moderate certainty of evidence on the superior effect of CsA compared to vehicle, AT, or other topical treatment alternatives for DED. All published trials were short-term and did not assess whether CsA has longer-term (over one year) disease-modifying effects, thus limiting the ability of clinicians to make informed decisions regarding the use of CsA for DED treatment; and importantly, being that DED is a chronic disorder requiring long-term therapy in most patients.
Future longer-term studies are needed to confirm or validate available evidence. Work is also needed to develop a framework of practical guidelines for the use of topical CsA. Moreover, there is a need to consolidate all available evidence and provide recommendations that will enhance appropriate clinical practices for the safe use of CsA for DED treatment.
More reading
Exposing the underlying factors contributing to dry eye
Considerations for low-dose atropine for myopia control in a non-Asian population
Insights from an Australian gonioscopy workshop – Part 2
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