Anti-Inflammatory Medications in Dry Eye Disease

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10 min read

Mark Milner, MD, and Darrell White, MD, discuss the role of anti-inflammatory medication in treating dry eye disease and share their prescribing protocols.

Despite the broadening of the anti-inflammatory therapeutic landscape as it becomes more widely researched, there are still practitioners who are reluctant to embrace these medications as a first-line treatment for dry eye disease (DED).
However, at its core, dry eye is a chronic inflammatory process and should be treated accordingly to break this vicious cycle of inflammation. Adopting an anti-inflammatory regimen is the most direct way to do so.

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Stopping the dry eye cycle

There are three primary components within the inflammation cycle: irritation, inflammation, and tear deficiency/instability, which can exacerbate the next in a continuous sequence. Irritation leads to an upregulation of T-cells and cytokines, which leads to an inflammatory response. To add insult to injury, when there is goblet cell morbidity, the homeostatic balance is thrown further out of kilter leading to meibomian and lacrimal glands inflammation, resulting in a decline in tear production.

That tear deficiency and instability causes further irritation. And the cycle begins again.

Of course, there are myriad factors in inflammation. Common culprits of irritation are smoking, pollution, contact lenses, LASIK, PRK, and topical glaucoma drops. Autoimmune diseases lending to the inflammatory stage can be Sjögren’s syndrome, graft-versus-host disease (GVHD), thyroid disease, polyarteritis nodosa, rheumatoid arthritis (RA), psoriatic arthritis, and Wegener’s granulomatosis. As for tear instability, among the contributors are rosacea, menopause, and certain oral medications, such as hydrochlorothiazide, fluoxetine, and loratadine.

Successful treatment for inflammation can be broken down into three key steps:

  1. Identify and treat the trigger.
  2. Regardless of the trigger, aggressively treat the inflammation. It is paramount to reduce/eliminate inflammation to break the cycle and potentially allow for the restoration of ocular surface homeostasis.
    1. If the cycle of inflammation is not broken, there is the possibility of heightened cumulative inflammatory spikes, commonly known as dry eye flares (DEF), which could lead to a compromised ocular surface causing further complications.
  3. Acknowledge that dry eye disease is a chronic, progressive disease and, therefore, must be treated chronically. If treatment is abandoned, the DED will progress.

The case for anti-inflammatories as first-line treatment

As we have established, dry eye is an inflammatory process and should be treated as such. The most effective intervention is through one of the available anti-inflammatory medications, cyclosporine (Restasis and Cequa) or lifitegrast (Xiidra). As they have very little downside, anti-inflammatory medications can be used as a first-line treatment prescribed at the initial visit. Anti-inflammatory medications are safe and easy to use twice a day.
The primary downside to these medications is that they must be taken every day for the duration of the patient’s life, as there is no cure for dry eye disease. However, there is ever-improving management.

Patient stratification for dry eye disease

Using the CEDARS algorithm, which uses a diagnostic- rather than a severity-based approach for classification, Dr. Milner separates patients into four basic groups, with anti-inflammatories being an efficacious treatment for the first three.
  • Tear/Aqueous Deficiency
  • Evaporative disease
    • Based on goblet cell loss, always accompanied by rapid tear breakup time, and could be with or without minimal blepharitis
  • Blepharitis
  • Exposure
The category—or categories, as there can be overlap—the patient falls into dictates the treatment and choice of anti-inflammatory. For instance, an individual with marked meibomian gland dysfunction coupled with collarettes or follicles will receive erythromycin at bedtime or azithromycin (AzaSite) twice daily for the first two days, then once daily dosing for 5 days to treat the Staph aureus.
While Restasis is indicated for the treatment of aqueous deficient dry eye, there is an off-label component by ameliorating signs of evaporative disease exhibiting partial replenishment of goblet cells in the original clinical trials and postmarket studies. In addition, based on several studies, each of these medications can improve meibomian gland function. A randomized controlled trial headed by Hank Perry, MD, and Eric Donnenfeld, MD, documented the success of Restasis in diminishing posterior blepharitis.

