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Inflammation is involved in the pathogenic mechanism of most of the chronic ocular surface disorders. In fact, the ocular surface can be considered as an ‘immunological’ unit that works with the aim to protect the visual system from external and internal noxae. This exposes the ocular surface structures to a continuous, subclinical, inflammatory condition. In this way, the ocular surface acts as an anatomical and functional unit that maintains a controlled immunological protection against several stimuli, such as allergens, chemical or physical irritants, traumas and infections from the external environment. Normally, the ocular surface system can modulate the immunological response to avoid possible negative consequences on its structures due to an ‘exaggerated’ response or chronic activation of the immune system. However, if the pro-inflammatory stimuli are prolonged or strong enough, they can induce morphological and functional ocular surface changes, which may lead to the maintenance of a chronic inflammatory status.1 ,2
Innate and adaptive immunity participate to the defensive systems of the ocular surface. Among the innate mechanisms, the activation of toll-like receptors (TLRs), also due to the modified ocular surface flora, and the increased expression of molecules, such as acidic mammalian chitinase,3 ,4 phospholipase A2 and transglutaminase 2, have been described.1 ,5
The initiation of innate immunity mechanisms via these molecules results in the activation of the mitogen-activated protein kinase and nuclear factor κB signalling pathways, which induce the expression of pro-inflammatory cytokines such as interleukin (IL)-1α, IL-1β, IL-6, IL-17, tumour necrosis factor α, and matrix metalloproteinases.6–10 The expression of these and other molecules, if the irritating stimuli are strong enough or prolonged in time, may trigger the consequent activation of the adaptive immune pathways with the homing of lymphocytes on the ocular surface and, hence, the maintenance of a chronic inflammatory condition.
Ocular surface epithelial cells directly participate in the onset and maintenance of the inflammatory process by expressing on their membranes major histocompatibility complex class II antigens, such as HLA-DR, thus acquiring antigen-presenting capability.11 ,12 In this way, epithelial cells either participate in the recruitment of inflammatory cells (dendritic cells, macrophages and lymphocytes) or become a target for cytotoxic reactions. These events result in epithelial damage in lacrimal glands, cornea and conjunctiva. Furthermore, apoptosis takes place, in part as the result of the inflammation carried out on epithelial cells but also as an integral part of disease mechanism,13 thus two main pathogenic mechanisms are responsible for the ocular surface damage.14
The awareness of the major involvement of inflammation in the pathogenic mechanisms of ocular surface dysfunction has prompted us to research possible anti-inflammatory treatments, adapted to long-term use with few side effects. Among these, cyclosporine A (CsA) has been indicated as an effective anti-inflammatory, antiapoptotic treatment with fewer unwanted side effects than those related to corticosteroids use, nowadays considered an important tool for the treatment of ocular surface inflammation.15
CsA is a cyclic undecapeptide produced by the fungi Tolypocladium inflatum and Beauveria naevus. It is widely used as an immunosuppressant to control the rejection of transplanted solid organs and to treat autoimmune disorders. Research on its mechanism of action initially focused on the molecule's ability to inhibit activation of T lymphocytes. Later it was appreciated that cyclosporine had other activities, such as the inhibition of apoptosis.16 These effects of CsA are mediated by the binding to two cytoplasmic proteins called cyclophilin A and cyclophilin D. The binding of cyclosporine to these molecules determines, ultimately, the inhibition of T-cell activation.17 ,18
Topical CsA can be used to treat a variety of ocular inflammatory conditions, including dry eye disease (DED), high-risk corneal transplants, autoimmune uveitis and vernal keratoconjunctivitis.19 ,20 Despite its promising efficacy in treating ocular surface diseases, the use of topical CsA has been approved only by the US Food and Drug Administration (FDA), and only for the use in patients with moderate to severe DED. In the EU the regulatory agency for drugs, the European Medicines Agency, did not approve CsA use because the trials assessed to demonstrate its superiority versus the vehicle in patients with DED failed to show a significant difference between the two treatments, for the outcome measures considered. This was probably the result of including in those trials patients with moderate dry eye, who could have experienced an improvement of their conditions even with the vehicle used as a tear substitute.
Sacchetti et al,21 in this issue of BJO, addressed this particular aspect of CsA therapy, trying to perform a meta-analysis of the results obtained by randomised clinical trials about the use of CsA in DED management. Studies dealing with the safety and efficacy of topical CsA in patients with DED, and using several CsA concentrations ranging from 0.05% to 2%, in various formulations, were included in this review. They concluded that it is not possible, with the present data, to conduct a meta-analysis due to the great heterogeneity among the studies with respect to outcomes, scales of evaluations of results, and time points considered. Furthermore, they raised another important issue regarding the variation in clinical presentation of patients with DED recruited, which differed either in aetiology or severity of the disease. These are important issues because, at least at the beginning of the disease, different forms of DED are based on different types of immunological involvement. For example, the pathogenic mechanisms for evaporative dry eye are mainly based on innate immunology mechanisms, while in Sjogren's syndrome, a cell-mediated and therefore an adaptive mechanism is at the basis of the tissue damage.4 ,22 This could explain why CsA treatment is more efficacious in Sjogren's disease, for which the tissue damage is due to cell-mediated injury, rather than in blepharitis, for which innate immunological mechanisms prevail. Furthermore, due to the multifactorial nature of DED, clinical and biological signs can be inconsistent, and sometimes discordant with symptomatology, leading to problematic diagnosis and classification of the disease. The existence of many subtypes of the disease explains the difficulties encountered in selecting standardised criteria to evaluate disease severity. Moreover, dry eye is not an even process; it is characterised by cycles of worsening and improvement accompanied by morph-functional changes of the ocular surface structure.23 Hence, the results obtained by therapies addressing different stages of the disease can be biased by this confounding factor. This is the case for CsA, which should be prescribed for long-term treatment of moderate–severe cases when lymphocyte participation in the disease pathogenesis has taken a relevant role. Furthermore, existing data indicate that CsA therapy achieves its best effect after at least 2 months of treatment.24 Therefore, it is advisable that, at the beginning of treatment, CsA should be used together with faster anti-inflammatory agents, such as corticosteroids.25 Table 1 reports a possible therapeutic schema for the treatment of severe dry eye.
Evidence-based medicine data indicate that topical CsA is helpful in the treatment of dry eye. However, to have an optimal cost-effectiveness ratio for this treatment, it is necessary to better understand which patients should receive this treatment, at what stage of the disease, under which therapeutic regimen it should be used, whether it should be used alone or in conjunction with other therapies, and for how long the treatment should last.
In conclusion, CsA appears to be a very useful therapeutic tool for the treatment of inflammatory conditions of the ocular surface. Nevertheless, its use has been registered only in some countries and only for dry eye. The studies performed included patients with heterogeneous disease pathogenesis and stage, and the CsA concentrations used in the formulations proposed were variable. Further studies addressing these topics will shed light on the best way to use CsA and will render it, even more, an invaluable tool in the treatment of DED and other ocular surface inflammatory conditions.
Competing interests None.
Provenance and peer review Commissioned; internally peer reviewed.
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