Current Treatment Strategies for DED Part 2: Aqueous Deficient Dry Eye

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Recent years have brought new ways to treat patients who make too few tears. They range from incremental advances, like a generic form of Restasis, to novel products that activate the nasal nerves within the tear-making apparatus. Meanwhile, blood-based tears are playing an in­creasing role in dry eye care, as regen­erative medicine comes to the fore.

Who is using these treatments? Most patients with aqueous deficiency have autoimmune disease or a long history of contact lens wear, said Mina Massaro-Giordano, MD, at the University of Pennsylvania in Philadelphia. And Esen Akpek, MD, at Johns Hopkins Univer­sity School of Medicine in Baltimore pointed out, “In a great majority of the patients with meibum-deficient dry eye, there’s some aqueous tear deficiency as well, but not as severe as Sjögren type of dry eye.”

Part 2 of this two-part series focuses on treatments for aqueous deficient dry eye, whereas, last month, Part 1 covered treatment advances for evapo­rative dry eye.

Autoimmune Patients

The most serious cases of aqueous deficient dry eye are typically seen in autoimmune patients, said Dr. Akpek. Many of these patients “require a longer journey down the road of various treat­ments,” said W. Allan Steigleman, MD, at the University of Florida College of Medicine in Gainesville. He said they tend to need more intervention earlier to get their disease under control.

Dr. Massaro-Giordano treats aqueous deficiency from autoimmune disease aggressively from day one. “I’m not just starting with tears; I’m right away prescribing something,” perhaps even multiple medications, she said. For a patient with Sjögren-related dry eye, Dr. Akpek might start with anti-inflam­matory topical medicine, tear supple­ments, and tear-conserving treatments such as punctal plugs. “That would be the least I would do for that patient,” she said. (Watch for next month’s Ophthalmic Pearls, “Understanding and Managing Sjögren Syndrome Dry Eye.”)

NASAL SPRAY. Patient using Tyrvaya (varenicline), the first in-class secretagogue to improve tear production.

Subduing Inflammation

As with evaporative dry eye, inflamma­tion is thought to contribute to aqueous deficient dry eye. Inflammation affects the lacrimal gland, and if the gland is not making enough fluid, that drives more inflammation, said Dr. Massaro-Giordano, who added, “You’ve got to break that cycle.” Toward that end, new steroids and immunomodulators target the inflammation that exacerbates dry eye disease (DED).

Steroids. For inflammation, Christo­pher E. Starr, MD, at Weill Cornell Medicine in New York City, favors a short course of a steroid. “Usually, that’s the quickest way to get ocular surface inflammation under control and get the patient feeling better as quickly as possible,” he said.

Dr. Starr noted that loteprednol is relatively mild, as steroids go, and less prone to causing pressure spikes, cataracts, infection, and epithelial wound-healing issues. Even so, the risks of continued use make even mild steroids ill-suited to managing chronic dry eye over the long haul. For that, he turns to a topical immunomodulator, either cyclosporine or lifitegrast.

(The discussion of steroids in Part 1 also applies to aqueous deficiency. It mentioned the first steroid specifically indicated for DED, Eysuvis, a loteprednol eyedrop, which gained FDA approval in 2020. Its labeling suggests using it for up to two weeks.)

Immunomodulators. All currently approved cyclosporine dry eye treat­ments show efficacy in increasing tear production in patients who make too few tears, but not in those with “totally scarred” lacrimal glands, said Dr. Akpek. Besides the first-in-category Restasis, cyclosporine comes in other formulations. For instance, Cequa provides a higher concentration of cyclosporine and a nanomicellar for­mulation, either of which may explain why patients seem to tolerate it better than Restasis, said Stephen Pflugfelder, MD, at Baylor College of Medicine in Houston. A generic form of Restasis became available in 2022.

For the minority of patients who cannot tolerate other cyclosporine drops, Dr. Massaro-Giordano pre­scribes Klarity-C, a compounded, preservative-free form of 0.1% cyclo­sporine. Soon she might be able to offer Vevye, an eyedrop that received FDA approval on June 8. Initially named CyclASol while in development, Vevye resembles Klarity-C in its concentra­tion of cyclosporine and its lack of preservatives, but, unlike Klarity-C, it contains no water.

To see if cyclosporine will help a giv­en patient, the patient must commit to using it twice a day for at least a couple of months, said Dr. Massaro-Giordano. She noted that Xiidra (lifitegrast) works by a different mechanism, so it might work where cyclosporines did not. “Xiidra is a little faster-acting, so we’ll know if Xiidra works sooner rather than later,” she said.

Deciding which immunomodulator to prescribe often comes down to cost, insurance issues, and patient preferenc­es. For example, Dr. Starr asks patients whether they would prefer the sting­ing and burning more common with cyclosporine or the bad taste caused by lifitegrast. “Patients are very definitive as to which they prefer, so it behooves you as a doctor to have the side-effects-and-expectations conversation,” he said.

Neurostimulation

In neurostimulation, an electromag­netic or chemical stimulus activates a neural target. “Now you’re harnessing the power of your own lacrimal gland to lubricate your eye,” said Dr. Massa­ro-Giordano. Dr. Steigleman pointed out that neurostimulation also relieves “drop burden,” a particular boon for patients who instill drops for both glau­coma and DED.

