Corticosteroids (Table 7.2) bind to and activate the cytoplasmic glucocorticoid receptor, inducing a wide range of effects including inhibition of pro-inflammatory and promotion of anti-inflammatory gene transcription in leukocytes as well as promoting lymphocytic apoptotic pathways [42]. Corticosteroids improve both the symptoms and signs of DES. Their beneficial effect has been documented in a variety of clinical and laboratory studies [43–46]. However their use is not routine owing to a number of ocular complications, most notably cataract, ocular hypertension that can lead to glaucoma, and opportunistic infection; consequently they are unsuited to long-term management strategies. They are useful in brief courses to manage acute exacerbations of DES. Generally more potent topical corticosteroid agents are associated with a greater incidence and severity of ocular complications. Certain milder agents, or agents with poor intraocular penetration have a reduced effect on cataractogenesis and raised intraocular pressure but may still be useful in controlling ocular surface inflammation in DES [47].

Topical nonsteroidal anti-inflammatory drugs (Table 7.2) can be effective in some ocular inflammatory diseases but have not been consistently shown to be effective in the management of DES [45, 48]. They can induce ocular complications such as reduced corneal sensitivity that can lead to persistent epithelial defects and corneal thinning; rarely they are associated with progressive corneal lysis. For these reasons they are not commonly used in the management of DES [49].

Tetracyclines have a significant effect on Meibomian gland dysfunction, improving flow and constitution of secretions primarily through inhibition of matrix metalloprotease activity [50]. In addition to stabilizing the lipid layer they have a modest anti-inflammatory effect on the ocular surface that may be beneficial in aqueous deficiency [20].

Pro-inflammatory epithelial cell surface antigens, including MHC Class II molecules, are downregulated by minocycline [51]. Osmotic stress-related cell-signaling pathways in epithelial cells, including c-Jun N-terminal kinase, extracellular signal–related kinase and mitogen-activated protein kinase in epithelial cells, are inhibited by doxycycline [52]. Consequently there is reduced production of pro-inflammatory cytokines by these cell-signaling pathways.

Tetracyclines are most commonly administered orally, however, topical formulations are available; experimental evidence suggests that liposomal-bound topical doxycycline may have increased bioavailability than non-liposomal topical preparations [53]. Dry eye related to Meibomian gland disease and contact lens wear can be successfully treated with topical azithromycin at 1 % concentration [54, 55].

Vitamin A (retinol) is an important tear film component that maintains a moist mucosal ocular surface [56]. Stored and reflexively secreted from the lacrimal gland, retinol influences gene transcription controlling proliferation and differentiation of corneal and conjunctival epithelial cells, preventing keratinization and squamous metaplasia [57]. A rabbit model of dry eye suggested that topical retinoic acid may be protective for osmotically stressed keratoconjunctival epithelial cells [58].

Topical vitamin A (retinol palmitate) is readily available for the treatment of dry eye (^® AFT Pharmaceuticals, Australia). As an emulsion it predominantly improves signs rather than symptoms of DES [59]. However, a recent clinical trial compared topical retinoic acid administered four times daily to cyclosporine administered twice daily; both had similar positive effects on the signs and symptoms of DES [60].

Mucin is an essential component of the tear film basal layer critical for lubrication of the corneal and conjunctival epithelial surfaces. Secretagogs stimulate secretion of mucin; this reduces instability of the tear film commonly associated with DES.

Autologous serum (AS) contains crucial tear film components such as neurotrophic growth factor, epidermal growth factor, vitamin A, fibronectin, and lysozyme. These key molecular and trophic factors optimize the ocular surface; accordingly AS is used relatively commonly in ocular surface disease and DES unresponsive to topical immunosuppressive agents [66]. Compounded from patients’ own blood, AS is an important therapeutic option for DES as well as other ocular surface conditions such as superior limbic keratoconjunctivitis, persistent epithelial defects and neurotrophic keratopathy [67]. AS can be prepared at a dedicated blood-bank service or with the use of an office-based centrifuge. 1–2 units of blood is donated by the patient each time AS is formulated; diluted or undiluted serum is extracted and stored in small plastic minims. These can be used immediately or frozen. The process is repeated as required, generally 6–12 monthly; newer preparation and storage techniques have been developed to optimize stability of growth factors and other ingredients [68]. Several randomized clinical studies have reported AS to have a superior effect over non-preserved artificial tears in the treatment of DES [69, 70].

Topical cyclosporine A (CsA) has been commonly used in the treatment of DES since FDA approval was granted in 2003 for a 0.05 % ophthalmic emulsion (Restasis; Allergan, Inc., Irvine, CA) [71]. As a potent immunosuppressive CsA exerts its effect by binding to intracytoplasmic chaperone proteins cyclophilins A and D. The cyclosporine–cyclophilin A complex inhibits calcineurin phosphatase, a pro-inflammatory transcription factor that stimulates T lymphocyte cytokine production including IL-2 [72]. This is complementary to the influence of the cyclosporine–cyclophilin D complex which reduces the permeability of mitochondria, preventing pro-apoptotic enzyme release such as cytochrome c and other mediators of pro-apoptotic caspase pathways [73]. Topical CsA administered for 3–6 months reduces surface expression of apoptotic markers including CD40, CD40 ligand, and Fas in addition to immunologic markers such as HLA-DR [32, 74]. These are expressed at increased ocular surface levels in patients with DES. Other markers of CsA-induced anti-inflammatory activity include increased density of mucin-secreting goblet cells, reduced squamous cell metaplasia, and increased tear flow; the latter may be mediated by release of parasympathetic-associated neurotransmitters [75, 76]. In clinical evaluation a randomized, double-masked, placebo-controlled, dose-ranging clinical trial demonstrated CsA to provide significant improvement in symptoms and signs with the 0.05 % dosage most effective [77, 78].

