How has the therapeutic DED landscape evolved over the past decade?
Over the last decade, better awareness and understanding of DED has led to a shift from primarily lubrication/supportive care, to mechanism-targeted therapy. There are several new classes of topical therapeutics and novel delivery vehicles and devices – cyclosporine formulations have been optimized (ex. Water-free, nanoemulsions, preservative-free vehicles), the T-cell integrin antagonist (lifitegrast) has demonstrated wide-ranging anti-inflammatory effects, mucin secretagogues (diquafosol, rebamipide) now target the mucin tear layer, semi-fluorinated alkane-based therapies target the lipid tear layer (PFHO), and an intranasal spray (varenicline) is now available to stimulate tear production.
In your systematic review, which topical agents demonstrated the strongest efficacy?
Anti-inflammatory topical agents (cyclosporine-based and lifitegrast), varenicline nasal spray, and PFHO have the most consistent randomized control trial evidence for improving the signs of dry eye disease (ex. corneal/conjunctival staining, Schirmers testing).
Were there any unexpected findings in the review?
Many randomized control trials showed statistically significant improvements in corneal and/or conjunctival staining or Schirmers testing, but failed to show strong or consistent patient-reported symptom improvements. This disconnect was emphasized in the review, and noted across different therapeutic agents. From a clinical perspective, objective improvement does not necessarily guarantee symptom relief, which is important when counseling patients and setting appropriate expectations.
The trials reviewed also varied in design, endpoints, control arms, and patient selection, thus head-to-head comparisons are difficult, and it is difficult to say that one drug is superior to another. In real world settings, any ophthalmologist will agree that there is no one set recipe to treat DED that works for every patient.
What do the findings indicate ophthalmologists should prioritize for DED treatment in everyday practice?
Identifying the predominant mechanism for a patient’s DED can help direct which treatments to suggest first (aqueous deficiency, evaporative meibomian gland disease, or mixed mechanism). For anti-evaporative approaches (if a decreased tear break-up time, meibomian gland dysfunction is noted), one could consider a lipid-based anti-inflammatory or a semi-fluorinated alkane like PFHO. For aqueous-deficiency (if more corneal and/or conjunctival staining noted with lid margins less affected) or mixed mechanism disease, anti-inflammatories (cyclosporine or lifitegrast) or an aqueous stimulator (varenicline) would be considered first.
Are there any emerging pharmacologic DED agents in development that look promising?
The therapeutic dry eye landscape is very exciting, since there are constantly new products coming down the pipeline. Currently, mucin secretagogues are used more in Asia, but show promise with supportive randomized controlled trials (RCTs). PFHO and similar products are not yet uniformly available worldwide, but they can be very effective with evaporative dry eye patients. The approval of a nasal spray has opened the door to other non-ocular stimulation devices that we will no doubt be hearing more about in the near future.
What takeaway message would you like ophthalmologists to remember from the review?
The main takeaway message for ophthalmologists is that there are many options available to treat patients with dry eye disease. Any patient who demonstrates corneal or conjunctival staining or has symptoms of dry eye, has triggered the inflammatory cascade on their ocular surface. Thus, prescribing some form of topical anti-inflammatory therapy is important to prevent progression and worsening of symptoms and signs, which is the natural course of dry eye disease. It is helpful to identify if a patient has more aqueous deficient versus evaporative dry eye (due to meibomian gland dysfunction) versus mucin deficiency in order to choose a therapy that is more targeted to that mechanism.
Is there anything else you would like to add?
Counseling patients and setting realistic expectations is important. Since objective signs improve more consistently than symptoms, often patients need additional reassurance, and combining therapies may be useful. Multiple additional modalities like lid hygiene, in-office gland optimization therapies, environmental modifications, and tear substitutes may also be required to obtain symptom relief. Continued and improved cyclosporine and lifitegrast data support their continued role.
