Dry eye disease: practical clinical considerations
Dry eye disease (DED) is a multifactorial disorder characterized by loss of tear film homeostasis with an estimated worldwide prevalence of 5% to 50%. In DED, dysfunction of the ocular structures that create and regulate components of the tear film, including the tear glands, meibomian glands, cornea, and conjunctiva, causes a qualitative and/or quantitative tear deficiency resulting in tear film instability and hyperosmolarity. This initiates a vicious cycle of ocular surface inflammation and damage that can ultimately compromise the quality of life and vision of affected patients. Current advances in DED research have revealed that inflammatory processes are implicated in the pathogenesis of DED, suggesting a vicious cycle of ocular surface inflammation involving inflammatory cytokines and immune cells. There are even hypotheses (to be proven) on an eye-intestine axis with the influence of the microbiota on the immune system.
Many factors can contribute to the development of DED, including ocular and systemic diseases (some autoimmunities such as Sjogren’s syndrome and rheumatoid arthritis as well), topical and systemic medications, and environmental conditions. Because DED is a chronic disease, treatment is most often long-term and can use both pharmacological and non-pharmacological interventions to address all etiological components. Long-term management of DED can be challenging and more often than not should involve referral to an eye care specialist. However, primary care physicians are often the first points of contact for patients with DED and, importantly, provide initial diagnosis and preliminary patient education about the disease process. Consideration of DED is also vital to multi-specialty practice due to the large number of comorbidities and medications that may contribute to the pathogenesis and progression of the condition.
Therefore, it is important for conducting physicians and clinical specialists to be aware of the etiology of DED and the treatment options available. Primary care physicians play an essential role in the management of dry eye disease by establishing a diagnosis, educating patients about the disorder, and providing referrals to eye care specialists for specialized treatment initiation and long-term follow-up. Primary care physicians and clinical specialists should consider prescribing medications with fewer ocular surface effects when possible in patients at risk of or with existing dry eye disease. But this is not always easy, due to the simple fact that all existing treatments are only symptomatic and work on average only in 15% of cases. While for systemic diseases, it is the background therapy that can mitigate the problem.
Treatment options under investigation
Usually artificial, isotonic tears, based on povidone or organic bases, or enriched with hyaluronic acid, or a corticosteroid or a dedicated anti-inflammatory are the most exploited practical options. Since DED is often associated with systemic diseases, as mentioned above, the options of an immunosuppressant such as cyclosporine or tacrolimus (also for local application) should be considered. Recently, the uridine derivative and P2Y2 receptor agonist diquafosol has come under the spotlight as a next-generation treatment for DED. Diquafosol stabilizes the tear film by stimulating both fluid secretion from conjunctival epithelial cells and mucin secretion from goblet cells.
In the conjunctival epithelium, diquafosol stimulates fluid secretion through the activation of calcium ion current-dependent chloride channels (CaCC). The epithelial sodium channel (ENaC) inhibitor, P321, has also been highlighted as the next breakthrough in the treatment of DED by preserving tear secretion and maintaining hydration in the ocular surface. Like these candidates, ion channels expressed in the ocular epithelium and involved in fluid and mucin secretion are emerging as novel targets for the development of DED therapies. From this perspective, research has been focused on the cystic fibrosis transmembrane chloride channel (CFTR) as a novel therapeutic target.
CFTR is activated via the cAMP signaling pathway and is expressed in a variety of secretory epithelia, including conjunctival and corneal epithelia, and CFTR activation induces fluid secretion in mouse and human ocular surfaces. Patients with cystic fibrosis, diagnosed by the loss of the functional mutation in CFTR, showed poor tear film stability and low ocular surface activity. A few years ago a new CFTR activator, Cact-3, was identified which has good potency and selectivity. However, due to its poor solubility, Cact-3 needs to be optimized for development as an eye drop for the treatment of DED. This is why pharmaceutical chemistry studies are underway to modify the molecule while maintaining its effectiveness but improving its bioavailability.
Published clinical trials
Referring to the immune component, a clinical trial published last December investigated the initial ocular safety, tolerability and efficacy of VVN001, a small molecule antagonist of the lymphocyte antigen LFA-1, in subjects with DED. This was a multicenter, double-blind, randomized, dose-response, vehicle-controlled, parallel-group study of 170 subjects with DED. Subjects were randomized to receive an ophthalmic solution of VVN001 (1% or 5%) or its vehicle, twice daily in both eyes for 84 days. The primary and secondary endpoints were not met and there was an overall symptomatic improvement of 25%. Adverse events with an incidence of 5% or greater in both active treatment groups were instillation site pain (5.3%), taste influence or dysgeusia (5.4%), and urinary tract infection (5,3%). No major security issues have been detected.
Finally, in a German, multicenter, randomized, unaware observer, active-controlled pilot study, patients self-treated their eyes with daily instillations of eye drops containing omega-3 PUFAs or povidone as the major components for three months. At four and twelve weeks, efficacy was evaluated on the basis of, among other things, the ocular surface disease index, intensity of ocular surface symptoms, general clinical impression, tear break-up time, corneal fluorescein staining of the tear volume and the concentration of matrix metalloproteinase-9 (MMP-9) in the tear film. Safety evaluation included visual acuity, intraocular pressure, and incidence of adverse events. A total of 80 patients were included, of which 37 in the omega-3 group and 39 in the povidone group were evaluable for the co-primary endpoints.
Both co-primary endpoints significantly improved from baseline in both treatment groups, at week 4 and week 12. Statistical analysis demonstrated that topical omega-3s were non-inferior to povidone 2% for these two parameters. Both treatments also led to significant improvement in most secondary efficacy endpoints, often with a slight difference in favor of omega-3s, but did not reach statistical significance. Omega-3 eye drops, therefore, have been shown to be non-inferior to povidone-containing eye drops in the treatment of DED. This treatment can therefore be an additional tool for managing the condition.
- edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
Kaercher T et al. Clin Ophthalmol 2022; 16:4021-4031.
Sheppard J et al. Annals Med. 2023; 55(1):241-252.
Kim YB, Oh C, Jeon D et al. J Med Chem 2022 Dec 26.
Schecter BA et al. Clin Ophthalmol 2022; 16:4145-4151.
Asbell P et al. BMJ Open Ophthalm. 2019; 4(1):e000315.
Dott. Gianfrancesco Cormaci
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