An Updated Overview of Inflammatory Dry Eye

Dry eye disease (DED) remains under-appreciated and under-treated, and involves a variety of presentations, including dryness, redness, mild discomfort, severe disabling pain, and visual impairment.¹ Early on in the disease, both environmental and physiological factors contribute to excess tear evaporation and changes in tear composition, but as it evolves, inflammation becomes a key driver, contributing further to the breakdown of ocular surface homeostasis and leading to the development of tissue damage.² In fact, research has shown that ocular surface inflammation is present in 40% to 65% of DED cases, regardless of disease etiology.³

This article examines the differential diagnosis of inflammatory dry eye, its management options, and more.

(DIFFERENTIAL) DIAGNOSIS

Inflammation expresses itself in two forms, primarily; either acute or chronic. Inflammation that lasts for months to years and comes on gradually is considered chronic. Such a sustained inflammatory state may be associated with an autoimmune disorder such as Sjögren syndrome, lupus, rosacea, or rheumatoid arthritis, or it could occur due to low-level exposure to an irritant.⁴ Because inflammation can be a manifestation of a systemic disease, differential diagnosis should be considered in the presence of ocular surface inflammation.⁵

Various risk factors contribute to the perpetuation of this inflammatory state, including advancing age, as it leads to the accumulation of free radicals; obesity, which intensifies proinflammatory cytokines; diets rich in saturated fats and refined sugars; smoking; sleep disorders; and stress.^4,6 Each of these factors can induce and sustain low-level chronic inflammation, thereby subjecting the body—eyes included—to significant physiological stress.⁴ These factors, in addition to age-related changes, can induce inflammation not only on the corneal surface, but also in the conjunctiva, lacrimal gland, and meibomian glands,⁷ the collective effect of which disrupts the balance of the tear film, ultimately leading to a loss of homeostasis, resulting in inflamed dry eyes.⁸

Ocular Demodex is a chronic inflammatory disease caused by an infestation of Demodex mites that affects the lid margin and ocular surface in up to 70% of the worldwide population.⁹Demodex mite infestation can also lead to dryness.

Sometimes, when putting together a patient’s clinical dry eye diagnosis, it’s not only helpful, but also essential to understand their symptoms, environment, occupation, diet, surgical histories, and any contact lens habits and/or autoimmune disease. To further help us in the diagnosis of DED, we need only look to our armamentarium of available tools. Surveys such as the SPEED questionnaire, tear break-up time, fluorescein staining of the cornea, and lissamine green or rose bengal staining of the conjunctiva to detect tissue damage are useful places to start. Additional evaluation may be conducted via corneal sensitivity, which is severely decreased in patients with diabetes, or incomplete lid seal testing,¹⁰ as well as tear osmolarity.¹¹ If you suspect meibomian gland dysfunction (MGD) is a factor, evaluate the quality of the meibomian glands at the slit lamp and perform meibography, if available.³

Tear film hyperosmolarity can be another indirect sign of inflammation. Indeed, although hyperosmolarity is regarded as the key triggering factor of ocular surface inflammation, inflammation itself may in turn lead to dysfunction of tear secretion and therefore increased osmolarity.^12,13 Even matrix metalloproteinase‐9 has been shown to contribute to the DED inflammatory process.^12,15 Direct measurement of this inflammatory biomarker is possible with a point-of-care immunoassay.¹⁶

MANAGEMENT

It’s important to break the cycle of DED and prevent chronic disease and progression. For patients with mild DED presenting with few symptoms and minimal signs (eg, limited punctate staining), effective therapy may include environmental/lifestyle adjustments, use of preservative-free artificial tears, and/or incorporation of oral omega fatty acid supplementation. Eyelid hygiene and warm compresses, particularly newer designs that precisely control temperature and duration, can also be effective for those who show early signs of MGD.

Hygiene and OTC Drops

Mild symptoms of DED may be managed by simply having a patient make adjustments to their environment, lifestyle, and/or diet (eg, supplementation with trigylcerides from omega-3 fatty acids); practice better ocular hygiene; and apply warm compresses. OTC preservative-free artificial tears may be used to mitigate and alleviate inflammation and relieve dry eye symptoms.

