Managing Inflammation in Dry Eye Disease
- Several US Food and Drug Administration (FDA)-approved agents are specifically designed to address the underlying inflammation associated with dry eye disease (DED).
- Selecting an anti-inflammatory treatment for DED depends on several factors, including the onset of action.
- Patients need to be educated on what DED is, specifically that it is a chronic condition for which there is no cure.
Ocular surface disease (OSD) is an umbrella term that includes several conditions, most commonly DED and meibomian gland dysfunction (MGD). In the United States, approximately 7% of adults are diagnosed with DED. Notably, DED is underdiagnosed, with 2.5% of Americans with symptomatic DED not receiving a diagnosis, a number not included in the previous 7%.1 The Tear Film and Ocular Surface Society Dry Eye Workshop II (TFOS DEWS II) defines DED as a “multifactorial disease of the ocular surface characterized by a loss of homeostasis of the tear film and accompanied by ocular symptoms, in which tear film instability and hyperosmolarity, ocular surface inflammation and damage, and neurosensory abnormalities play etiological roles.”2 In the last several decades, our knowledge of the inflammatory process in DED has evolved, and there are now several FDA-approved agents specifically designed to address the underlying inflammation associated with DED.3
In the following interview, Francis Mah, MD, an ophthalmologist with Scripps Clinic in La Jolla, California, provides insights on the role of inflammation in DED development and self-perpetuation, explains a stepwise approach to therapy, and discusses how to tailor treatment to specific patient needs.
The 2017 TFOS DEWS II included inflammation as part of its DED definition.2 In the years since, what have we learned about the role of inflammation in DED?
In general, the etiology or pathophysiology of DED has been a dynamic learning process for researchers, clinicians, and patients. Every day, there is new research coming out to help further delineate the various aspects of dry eyes. We do not yet have all the answers, and the definition of DED will continue to evolve. The major learning points from TFOS DEWS II included an updated clinical decision algorithm to remove the perception of exclusivity between aqueous deficient and evaporative DED and the recognition that disruption of homeostasis of the tear film that damages the ocular surface and leads to inflammation as the central pathophysiological concept behind DED.2 But you need to ask what is really causing this OSD? If it is surgery, that is acute — there are lots of drops going on the eye that may have preservatives. We are creating an incision in the cornea, depending on the type of procedure. Infections and allergic conjunctivitis could cause OSD. Digital device use is not an acute or dramatic event per se, but there is chronic waxing and waning tear loss as well as exposure, which improves when we blink or look away from the screen. In this case, there is a slow build-up of inflammation over time. But inflammation is always part of the picture. There is an inflammatory component to all of these underlying causes that evolves over time, varying based on what type of DED is present.
When you begin to treat a patient with OSD, do you still use a stepwise approach, per TFOS?
We do use a stepwise approach, but instead of 1 step at a time, now we may combine 3 or 4 steps. Patients need to be educated about their disease and they do not always want to jump to medication. From what I have seen, upwards of 90% of patients have a combination of evaporative and aqueous deficient DED, so we need to address both types. I first recommend a thermal treatment. Historically, we have called these warm compresses. I advise patients to purchase a bead-filled or gel-filled mask, which can be heated in a microwave — or even better, an electric heating mask. It heats to the appropriate temperature for the recommended amount of time. This helps decrease the viscosity of the oil in the meibomian glands. I also recommend that patients clean the base of their eyelashes, for example, with a product containing hypochlorous acid, as well as use a little bit of preservative-free ointment before bed in case they cannot close their eyes all the way (which is known as lagophthalmos). Finally, I recommend using preservative-free artificial tears up to 4 times a day. This is where you start, and patients appreciate the education and these management approaches before prescribing medications.
