Current Treatment Strategies for DED, Part 1: Evaporative Dry Eye

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At one time, ophthalmologists could offer little but artificial tears for patients with dry eyes. Restasis changed that; it revolutionized the field by targeting the inflammation behind dry eye, said Esen Akpek, MD, at Johns Hopkins University School of Medicine in Baltimore. After that, research on dry eye blossomed and eventually led to other new therapies. Recent additions include new inflam­mation-fighting drugs, devices to im­prove meibomian gland function, and products to boost tear production.

Every FDA-approved treatment for dry eyes has been an “exciting advance,” said Christopher E. Starr, MD, at Weill Cornell Medicine in New York City. Yet, he noted, with so much happening, it can be hard to stay on top of all the new developments. Dry eye used to be simple to treat, but now it has become “ridicu­lously complex,” said Mina Massaro-Giordano, MD, at the University of Pennsylvania in Philadelphia.

To sort it all out, experts discuss the panoply of treatments for dry eye dis­ease (DED) and when and how to use them. Part 1 focuses on evaporative dry eye, Part 2 on aqueous deficiency.

Identifying Treatment Targets

Three types of dry eye. The variety and complexity of treatment reflects a grow­ing understanding of the various forms of dry eye. DEWS II classified DED into two main types, aqueous deficient and evaporative, which occur on a contin­uum.¹ More recently, an international study group² proposed adding a third type, decreased wettability dry eye, which is a goblet cell dysfunction leading to insufficient or abnormal mem­brane-associated mucins. According to the Asia Dry Eye Society, each type reflects a deficiency of a particular component of the tear film.²

“If we don’t have all three compo­nents working well together, then the patient is going to experience some trouble,” said W. Allan Steigleman, MD, at the University of Florida College of Medicine in Gainesville. As Dr. Starr explained, too little mucin or meibum in the tear film leads to evaporative DED; too little fluid points to aque­ous-deficient DED. And often, dry eye results from more than one of these causes.

Testing. “We need to know what type of dry eye we are treating,” said Dr. Akpek. Before devising a treatment plan, she performs an unanesthetized Schirmer test, measures tear osmolarity, quantifies tear breakup time, and looks for corneal and conjunctival staining. She inspects eyelids, eyelashes, and meibomian glands; evaluates the quali­ty of meibum; and checks for Demodex infestation. To gauge inflammation, she may test for elevated levels of matrix metalloproteinase-9 (MMP-9). She also weighs the impact of conjunctival cha­lasis, pterygium, and anterior basement membrane dystrophy.

Her assessment reveals, for exam­ple, whether patients have abnormal tear production, atrophied meibomian glands, inadequate blinking, or some combination of problems. The exam tells her the type and severity of DED, which are the keys to treatment.¹

Generally, DEWS II recommends a stepwise approach to treatment, start­ing with low-risk approaches and ad­vancing to more aggressive treatments as the severity of DED warrants.¹

LIPIFLOW. Dr. Starr applies the Lipiflow activator on a patient right after finishing the Blephex microblepharoexfoliation.

Drugs for Improving Meibomian Gland Function

Meibomian gland dysfunction (MGD), the primary abnormality in evaporative dry eye, contributes significantly to DED by increasing local inflammation and is a common finding in patients with mild-to-moderate disease, said Stephen Pflugfelder, MD, at Baylor College of Medicine in Houston. He cautioned, however, that some MGD patients need more than conservative care. Strategies for treating advanced or refractory MGD vary but may include antibiotics, anti-inflammatory drugs, and in-office procedures.

Antibiotics

A literature review published in 2022 concluded that antibiotics relieve signs and symptoms of DED from MGD and blepharitis, at least temporarily.³ To treat MGD, Dr. Pflugfelder uses antibiotics more for their anti-inflammatory effects than for their antimicrobial action. He said that both doxycycline and azithromycin inhibit MMP-9 and other inflammatory mediators in patients with overt inflammation. “They do that at very low concentra­tions,” he explained.

Prescribing strategies. For MGD-associated inflammation, Dr. Pflug­felder prescribes a month of oral doxycycline or azithromycin, unless the patient objects to taking systemic antibiotics. If the oral treatment helps, he might maintain patients on topical azithromycin. In contrast, Dr. Akpek prefers to start with a topical antibiotic. “If the patient does not respond to that, you could add oral antibiotics,” she said.