CsA has very low solubility in aqueous solutions and the tear film, resulting in highly variable and incomplete absorption from conventional topical formulations [3, 79]. This is largely due to its structure consisting of a rigid cyclic peptide with four intramolecular hydrogen bonds that is highly hydrophobic [80]. To counteract its low bioavailability several methods of drug delivery have been developed. The preservative benzalkonium chloride enhances corneal penetration by disrupting epithelial cell barriers; however, it also increases surface irritation [81]. Microspheres, micelles, cyclodextrins, nanoparticles, and liposomes have been used—each system working by surrounding the hydrophobic CsA to enhance corneal penetration; however, these are typically associated with rapid clearing of CsA from the tear film [82–85].

Calcineurin phosphate inhibitors exert their anti-inflammatory effect by forming a complex with intracellular macrophilin-12, which inhibits calcineurin-related transcription of T lymphocyte pro-inflammatory cytokines [86]. Commercially available topical calcineurin phosphate inhibitors include tacrolimus (Protopic, Astellas, Tokyo, Japan) and pimecrolimus (Elidel, Novartis, Basel, Switzerland). Although initially developed for the treatment of atopic dermatitis [87], topical tacrolimus has good efficacy in the treatment of DES [88]. A more recently developed topical calcineurin phosphate inhibitor, LX-214 (voclosporin), was shown in a phase I study to be well tolerated [89]. It has been suggested that in addition to their anti-inflammatory effect, topical skin preparations applied on the eyelids may improve meibomian gland function. No topical calcineurin phosphate inhibitors have yet received FDA approval for DES.

When systemically administered, calcineurin phosphate inhibitors may have a contributory role in oncogenesis; this trend has been mostly noticed when used post organ-transplantation associated with non-melanoma skin cancers and lymphoproliferative malignancy [90]. Whether this risk translates to topical administration is unclear; however, a certain amount of systemic absorption occurs with the use of all topical ophthalmic preparations and can be minimized by digital occlusion of the lacrimal sac and puncta or use of punctual plugs.

Dietary supplements of oral essential polyunsaturated fatty acids (FAs) omega-6 (linolenic acid) and omega-3 (α-linolenic acid) have been shown to be beneficial in various inflammatory conditions including ulcerative colitis, Sjogren’s syndrome, and rheumatoid arthritis [91]. Essential fatty acids are precursors essential for synthesizing eicosanoids. Eicosanoids include prostacyclins, prostaglandins, leukotrienes, and thromboxanes which are all involved in key modulatory functions of immune activation. In general, omega-3 is anti-inflammatory and omega-6 is pro-inflammatory [92]. Omega-3 FAs reduce levels of key pro-inflammatory eicosanoids including prostaglandin E2, leukotriene B4, and cytokines IL-1 and TNF [93, 94].

Topical application of omega-3 has a clinically and experimentally demonstrated anti-inflammatory effect [93, 95]. Resolvin E1, a topically administered omega-3 FA derivative, was evaluated in a murine model of DES, and promoted corneal epithelial integrity, tear volume and decreased COX-2 expression [96]. It has recently been investigated clinically and has completed Phase II investigation [97].

Rebamipide is a mucoprotective agent that stimulates mucus secretion by inducing prostaglandin E2 production [98]. It is occasionally used to treat gastric ulcers. It has been evaluated as an ocular surface mucoprotective agent. Experimental work suggests that it improves ocular surface mucin secretion; current Phase III investigation is underway evaluating it as a treatment for DES [99]. Ecabet sodium, also used for ulcers of the gastrointestinal tract, is another medication that upregulates prostaglandin E2 pathway and mucous production. It is also currently being evaluated for the treatment of DES with phase III investigation [99].

With ongoing discovery of new molecular targets, increased understanding of the immunopathogenesis of DES and the success of new systemic anti-inflammatory agents including biological agents in treating inflammatory disease there is likely to be several new therapeutic agents to treat DES in the near future. A comprehensive review of therapeutic targets currently under investigation is beyond the scope of this chapter; however, a few will be discussed.

Tasocitinib (CP-690,550, Pfizer, New York, NY) is a Janus kinase 3 (JAK) inhibitor that has shown promise for treating rheumatoid arthritis and increasingly there is supportive evidence for its role in other inflammatory diseases [100]. JAKs are receptor-associated kinases involved in pro-inflammatory cytokines signal transduction that are specific to immune cells [101]. Aquaporins influence lacrimal gland fluid secretion, and their expression in Sjogren’s disease is altered; [102] aquaporin may have a role as a potential therapeutic target in DES but this is not yet elucidated. Other molecular targets implicated in DES immunopathogenesis include integrin α4β1 and the T_H17 subset of lymphocytes; these may have a role in treating DES [103, 104].

DES is a common, chronic ocular surface disorder that causes reduced visual function, surface discomfort and can affect workplace productivity and quality of life. Treatment of DES predominantly involves a combination of ocular surface lubricants and topical anti-inflammatory agents. Some agents such as corticosteroids and cyclosporine A have an established role in the treatment of DES; more are currently undergoing evaluation in clinical trials. As knowledge of the immunopathogenesis of DES grows, there is the potential for new therapeutic targets to be identified and evaluated as therapeutic agents. The process of translation of experimental to clinical evaluation is key to this process; hopefully new immunomodulatory and tear-film enhancing agents will lead to improved management for patients with DES.