Although often disregarded as a minor problem, keratoconjunctivitis sicca, commonly referred to as dry eye, is a growing public health concern affecting as many as 17% of women and 11.1% of men in the United States (Moss SE et al, 2000). This is likely to be an underestimate if one also considers self-treating patients and milder/periodic cases with intermittent symptomatology. Risk factors for dry eye disease included advanced age, female sex, mobile phone and computer use.
In 2007, the Dry Eye Workshop (DEWS) defined dry eye as a “multifactorial disease of the tears and ocular surface that results in symptoms of discomfort, visual disturbance, and tear film instability with potential damage to the ocular surface which is accompanied by increased osmolarity of the tear film and inflammation of the ocular surface” (DEWS, 2007). Identification of inflammation as a major factor in dry eye helped make a tremendous step forward in the description and treatment of this condition.
The DEWS also recognized two subgroups of dry eye based on etiopathogenesis: aqueous deficient and evaporative. Among the aqueous deficient group, there are two major subclasses: Sjögren’s syndrome (SS) dry eye and non-SS dry eye.
According to the classification criteria from the European-American collaboration, secondary SS (sSS) consists of features of primary SS (pSS) together with features of an overt autoimmune connective tissue disease, the most common of which is rheumatoid arthritis. There is a well-known association of several systemic diseases with dry eye syndrome such as SS, rheumatoid arthritis, scleroderma, polymyositis, lymphoma, amyloidosis, hemochromatosis, sarcoidosis, and systemic lupus erythematosus (Djalilian AR, 2005). Although the rate of dry eye in various inflammatory diseases is known, the frequency of associated systemic rheumatic conditions in patients with dry eye is currently unknown. Studies have concluded that ophthalmologists manageing patients with clinically significant dry eye should have a high index of suspicion for underlying SS and a low threshold for diagnostic work-up (Akpek EK et al, 2009; Liew M, et al 2012).
Previously unrecognized autoimmune thyroid disease has also been shown to be a cause of inflammatory ocular surface disease with dry eye symptomatology and should be considered when evaluating patients with dry eye (Gupta A et al, 2009).
Based on multiple epidemiological studies, older age and female sex are widely recognized as the two most common risk factors for dry eye (Conner CG et al, 1999; Report 1, 2007). Peri- and postmenopausal females seem to be particularly at a higher risk which perhaps suggests that dry eye is an involutional disorder. In addition, hormonal studies demonstrate that sex hormones influence ocular surface conditions through their effects on aqueous tear secretion, meibomian gland function, and conjunctival goblet cell density (Krenzer KL et al, 2000; Schaumberg DA et al, 2001).
Several other external factors are also known to precipitate and exacerbate dry eye, such as long-term contact lens wear, refractive laser surgery, smoking, and extended visual tasks like computer and mobile phone use, watching television and prolonged reading (Ang RT et al, 2001; Lee AJ et al, 2002; Schlote T et al, 2004). Worsening of dry eye may also be attributed to low relative humidity conditions that are common in office environments, air-conditioned cars, airplane cabins, and extreme hot or cold weather (Wolkoff P et al, 2006). Dry eye may be caused by systemic medications with anticholinergic effects (e.g. antihistamines, antidepressants, antipsychotics) as well as diuretics (Report 2, 2007). Frequent instillation (>4-6 times daily) of preserved eye drops, particularly with benzalkonium chloride for example for glaucoma, may also contribute to dry eye because of their well-established ocular surface toxicity (Report 1, 2007).
Irrespective of the presence of any identifiable underlying local or systemic inflammatory disorder, dry eye seems to be invariably associated with chronic inflammation of the ocular surface, as detailed below, although it is not known whether the local inflammation is causative or simply occurs as a consequence of ocular dryness. Nevertheless, recognition of the role of inflammation in dry eye has been a crucial factor in facilitating dry eye treatment.