Dosing strategies vary. For doxy­cycline, Dr. Pflugfelder prescribes a sub-antimicrobial dose of 20 mg twice a day. Dr. Steigleman, on the other hand, starts patients on 100 mg a day, and if that decreases symptoms, he lowers the dose to 20 mg.

Treating concomitant conditions. Patients with facial rosacea tend to have MGD that is more difficult to manage, so Dr. Steigleman prescribes antibiotics sooner for patients who have both conditions. Additionally, treating any asso­ciated blepharitis can be very helpful for MGD, he noted. “The glands can actually start to scar after years of blepharitis, and topical azithromycin has been reported to be associated with improving some of that scarring,” he said.

The controversy. After treatment stops, the benefits of antibiotics often fade away. In a review paper³ on the use of antibiotic treatment for DED, the authors concluded, “Given the unclear long-term benefits, common side effects, and increasing antibiotic resistance seen globally, the existing literature is not sufficient to conclude that antibiotics are useful in long-term MGD management.”

To prolong the benefits of antibiotic treatment, Dr. Steigleman maintains patients on topical azithromycin the first week of every month. He agreed that this approach raises concerns about antibiotic resistance, but “when you have someone in front of you who is suffering, you want to try to relieve their suffering,” he said.

FORESHORTENING. Meibography from a patient with moderate meibomian gland truncation and loss.

Steroids

For patients with overt inflammation, redness, or a positive MMP-9 test, Dr. Starr has adopted “a very low threshold for jumping to steroids.” Dr. Steigleman, on the other hand, prefers not to treat chronic MGD or blepharitis with ste­roids because patients who feel better on them want to stay on them long-term, increasing the risk of adverse effects.

The first DED-specific steroid. In 2020, the FDA approved Eysuvis, the only steroid specifically indicated for DED. Dr. Massaro-Giordano explained that the loteprednol etabonate eye drop should be used only for short bursts of treatment. Although Eysuvis causes fewer side effects than stronger steroids, it’s important to be careful with it, as with any other steroid, she said. She typically prescribes it for two weeks, or occasionally up to a month.

Dr. Starr said Eysuvis is particularly useful when DED flares up after, say, a long plane flight or exposure to poor quality air from wildfires. He explained that some patients have as many as sev­en flares a year, so he tries to limit their cumulative steroid exposure by talking to them about what could be triggering their flares.

Other considerations. Dr. Pflugfelder often uses loteprednol or another so-called “soft” steroid, fluorometholone. He reserves dexamethasone for severe cases due to its higher potential to raise intraocular pressure. Dr. Akpek said that while stronger steroids like dexamethasone curb intraocular inflam­mation better, loteprednol is “strong enough.” Dr. Massaro-Giordano sometimes prescribes a short course of TobraDex ST (tobramycin and dexametha­sone ophthalmic suspension) because it contains a relatively low dose of dexa­methasone in addition to the antibiotic tobramycin.

Drugs for Goblet Cell Function

While the role of meibum loss in tear evaporation garners more attention, the role of mucins in preventing evapora­tion often gets overlooked—but that may be starting to change, said Dr. Starr.

In normal eyes, mucins from goblet cells in the conjunctiva coat the eye surface. There they play important roles in stabilizing the tears and protecting the eyes from pathogens, debris, and other threats.⁴ “Goblet cell loss is usually associated with more severe dry eye,” Dr. Pflugfelder said.

How to assess and treat. An insuffi­ciency of goblet cells shows up as lissa­mine green staining of the conjunctiva, Dr. Pflugfelder said. Treatment with one of the cyclosporines may reverse the shortfall. “The evidence⁵ is that they can regenerate goblet cells and can ac­tually double the number of goblet cells in about 6 to 12 weeks,” he said.

The nasal spray Tyrvaya (vareni­cline), which is used to increase tear production, may also address goblet cell dysfunction.⁶ The cholinergic ago­nist received FDA approval in 2021. Dr. Starr said it seems to push goblet cells to release more mucin and slows tear evaporation.

Devices for MGD

In-office devices may improve inspissat­ed meibomian gland orifices by using heat, intense pulsed light, exfoliation, or other means. However, to date, independent, randomized clinical trials have not yet been performed to assess the efficacy of these treatments, although there have been industry-sponsored studies. Physicians also should be aware of the costs and burdens on patients. Treatments are usually not covered by insurance, are relatively costly, and have to be repeated in-office to sustain long-lasting effects.