Devices. One device on the market is the iTear100, which uses an oscillat­ing tip to apply stimulation through the outside of the nose. Patients use the palm-sized unit at home after receiving instruction from a health care provid­er. Treatment takes 30 seconds a day twice a day. To date, there have been no independent studies comparing it with other treatments.

A nasal spray. Dr. Pflugfelder no longer uses neurostimulation devices. Now, he boosts tear production chem­ically with Tyrvaya, a varenicline nasal spray, approved in 2021. According to Dr. Massaro-Giordano, it is thought to activate the anterior ethmoidal nerve.

Dr. Pflugfelder prescribes Tyrvaya for anyone with aqueous-deficient dry eye who needs more than conservative care. “When they like it, actually, they love it,” he said, noting that it is “usually a home run” for contact lens wearers. Dr. Akpek said it provides nearly instant relief from dry eyes, without bothering the ocular surface as eyedrops do.

Even so, Dr. Massaro-Giordano said, “It doesn’t work for everyone,” and it may cause coughing and sneezing. Dr. Starr noted that patients with chronic sinusitis do not want a spray, but many patients who have arthritis in their hands prefer it over eyedrops.

Blood-Derived Tears

Eyedrops made from patients’ own blood have been gaining a foothold in the treatment of ocular surface disease, including DED.¹ Dr. Akpek uses autolo­gous serum tears and platelet-rich plasma to boost tear production in patients with severe aqueous deficiency, noting that they contain many of the beneficial ingredients found in natural human tears. As Dr. Pflugfelder noted, “The blood products have lots of growth fac­tors and anti-inflammatory factors, as well as proteins that can coat the ocular surface.”

All five experts offer autologous serum; some also offer platelet-rich plasma. “I prefer platelet-rich plasma because it seems to be more effective, but that’s only prepared at certain places,” said Dr. Pflugfelder, whose office makes it. Yet, he prescribes serum for patients who cannot get back to his office. They get their blood drawn at a nearby lab; it is then shipped to a compounding pharmacy or another company that makes serum tears.

Dr. Massaro-Giordano always sends her serum patients to specialty compa­nies. She considers that safer and more practical than making serum in-house, which requires special machines, train­ing, and precautions. She noted that nationwide companies like Vital Tears, of Kansas City, Missouri, can make the serum and ship it to patients in sterile fashion on dry ice.

Dr. Pflugfelder said platelet-rich plas­ma “has a huge satisfaction level” among patients who can afford it. However, he noted, blood-based tears can be costly, and despite their effectiveness and safe­ty,² insurance does not cover them.

A Reality Check

Insurance issues hamper access to other DED treatments as well. “We have struggled with getting insurance approval for a lot of the newer agents,” said Dr. Steigleman. He said some insurers prefer Xiidra, others Restasis; one covers Restasis but not its generic counterpart. Most do not cover treat­ment with any of the devices either, Dr. Massaro-Giordano said.

Additionally, Dr. Akpek said that many DED patients have multiple chronic conditions, and they cannot afford $600 a month for just one eye medicine. Moreover, patients may have six different reasons why their eyes are dry, each of which needs treatment, said Dr. Massaro-Giordano.

Up-and-Coming Treatments

The plethora of treatments indicates that none is perfect, so clinicians must cobble together a menu of treatments to address the specific causes of dry eye in each patient, said Dr. Steigleman. Every kind of DED—from meibomian gland dysfunction (MGD) and decreased wet­tability dry eye to aqueous deficiency—calls out for new treatments.

MGD-targeted drugs. The first eye-drop specifically for MGD received FDA approval on May 18 and could become available later this year. Miebo consists solely of perfluorohexyloctane, which reportedly spreads quickly over the ocular surface and slows tear evap­oration.³ Previously called NOV03, it relieved signs and symptoms of dry eye associated with MGD in two large, ran­domized, placebo-controlled trials.^1,4

In another development, Azura Ophthalmics has been testing a seleni­um sulfide ointment for MGD. Dr. Starr said it could help break down keratin build-up and unblock the meibomian glands.

A novel anti-inflammatory. Dr. Starr signaled that a new class of anti-inflam­matory treatment may be coming, if the FDA approves reproxalap from Aldeyra. He noted that the data⁵ for the aldehyde trap “look really good.” As Dr. Pflugfelder explained, “It scavenges aldehyde radicals on the ocular surface; they induce inflammation.”

Some interesting directions. For aqueous deficiency caused by systemic disease, relying solely on topical medi­cations makes no sense, said Dr. Akpek. She disclosed that several drug com­panies are trying to develop systemic treatments for Sjögren-related dry eye.

If Dr. Massaro-Giordano has her way, the future of treatment for ocular surface disease, including DED, lies in personalized medicine. Someday, she said, clinicians could sample patients’ tears to discern what they lack at the most basic protein and genetic level. She anticipated how good it would feel to tell patients, “This is what you’re missing, and this is what we need to give you.”

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1 Bernabei E et al. J Clin Med. 2019;8(9):1478.

2 Yu MD et al. Clin Opthalmol. 2021;15:4219-4226.

3 Sheppard JD et al. Am J Ophthalmol. 2023;252:265-274.

4 Tauber J et al. Ophthalmology. 2023;130(5):516-524.

5 Clark D et al. Am J Ophthalmol. 2021;226:22-31.

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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; Verséa; C.

Dr. Steigleman is Associate Professor, University of Florida College of Medicine in Gainesville. Relevant financial disclosures: None.

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