There is growing evidence from the past decade indicating that dry eye-related ocular surface inflammation is mediated by lymphocytes (Kunert KS et al, 2000). Based on earlier immuno-histopathological evaluations, patients with both SS-related as well as non-SS dry eye have identical conjunctival inflammation manifested by T cell infiltrates and upregulation of CD3, CD4, and CD8 as well as lymphocyte activation markers CD11a and HLA-DR (Stern ME et al, 2002). These results suggested that clinical symptoms of dry eye may be dependent on T-cell activation and resultant autoimmune inflammation. Multiple other studies followed and demonstrated the role of pro-inflammatory cytokines and matrix metalloproteinases (MMPs) in the pathogenesis of dry eye. Interleukin (IL)-1 is one of the most widely studied cytokines accompanying dry eye. An increase in the pro-inflammatory forms of IL-1 (IL-1α and mature IL-1β) and a decrease in the biologically inactive precursor IL-1β have been found in the tear film of dry eye patients (Solomon A et al, 2001). The source of increased levels of IL-1 was thought to be the conjunctival epithelium based on immunohistochemical studies (Solomon A et al, 2001). More recently, reactive nitrogen species expressed by conjunctival epithelium have been recognized in the pathogenesis or self-propagation of SS-related dry eye (Cejkova K et al, 2007). In the same study, IL-1β, IL-6, IL-8 and tumour necrosis factor (TNF) α were also investigated and found to play a significant role in SS-related dry eye as compared to normal eyes.
The response of cells to extracellular stimuli such as ocular surface stress, including changes in the composition of tear film or hyperosmolarity and ultraviolet light exposure, is mediated in part by a number of intracellular kinase and phosphatase enzymes (Paul A, et al 1997). Mitogen-activated protein (MAP) kinases are integral components of parallel MAP kinase cascades activated in response to a number of cellular stresses including inflammatory cytokines (e.g. IL-1 and TNF-alpha), heat shock protein, bacterial endotoxin and ischemia. Activation of these MAP kinase homologues mediates the transduction of extracellular signals to the nucleus and is pivotal in regulation of the transcription events that determine functional outcomes in response to such stresses. These stress-activated protein kinases have been identified in the tear film of patients with dry eye. It has been documented that activation of these stress pathways results in transcription of stress-related genes, including MMPs, mainly MMP-9 (Pflugfelder SC et al, 2005). In another study, MAP kinases were found to stimulate the production of inflammatory cytokines including IL-β, TNF-α, and MMP-9 and thereby cause ocular surface damage (Luo L et al, 2004).
As previously mentioned, hyperosmolarity is one of the factors contributing to ocular surface inflammation. Hyperosmolarity induces inflammation in human limbal epithelial cells by increasing expression and production of pro-inflammatory cytokines and chemokines such as IL-1β, TNF-α, and the C-X-C chemokine IL-8 (Li DQ et al, 2006). This process appears to be mediated through activation of the c-Jun N-terminal kinases and MAPK signalling pathways.
All of these inflammatory mediators and pathways are considered important as they relate to the pathogenesis of dry eye; thus a locally applied safe and potent MAPK inhibitor, such as JEL0305, could have a major role in the management of most types of DED.
As it is widely recognized that inflammation has a significant role in the etiopathogenesis of dry eye, promoting ocular surface disruption and symptoms of irritation, a number of anti-inflammatory treatments are currently in use for its management, for example cyclosporine A, tacrolimus, corticosteroids. Although they are somewhat effective, they do show systemic absorption and side effects that reduces their tolerability and use. Many more anti-inflammatory medications are in development or clinical trial phases, including JAK-inhibitors, IFA-1 antagonist, IL-1 RA, Resolvin E1. In particular, ReGenTree’s RGN-259, a Tβ4-based sterile and preservative-free eye drop, is an example of a major industry development of recent times. Recently, the company announced that it will be initiating phase-3 clinical study of the product, a step that is consequential to the huge success of the product, towards treatment of dry eye disease.
JEL0305 could have a pivotal role in the DED treatment market because of its mode of action and its safety. The route for topical ocular therapy development can be faster than standard drug development as the clinical trials can be smaller and, because JEL0305 is a peptide, toxicology studies may be significantly reduced.
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