Dual strategies, singular goal to treat inflammation

When it comes to the implementation of steroid treatment, the doctors have differing philosophies, both stemming from their early medical training. However, the goal is the same—timely anatomical repair and symptom relief resulting in patient satisfaction.
Dr. White follows the axiom of a prior mentor, a neuro-ophthalmologist who taught, “If you don't make the patient feel better the first time you see them, they're not going to think you're a good doctor, and they're not coming back.” To ensure patients see an immediate improvement, he employs topical steroids as adjuvant therapy when starting them on an immunomodulator. This also helps reduce some of the potential side effects associated with Restasis, Cequa, and Xiidra.
He chooses the specific steroid based on the severity of the dry eye disease. For mild to moderate dry eye patients, Dr. White opts for loteprednol (Eysuvis). For more severe cases with greater inflammation, he prescribes Flarex. As a fluorometholone acetate, in his professional opinion, Flarex provides better penetration than fluorometholone alcohol but has the power of prednisolone acetate, offering both efficiency and a favorable safety profile.

On the other hand, Dr. Milner takes a more conservative approach to steroid use, reserving topical steroids for three main instances.

First, for acute cases with extreme swelling, presence of filaments, and erythema. Second, for patients who complain of a prior history of burning or other side effects with one of the anti-inflammatories.
For patients who have been seen by more than one other doctor and are frustrated with the results, he prescribes topical steroids alongside an immunomodulator, knowing that without immediate relief, these individuals are likely to discontinue treatment. Generally, Dr. Milner prescribes a 2-week course of steroids along with a continued course of an anti-inflammatory to be started simultaneously. He sees patients at 4 to 6 weeks to gauge results and intraocular pressure measurements.

Dry eye flares (DEF)

As alluded to earlier, many dry eye patients will suffer a resurgence of symptoms at some point. As with any chronic inflammatory process, flare-ups are to be expected. It is important to educate the patient on the likelihood of breakthrough symptoms and that this does not mean the immunomodulator is no longer working.
Also, it is advantageous to make them aware that a multitude of circumstances can contribute to dry eye flares, including medications (i.e., antihistamines for their allergies), environmental aggravators, recent surgeries, dehydration, or a compromised immune system. To relieve interim discomfort, add a topical steroid, such as Eysuvis or Flarex, for 2 to 4 weeks to reduce and extinguish the inflammatory response.

Addressing false failures

Every eyecare provider has had to mitigate false failures in a patient who, despite all management efforts, reports only a nominal level of improvement. Most often, there is a logical reason as to why the results have not been as expected.

3 common reasons underlying false “failures” include:

  1. Unrealistic patient expectations: The patient believes they will be symptom-free in just one week or some other unreasonable time frame.
  2. Patient misunderstanding leads to noncompliance: The patient does not start the steroid and anti-inflammatory in tandem or discontinues one or the other prematurely.
  3. Misconception: Patients believe that burning means the medication is doing harm, not good.
In addition, both physicians and patients need to shift their perspective from full failure to partial success. A 60% resolution in symptoms, though not complete, is still an improvement. Using the glaucoma analog, if a patient’s initial IOP is 27 with a goal of 17 and, after treatment with drops, lowers to 22, this would still be considered progress. The same applies to dry eye disease; any percentage of alleviation of symptoms and rejuvenation of the ocular surface should be seen as a victory.
The belief around Restasis failure was challenged in the PERSIST study, in which doctors reported “failures” with patients under 12 weeks of treatment, many for the reasons listed above. After reinitiating Restasis with proper patient education and ancillary therapy (i.e., topical steroids, punctal plugs, etc.), the research determined an 80% success rate based on improvement in signs, including corneal staining.

In conclusion

We must acknowledge that DED, and by extension, dry eye flares are chronic inflammatory processes. The best results are achieved by following the protocol of identifying the trigger, then proactively targeting inflammatory control by treating the disease persistently and continually.
Though a single intervention seldom yields complete improvement, anti-inflammatories play an essential role in breaking the vicious cycle of dry eye inflammation.
Mark S. Milner, MD
About Mark S. Milner, MD

Dr. Mark Milner is the director of cornea at Goldman Eye in Palm Beach Gardens, Florida, and an associate clinical professor of ophthalmology at Yale School of Medicine.

Mark S. Milner, MD
Darrell E. White, MD
About Darrell E. White, MD

Darrell White, MD, is the president and CEO of SkyVision Centers in Westlake, Ohio. He successfully planned, launched, and built his patient-centered eyecare business, in addition to creating a unique business and marketing model for the integration of multiple types of practitioners. Dr. White is a consultant for Bausch & Lomb as well as a member of the editorial board for Ocular Surgery News.

Darrell E. White, MD
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