Prescription Therapeutics

For patients whose DED is not sufficiently managed with OTC approaches and eyelid hygiene, a variety of pharmaceutical options are available. For example, antiinflammatory therapies include immunomodulators such as lifitegrast ophthalmic solution 5% (Xiidra, Bausch + Lomb), various iterations of cyclosporine, and loteprednol etabonate ophthalmic suspension 0.25% (Eysuvis, Alcon). Anti-evaporative drops, such as perfluorohexyloctane ophthalmic solution (Miebo, Bausch + Lomb),^17-19 and neurostimulators such as varenicline nasal spray 0.03 mg (Tyrvaya, Viatris) are other options. Lotilaner ophthalmic solution 0.25% (Xdemvy, Tarsus Pharmaceuticals) is a pharmaceutical option.²⁰

A LOOK AT THE CLINICAL DATA

In looking at the trial data for some of these available dry eye therapies, the results prove them all to be effective, which offers us leverage as health care practitioners when discussing treatment protocols with patients.

In one clinical trial, researchers randomly assigned 1,061 patients across three arms to receive either varenicline solution nasal spray (VNS) 0.06 mg, VNS 0.006 mg, or vehicle control. Treatment-emergent adverse events aside, 93.5% of patients receiving VNS completed the treatment period, while only 80% of patients in the integrated clinical trials for cyclosporine ophthalmic emulsion and 91% of patients in the integrated trials for lifitegrast completed the full treatment period, respectively.²¹

Researchers in another trial evaluated the safety of loteprednol etabonate ophthalmic suspension 0.25% (then KPI-121 0.25%) in 1,430 patients with DED in one phase 2 and three phase 3 randomized trials of similar designs. They found the suspension to be safe and well-tolerated when dosed four times daily for 2 to 4 weeks in patients with DED.²²

In an investigation seeking to explore the heterogeneity across different subgroups of DED and identify which participants were most likely to achieve clinically meaningful benefit with lifitegrast treatment, researchers analyzed 1,429 participants (716 in the placebo group and 713 in the lifitegrast group; 1,087 women [76.1%]; mean [SD] age, 58.7 [14.3] years). This post-hoc responder analysis was performed using data from the phase 3 OPUS-2 and OPUS-3 studies (12-week, prospective, double-masked, multicenter, placebo-controlled, randomized, parallel-arm clinical trials that previously demonstrated the efficacy of lifitegrast in DED). The study researchers stratified pooled data into four subgroups based on severity of inferior corneal staining score (ICSS; ≤ 1.5 vs > 1.5) and eye dryness score (EDS; < 60 or ≥ 60) at baseline. For the overall pooled population, responder and composite responder rates favored lifitegrast versus placebo (OR range, 1.29 [95% CI, 1.05-1.59] to 2.10 [95% CI, 1.68-2.61]; P ≤ .02).²³ In the composite analysis, the subgroup with ICSS of greater than 1.5 and EDS of at least 60 at baseline (ie, moderate to severe DED) demonstrated a 1.70- to 2.11-fold higher odds of achieving a clinically meaningful improvement with lifitegrast across all sign and symptom endpoint pairs (P ≤ .001).²³

It is important to understand that not managing ocular surface disease (OSD) aggressively is one of the main reasons patients switch providers and seek care elsewhere. From a practice management standpoint, this is a disaster. Poorly managed OSD is also one of the main reasons patients drop out of contact lenses. Again, a practice management nightmare. Many cataract surgery patients are choosing specialty IOLs. If their OSD is not managed or even tested for preoperatively, they will not have good vision postoperatively. This leads to unhappy patients who have spent a lot of money on IOLs. It is not uncommon for me to hold a patient for 2 to 3 months before I am comfortable with the health of their corneas. Many head into surgery on some immunomodulator, triglyceride omega-3s, and with punctal plugs. This is quality, comprehensive care.

With all of the dry eye treatment options available to us, our job is to determine which therapy will work best for each individual patient we treat. Sometimes that is accomplished through trial and error; other times we hit the jackpot on our first attempt. As we all know, no two patients are the same.

IDENTIFY, TREAT, AND MANAGE

DED is distinguished by a persistent inflammatory response of the ocular surface. If ignored, this perpetual inflammation can lead to chronic disease. To break the cycle of DED and prevent chronic disease and progression, we need to employ treatments that target specific inflammatory effectors and/or pathways. Several therapeutic options for treating the root causes of this disease are available, with more on the horizon. It’s our job as clinicians to be on the lookout for dry eye in our patients, so we can detect it early and find effective treatment options to break the cycle of disease, quell their signs and symptoms, and prevent tissue damage.