Dr. Massaro-Giordano finds devices may be helpful for patients who can’t or won’t use warm compresses. When antibiotics and other interventions fail to help and she sees turbid or thick­ened meibum, Dr. Akpek turns to the LipiFlow Thermal Pulsation System, which she finds especially useful when combined with microblepharoexfolia­tion. Dr. Pflugfelder often uses drugs in tandem with devices.

Recent years have brought new devices to treat MGD. They include TearCare and Optilight.

In-office thermal systems. TearCare, which was cleared by the FDA in 2021, features bubble stickers that fit over the eyelids to heat and thin the meibum. Unlike LipiFlow, it does not massage the glands, leaving the manual expres­sion of oil to clinicians.

Dr. Steigleman prefers the iLux, which warms the gland using light-emitting diodes and massages the lids. He found it to be more affordable than LipiFlow. While the first iLux gained approval in 2017, a second version, approved in 2020, added technology for digital imaging of the meibomian glands.

Dr. Pflugfelder uses the OCuSOFT Thermal 1-Touch Device, which resem­bles a pair of eyeglasses and heats the lids in about 10 minutes. He said his patients tolerate it well. He noted that the lack of independent, comparative studies makes it hard to say whether one device works better than another.

Intense pulsed light. Intense pulsed light (IPL) devices apply bursts of energy that transform to heat on absorption. Dr. Massaro-Giordano said patients have been asking about an IPL device called OptiLight, which the FDA cleared in 2021. She said it is designed to liquefy the oil in the glands, and it destroys small telangiectatic blood vessels that could carry inflammatory mediators to the eye surface.

It’s worth noting that highly pigmented skin absorbs more light energy than paler skin, increasing the risk of hypopigmentation and other adverse effects. Therefore, Dr. Massaro-Giordano offers patients with very dark skin LipiFlow or TearCare instead.

The Big Picture

There is no standard treatment for evaporative dry eye. Treatment typically proceeds by trial and error, taking into account patients’ preferences and insur­ance coverage. Despite the challenges, Dr. Steigleman said that aggressive treatment may prevent foreshortening of the meibomian glands (see Fig. 2). “You can kind of salvage what you have left, but if they’re gone, they’re gone,” he warned.

Many of Dr. Starr’s patients come to him still suffering after seeing several other doctors. Treating these complex patients requires detective work, he said, noting that it can be time-consuming and challenging to put all the pieces together. When successful, however, he finds it uniquely satisfying.

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NEXT MONTH. Many people with MGD also have aqueous deficiency, which will be covered in Part 2 in the October EyeNet. Part 2 also covers new drugs in the pipeline for MGD.

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1 Craig JP et al. Ocul Surf. 2017;15(4):802-812.

2 Tsubota K et al. Eye Contact Lens. 2020;46 Supp 1(1):S2-S13.

3 Vernhardsdottir RR et al. Ocul Surf. 2022;26:211-221.

4 Alam J et al. Ocul Surf. 2020;18(2):326-334.

5 Pflugfelder SC et al. Cornea. 2008;27(1):64-69.

6 Dieckmann GM et al. Ophthalmol Ther. 2022;11(4):1551-1561.

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Dr. Akpek is professor of ophthalmology and rheumatology at the Johns Hopkins University School of Medicine in Baltimore. Relevant finan­cial disclosures: None.

Dr. Massaro-Giordano is professor of ophthal­mology at the Scheie Eye Institute, Perelman School of Medicine, University of Pennsylvania and codirector of the Penn Dry Eye and Ocular Surface Center, Philadelphia. Relevant financial disclosures: Anida: C; HanAll Bio: C; Oyster Point: C; PRN: SO.

Dr. Pflugfelder is professor and James and Margaret Elkins Chair in Ophthalmology at Baylor College of Medicine in Houston. Relevant financial disclosures: Kala: C; Théa: C.

Dr. Starr is associate professor of ophthalmol­ogy at Weill Cornell Medicine and director of the refractive surgery service and ophthalmic education at New York-Presbyterian Hospital in New York City. Relevant financial disclosures: Aerie: C; Aldeyra: C; Allergan: C; Bausch + Lomb: C; BlephEx: C; Bruder: C; CSI Dry Eye: C; Dompé: C; Essiri Labs: C, PS; Humidifeye; C; Johnson & Johnson: C; Kala: C; Novaliq: C; Novartis: C; Oyster Point: C; Quidel: C; Sight Science: C; Sun: C; Tarsus: C; Trukera, C; Vision­ology: C, PS; Versea; C.

Dr. Steigleman is associate professor, University of Florida College of Medicine in Gainesville. Relevant disclosures: None.

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