Now, some patients come in and they have already tried these things, or their eyes are obviously inflamed. They have swelling of the eyelids, conjunctival hyperemia, keratitis, or corneal and conjunctival staining. In these cases, you need to be a lot more aggressive and use anti-inflammatories such as steroids that will act quickly. We do not like using steroids long-term because of the risk of intraocular pressure increase and cataract formation. In conjunction with steroids, we will prescribe a safer anti-inflammatory like lifitegrast or cyclosporine and then taper off the steroid as the more targeted anti-inflammatory effects of lifitegrast or cyclosporine ramp up.
Because DED never fully resolves, do you recommend that patients use warm compresses daily?
If there is evidence of MGD or blepharitis, I recommend doing some form of warm compress or an in-office thermal procedure regularly in order to keep the meibomian glands healthy. The analogy I use is that it is similar to brushing and flossing your teeth. You would never ask a dentist when you can stop brushing and flossing. Just like taking care of your hair, skin, or teeth, you need to take care of your eyes. To some degree, it needs to be long-term and part of the routine. It is very important to educate patients on their care. Many have heard of DED but think they have allergies or an infection. They need to understand what DED is and that there is no cure. Right now, it is about trying to improve their daily functioning so that they can have healthy eyes.
When you do have to use an anti-inflammatory, how do you choose between the various options?
I think the easiest way is to look at the speed at which the anti-inflammatories affected the eyes in their FDA clinical trials. For example, cyclosporine 0.05% takes between 1 and 6 months before it effects any change,4,5 which can be a long time to ask someone to use those eyedrops. Lifitegrast takes 2 to 12 weeks,6 and cyclosporine 0.09% takes 2 to 4 weeks.6-8 Some of these drops are only indicated for the clinical signs of DED, like cyclosporine, and others are for both the clinical signs and symptoms, like lifitegrast. Unfortunately, the decision can often be guided by insurance and formulary access. What will the insurance approve, and what will they pay for? Every clinician will have their personal preference and choice. I like using lifitegrast and cyclosporine 0.09% because they work a little faster. If there is a flare, or acute inflammatory change, I like to use loteprednol. There is an FDA-approved formulation of 0.25% for this drug that worked within 2 weeks for signs and symptoms.3
Are there any noteworthy differences in side effects that you consider?
All the drops have some amount of instillation site burning or irritation. There is not a single eyedrop that does not. The thought is that the surface of the eye is dry and inflamed anyway, so anything you put on top of it will create some burning or stinging at the beginning of treatment.
How long do patients need to be on DED mediation?
Theoretically, patients should use lifitegrast or cyclosporine continually. I have had patients decrease their drops successfully to once per day, every other day, or even a couple times per week. I have had some patients stop the drops completely if their dry eyes were induced by an acute change, like LASIK or cataract surgery, and they did not have signs or symptoms of DED previously. But you need to set expectations right away with the patient—DED does not go away.
This Q&A was edited for clarity and length.
Francis Mah, MD, reported affiliations with Allergan, Inc; Bausch & Lomb, Inc; Novartis Pharmaceuticals Corporation; Sun Pharmaceutical Industries, Ltd; Kala Pharmaceuticals; and Oyster Point Pharmaceuticals, Inc.
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6. Holland EJ, Luchs J, Karpecki PM, et al. Lifitegrast for the treatment of dry eye disease: results of a phase III, randomized, double-masked, placebo-controlled trial (OPUS-3). Ophthalmology. 2017;124(1):53-60. doi: 10.1016/j.ophtha.2016.09.025
7. Schechter BA, Urbieta M, Bacharach J, et al. Effect of OTX-101 in patients with dry eye disease at day 14 of treatment: ocular surface endpoint results from the phase 2b/3 clinical trial. Clin Ophthalmol. 2022;16:4145-4151. doi:10.2147/OPTH.S392315
8. Goldberg DF, Malhotra RP, Schechter BA, Justice A, Weiss SL, Sheppard JD. A phase 3, randomized, double-masked study of OTX-101 ophthalmic solution 0.09% in the treatment of dry eye disease. Ophthalmology. 2019;126(9):1230-1237. doi:10.1016/j.ophtha.2019.03.050
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Reviewed May 2023