Discussion

‘Dry eyes’ is both a symptom and a diagnosis. A symptom, reflecting the subjective sensation experienced by the patient and a diagnosis by virtue of the label assigned to the condition based on clinical signs, such as narrow tear meniscus, rapid tear film break-up time and punctate OS erosions; with or without the support of tests ranging from the Schirmer’s test to in vivo confocal microscopy of the corneal epithelium and impression cytology of the OS.19–21 The nomenclature is varied with ‘DED’ being the most popular but terms such as keratoconjunctivitis sicca, xerosis ophthalmia and others are also used with the same connotation. Arguably DED is not one condition but a common downstream manifestation of a host of local or systemic diagnoses. In addition, disruption of the homeostasis of the OS induced by ocular surgery could also trigger or exacerbate the manifestation of DED, leading to potentially sight-threatening complications.22–24 DED related to laser refractive surgery, connective tissue diseases, menopause, graft versus host disease, cicatrising conjunctivitis or old age may have similar characteristic symptoms and signs but are clearly not the same disease entity. The term ‘dysfunctional tear syndrome’ though less popular, is more apt.6

The first global attempt at a unified definition of DED was made in 1995 by the National Eye Institute/Industry working group on Clinical Trials in Dry Eye.25 This definition did not include the term ‘inflammation’. In the years that followed evidence appeared in the literature to demonstrate the key role played by inflammation in DED and it became recognised as an inflammatory disorder,10 11 which was reflected in the publication by Behrens et al,6 in the international consensus definition of DED. The word ‘inflammation’ was incorporated in the definition of DED, proposed and published by the Dry Eye Workshops I and II.5 7 The latter added ‘neurosensory abnormalities’ to the definition to emphasise the role played by damage to OS innervation, including nerve inflammation, in DED.5

Anti-inflammatory agents were added to the variety of medications used to treat DED. Steroids were the obvious choice but with known complications associated with their long-term use. CsA 0.2%, under the name of ‘optimmune’, has been used by veterinary colleagues to treat DED in dogs since the early 1990s.26–28 CsA in varying concentrations, notably Restasis, and more recently Cequa (CsA 0.09%, Sun Pharma, Cranbury, NJ, USA), in 2018, has also been used to treat a variety of OS inflammatory diseases including DED.12 14

CsA is a lipophilic cyclic polypeptide derived from the fungus, Hypocladium inflatum gams. Its major immunomodulatory activity relates to its effect on calcineurin. Calcineurin, a cytosolic protein, is a serine/threonine phosphatase enzyme, the activity of which is regulated by calcium/calcium-binding messenger protein (calmodulin) and is important in the activation of T lymphocytes. Calcineurin, in a calcium dependent manner, dephosphorylates nuclear factor(s) of activated T cells (NFAT proteins) allowing them to translocate to the nucleus where they activate gene expression of cytokines. CsA binds to ubiquitous cytosolic proteins called cyclophilins. Cyclophilin–CsA complex binds to calcineurin and inhibits calcineurin-mediated dephosphorylation thus blocking the nuclear translocation of NFAT protein, thus preventing gene expression and transcription of several cytokines, in particular interleukin-2, involved in differentiation and survival of T helper cells.29 30

Ikervis is a 0.1% (1 mg/mL), sterile, unpreserved, oil-in-water emulsion of CsA. The eye drops also contains the cationic agent, cetalkonium chloride (CKC), which increases the resident time of the drops on the OS. Its anti-inflammatory effect covers the OS and the lacrimal gland. The same preparation, in a different presentation format and licensed for use in children (above 4 years) at a frequency of four times a day to treat VKC, is called Verkazia.16 When we started our patients with Ikervis, Verkazia was not in the market. We did however treat our patients with VKC with Ikervis at a frequency of 2–4 times a day and noticed good efficacy but unfortunately comparatively poor tolerability. Our results are consistent with the VEKTIS (VErnal KeratoconjunctiviTIs Study) study that analysed the efficacy of topical CsA 0.1% in severe VKC. The authors reported successful use of high dose CsA (four times a day) in controlling acute symptoms of VKC thereby reducing the need of rescue drugs in nearly one-third of each high-dose and low-dose group.31 However, it is to be noted that the VEKTIS Study analysed only paediatric patients with severe VKC. In the current study, we have analysed patients with VKC or AED in all age groups.

Twice as many patients with AED had resolved or were stable compared with those that needed additional treatment. Unfortunately, the number that were intolerant were as many as those who benefitted. If the tolerance of the medication could be improved, the data suggest that many more patients of AED would benefit. It is not clear why patients in the older age group tolerated the drug better than those in the younger age group. It could well be due to the difference in pain threshold of these two populations of individuals or sensitivity to excipients including CKC. A future longitudinal study will address these effects. AED patients also had a greater frequency of instillation compared with the DED group but so did the OMMP/SJS and ‘others’ groups where tolerability was better. Technically speaking, the use of Ikervis for treatment of VKC, through the course of this study, would be off-label. DED was the only licensed indication and also the one that showed the best outcome in that 82% of patients had resolved or were stable and maintained on the medication. This group also had the best tolerance, with only 11.5% having to withdraw treatment due to intolerance. Our study demonstrated comparable results in DED patients as the SANSIKA Study in which 29.2% patients reported pain on instillation with 12.3% having moderate to severe pain.32 Since the use of CsA 0.1% in DED is established, we used DED as a comparator for the other conditions treated.

