Clinical Challenges: The Role of Inflammation in Dry Eye Disease

Inflammation is critical in the diagnosis and treatment of dry eye disease (DED), though clinicians are unable to directly test for inflammation. Furthermore, the mainstay of DED therapy, preservative-free lubrication, does not treat inflammation.

Research has shown that DED is primarily an inflammatory disease. Ocular surface stress induces an innate inflammatory response. Since both innate and adaptive immune responses are involved, both responses must be suppressed. Understanding the dysregulation of the immune responses may lead to improved mechanisms for controlling inflammation of the ocular surface associated with DED.

“There is an inflammatory component in most types of dry eye that is greater in moderate to severe aqueous deficiency, particularly when there is a systemic autoimmune condition,” said Stephen C. Pflugfelder, MD, of Baylor College of Medicine in Houston. “Inflammation is also high in ocular rosacea and some cases of conjunctivochalasis.”

DED flares may cause damage to ocular tissues. Dysregulated ocular immune responses result in ocular surface damage, which is a further contributing factor to DED pathology.

Diagnosing Inflammation

DED is accompanied by changes in tear composition, including enhanced hyperosmolarity and secretion of pro-inflammatory mediators such as cytokines, chemokines, matrix metalloproteinases (MMPs), and adhesion molecules. Ocular surface dye staining, particularly conjunctival lissamine green staining, is a surrogate marker for inflammation.

The inflammatory MMP-9 immunoassay is another point-of-care marker of ocular surface inflammation, said Pflugfelder.

MMP-9 testing is a valuable diagnostic tool, correlates well with other dry eye tests, and identifies the presence of ocular surface inflammation in 40% of confirmed DED patients. It may be especially helpful to identify patients with ocular surface inflammation and autoimmune disease, and may facilitate the decision to institute anti-inflammatory treatment in these patients.

A recent retrospective longitudinal study of 67 DED patients showed eyes with detectable MMP-9 levels of more than 40 ng/mL had significantly decreased tear production over time compared with those without detectable MMP-9.

MMP-9 testing can indicate a higher level of inflammation when positive. The challenge for clinicians is what to do therapeutically after an MMP-9 test shows positivity.

“Some research shows DED patients have much higher positivity levels on MMP-9 testing, up to 1,000 ng/mL. The test is never going to be negative,” said Chantal Cousineau-Krieger, MD, of the NIH’s National Eye Institute in Bethesda, Maryland.

Clinicians have to decide how to judge the quality of the test. The sensitivity is enough to detect inflammation, but it may not be helpful in guiding further therapy.

“The question is, are we making improvements or do I need to switch paths and think about a stronger therapy?” Cousineau-Krieger said.

Treatment of Inflammation

Eye lubrication does not address the inflammatory components of DED. Treatment with corticosteroid eye drops, such as loteprednol (Eysuvis) and fluorometholone, can lead to significant improvements in the signs and symptoms of DED. Duration of therapy should be kept short to avoid steroid-related adverse events, including increased intraocular pressure and cataract formation.

Because of the chronic nature of DED and the likelihood of patients developing steroid-related complications with long-term use, topical corticosteroid therapy appears to be most appropriate for short-term “pulse” treatment of DED.

When an MMP-9 test is positive, indicating breakdown of the corneal epithelial barrier, Pflugfelder said he uses topical corticosteroids and oral doxycycline or azithromycin. “Steroids inhibit many inflammatory mediators and provide relatively rapid relief of signs and symptoms of DED,” he said. They are often used in conjunction with more chronic therapies.

Patients love to take corticosteroids because their eyes feel better, but they are not good long-term therapy, noted Cousineau-Krieger. Adverse effects from long-term use, besides formation of cataracts and glaucoma, can include droopy eyelids due to loss of muscular tissue around the eyes.

Many medications on the market are aimed at the inflammatory component of eye dryness. T-cell inhibitors, such as cyclosporine 0.05% (Restasis) and lifitegrast (Xiidra), can also be used to inhibit subacute and chronic conditions.

“I use cyclosporine A when there is moderate to severe ocular surface dye staining, particularly conjunctival lissamine green staining. I use lifitegrast for more symptomatic DED, with greater symptoms than signs,” said Pflugfelder.

These anti-inflammatory agents can take several weeks to work compared with short-acting corticosteroids. They also can cause eye stinging or burning, and some patients may not tolerate them well.

“In the office, I see whether the patient can tolerate these anti-inflammatories for a few minutes, and then flush the eyes with artificial tears. I start patients on these anti-inflammatories once a day in the morning, and council patients it may take several weeks before they see improvement,” said Cousineau-Krieger. Patient education makes a big difference in describing what patients can expect before seeing a benefit, she added.

For more severe inflammatory DED cases that do not respond to any other therapy, Cousineau-Krieger uses autologous serum tears and scleral contact lens as alternative therapies. There are also a number of anti-inflammatory therapies in development, including free radical inhibitors, signaling inhibitors, and cytokine inhibitors.

“There’s no one magic bullet that works for everyone with inflammation,” noted Cousineau-Krieger. “It depends on how much DED bothers them, how much they can tolerate, and the time and effort they devote to treatment.”

The ultimate goal is to find a regimen that the patient is willing to take that provides enough symptom relief. “We need to get patient input to customize the treatment based on what steps the patient is willing to undergo to improve inflammatory symptoms and vision,” she said. “Symptoms are helpful to close the gap between what the patient is feeling and what we are seeing clinically.”

The bottom line, said Cousineau-Krieger, is that “we cannot separate DED from inflammation. In moderate to severe DED, there is at least some level of inflammation, and the patient is going to react.”