Dry eye has an estimated prevalence of between 5 and 50% worldwide and has physical, psychological and socioeconomic consequences for the human population [1]. Loss of tear film homeostasis with associated ocular surface inflammation causes symptoms ranging from ‘tired’ eyes and foreign body sensation to neuropathic chronic pain and visual disturbance [2].
Inflammation has long been a target of dry eye therapy with steroids an obvious and popular choice [3]. However, there has been a slow trend in recent decades from steroid use in dry eye as a last resort, only to be used in severe Sjogren’s syndrome or when vision is threatened [4], to being reached for at the first sign of symptoms by ophthalmologists worldwide. Side effects such as raised intraocular pressure and early, accelerated cataract formation limit the suitability of steroids in the long term [5], despite the development of lower concentration, lower risk preparations like loteprednol etabonate (marketed as Lotemax 0.5%, Bausch & Lomb UK Ltd) and Hydrocortisone (Softacort 3.35mg/ml, Thea Pharmaceuticals Ltd).
The concern over steroid use in dry eye promoted research into a possible role for topical non-steroidal immunosuppressives. Non-steroidal anti-inflammatory preparations such as nepafenac have not been shown to be as effective as steroids for dry eye in lab research [6] and there remain concerns about possible ocular surface toxicity with these drops in some patient groups [7]. Ciclosporin A (CsA), a calcineurin inhibitor isolated from the fungus Tolypocladium inflatum in 1971, continues to be an important and powerful immunosuppressant used to prevent organ transplant rejection [8], and in 2003 the first FDA-approved commercial ciclosporin eye drop was developed (Restasis® 0.05%, Allergan (now part of AbbVie), USA) – this is thought to exert its effects by inhibiting T cells and cytokine release whilst also stabilising goblet and epithelial cell density and survival through immunomodulation [9]. Randomised controlled trials have shown the efficacy of ciclosporin for the treatment of dry eyes, with improvements in symptom control, tear function and ocular surface [10].
Successors include Ikervis® 0.1% (Santen, Japan) used once nightly in adults with severe keratitis not responding to lubricants; Verkazia 0.1% (Santen, Japan) for children aged 4–17 four times a day for severe vernal conjunctivitis; and the recently approved Cequa® 0.09% (Sun Pharma, India) used twice a day for adults with moderate-to-severe dry eye not responding adequately to lubricants. Ciclosporin is a highly lipophilic molecule with low aqueous solubility, and different preparations differ not only in concentration of the active ingredient but also in the vehicle, which aim to improve ocular bioavailability; Cequa® and Ikervis® are both coated with nano-particles to help travel through the tear film, which is thought to help both efficacy and reduced irritation on application [11]. They are also both preservative free.
Topical ciclosporin for dry eye remains a mainstay for most corneal specialists but has several nuances which make prescribing, uptake, compliance and continuation a significant challenge. It is an expensive treatment, with monthly costs far exceeding that of commonly used topical steroids. Ciclosporin remains contra-indicated in patients with active or suspected ocular or peri-ocular infection, malignancy or premalignant conditions. Manufacturer recommendations around pregnancy and breastfeeding suggest avoidance.
My practice is therefore to reserve ciclosporin prescribing to those in whom there is a clear inflammatory type symptomatology and examination (intermittent redness, pain and blurred vision, with abnormal tear films), in patients with significant aqueous deficiency e.g. in Sjogren’s syndrome, and in those who have failed to respond despite compliance with multiple different lubricants used appropriately. I treat any co-existing pathology such as blepharitis, meibomian gland dysfunction and allergic eye disease.
‘Selling’ ciclosporin is also a considerable challenge. Patients are naturally cautious to take immunosuppressants, and the main side effect of stinging on application/irritation reported in up to 20% of patients [12] but possibly experienced by the majority of users can put off others. However, encouragement and reassurance can go a long way, as can advising patients to keep the drops in the refrigerator before use, which is said to reduce the stinging.
Once commenced, as is common in non-steroid immunomodulatory medications, patients often do not see the effects for several weeks and may cease use for this reason. Compliance is often variable due to the lack of instant relief ciclosporin drops provide and the concomitant stinging. However, those who do persevere frequently comment on the efficacy and the resultant reduction in dependence on lubricant use. Cautiously co-prescribing with a mild topical steroid for the initial few weeks might be an effective strategy to both reduce the stinging but also diminish the dry eye symptoms in the short term whilst the ciclosporin has time to take effect [13].
My practice is to initiate treatment and review patients after 3–4 months. Should there be no improvement, patients are offered the choice to continue on ciclosporin or stop, and then alternatives are discussed. Conventional alternatives include punctal plugs and serum drops, provided eligibility criteria are met. In the context of severe and neuropathic sounding chronic pain, I consider referring to pain specialists in case systemic specialist intervention can ameliorate symptoms.
The horizon is varied and exciting. Several therapies have been approved by the FDA in the US and await arrival on our shores. VEVYE® 0.1% (Novaliq, Germany) is a newer preparation which is said to have better bioavailability and ocular penetration, using perfluorobutylpentane as a vehicle, and is preservative free. The ESSENCE phase III randomised study showed VEVYE® use was associated with excellent, statistically significant efficacy and only mild pain on instillation (in just 6.5% of participants) with effects sustained at one year [14].
With dry eyes on the rise, not least due to us being constantly glued to our screens [15], ciclosporin offers a safe and efficacious weapon against the wave of disease. Its favourable side effect profile and low-frequency dosing regime, together with newer more bioavailable and better penetrating varieties, mean ciclosporin is likely to be the backbone of our dry eye treatment strategy for generations to come.
References
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Declaration of competing interests: None declared.