Other main OS inflammatory conditions where Ikervis was used off-label, were OMMP, SJS and ‘others’. As illustrated in table 3, if patients who did not tolerate the drug (hence efficacy could not be determined) are excluded; more patients benefitted relative to those who did not. Overall, it was encouraging to see that the majority of patients in these groups benefitted on treatment with Ikervis, making it a viable steroid-sparing option for controlling inflammation manifest at the OS, negating the long-term risks of steroid induced secondary rise in intraocular pressure and cataract.33 Use of topical ciclosporin in high risk grafts to prevent graft rejection has been described. In 2004, the Cornea Society Survey revealed that 48% clinicians used topical CsA in high risk keratoplasties.34 The evidence of the benefits of topical CsA has been inconsistent.35 Although a few studies have described improvements in rejection-free rates and graft survival,36–38 majority of the studies have not been able to demonstrate any benefit of the use of topical CsA.39–41 Theoretically, Ikervis could be a potentially useful alternative in corneal transplant patients who were ‘steroid responders’. Unfortunately, this was not borne out in this study as the efficacy in managing or controlling rejection was not significant, with half the patients requiring additional steroid medication. However, the number of patients was too small for a meaningful conclusion to be drawn and a further study of this group of patients with Ikervis is warranted to determine appropriate frequency and duration of instillation, and efficacy. Use of topical CsA has been shown to be of benefit in OMMP/SJS cases.42 43 Our study showed that patients with OMMP/SJS were almost as likely to require additional topical steroids as DED patients and were more intolerant to Ikervis. Stable OS was achieved in 63.2% cases, however the sample size was small and larger studies are required to establish the efficacy and tolerance of Ikervis in these patients.

Based on this study of our real-world experience, we would recommend that all non-infective chronic OS inflammatory diseases be treated with a short course of preservative free topical steroid medication and then switch to CsA drops when a response is induced. Those that develop a relapse would require additional medication with or without the continuation of CsA. This approach will also identify initial steroid non-responders where CsA alone is unlikely to help and where systemic immunosuppressive agents may be required to induce a remission. In this study, overall 74% of patients benefitted and 16% showed intolerance across all groups. Improving tolerance of future preparations of CsA could improve the overall efficacy.

The natural course of the chronic conditions included in this study is characterised by relapses and remissions. When an acute episode was treated and resolved sufficient to discharge the patient it was taken as the end point. Hence the term ‘resolved’ is used as defined in the Methods section and does not equate to a cure. The large number of patients, the long mean follow-up duration, the real-world experience and the identification of the outcomes to be expected in different groups of inflammatory conditions are important strengths of the study. However, there are some limitations. As this was a retrospective study, it was difficult to capture quantitatively the data for all 463 patients. The lack of definitive quantitative data related to all the parameters of DED and inflammation is a limitation. The inherent limitations of a retrospective study, related to use of other topical and particularly systemic medications also apply to this study though we have analysed and presented concomitant use of steroid drops. In modern day clinical practice, cost is an important issue and cost benefit analysis is increasingly being taken into consideration for approval of drugs funded by the public purse. Such an analysis for Ikervis was beyond the scope of this study.

As the incidence and prevalence of DED affecting younger and older patients is ever increasing, the quest for alternative treatments continues. New studies on immunomodulation of OS inflammation place emphasis on novel drug delivery or mechanisms targeting T-cells. Cequa (CsA 0.09%) is a nanomicellar ciclosporin formulation that enables improved drug penetration achieving drug concentrations in conjunctival and corneal cells, however, symptoms of stinging and pain continue to be reported in 22%.44 OTX-CSI is a long-acting, preservative-free ciclosporin intracanalicular hydrogel insert designed to deliver ciclosporin up to 12 weeks while also occluding the lower punctum is currently being evaluated in a Phase I/II safety and tolerability study. Lifitegrast, an integrin antagonist that blocks the interaction of lymphocyte function-associated antigen-1 (LFA-1) / intercellular adhesion molecule-1 (ICAM-1)inhibiting T-cell activation and release of pro-inflammatory cytokines, is FDA approved as 5% ophthalmic solution (Xiidra) for use in DED. While this shows some promise, it currently does not have global marketing authorisation.45

The immune system is fundamental to the survival of the host against environmental onslaughts from a multitude of agents both innate and living. It has evolved and adapted through evolution into a very complex system that can deal with current and potential future antigens. The approaches adopted above by targeting a single molecule are probably inadequate. The plethora of molecules, the interlinked pathways, the redundancy and ability to constantly adapt imply that no single molecule in the immune system is indispensable. Targeting a single specific key molecule may contain an immune response (inflammation) for a varying period of time but unlikely to make a permanent impact. Perhaps this is why the results of studies are so variable, often conflicting, with some patients responding, some responding for some time and others not at all.