June 2019


Dry Eye Developments
Anti-inflammatory therapeutics for ocular surface management

by Chiles Samaniego EyeWorld Contributing Writer

Aqueous deficient dry eye disease, showing decreased tear film meniscus and
positive lissamine staining
of cornea and conjunctiva
Source: Vincent de Luise, MD


Ocular surface disease has many different etiologies, but inflammation is a common component in the majority of patients,” said Edward Holland, MD. “Over the years we’ve developed treatment strategies to include anti-inflammatories.”
Anti-inflammatory agents currently in use for ocular surface management broadly fall into two categories: steroids, mainly loteprednol etabonate, which “are immediate and work consistently,” said John Hovanesian, MD; and immunomodulators, encompassing cyclosporines and lifitegrast (Xiidra, Shire), which, according to Vincent de Luise, MD, do not have the side effect profile of the topical steroids.
Nonsteroidal anti-inflammatory drugs (NSAIDs) are no longer used in the management of dry eye by Dr. Holland, Dr. Hovanesian, and Stephen Pflugfelder, MD, having fallen out of favor since “the complication of scleral and corneal melts that are associated with NSAIDs, especially the generics, make this class of drug less ideal for chronic use for dry eye,” Dr. Holland said. “The melt complication is a greater risk in dry eye patients.”
Drs. de Luise, Holland, Hovanesian, and Pflugfelder shared their expertise on the current use of anti-inflammatory therapeutics for ocular surface management.

Steroid use

“If you’ve got a very inflamed, red eye that needs quieting down, there’s nothing that substitutes a steroid for doing that,” Dr. Hovanesian said. Prior to cataract surgery, for instance, many doctors prefer steroids “because they are so rapid, they work fairly universally, they’re well-tolerated by patients. They do have the side effect of causing intraocular pressure increases and the long-term risk of cataract, but in the short term, in a patient being monitored, those are pretty small risks.”
Dr. Hovanesian situates steroid pulses in the context of dry eye. “Dry eye is a chronic disease that has acute exacerbations, and during those exacerbations, nothing substitutes for a steroid,” he reiterated.
“The use of topical steroids depends on diagnosis,” Dr. de Luise said, adding there is no “one-size-fits-all” regimen.
“For routine postoperative care, for example after uncomplicated cataract and IOL surgery, a TID or QID regimen for a week with a rapid taper is one effective strategy,” Dr. de Luise said. “Often, if a topical NSAID is used concomitantly with the topical steroid in the postoperative period, it is begun and tapered in similar or identical frequency.”
For “episodic dry eye”—a term Dr. de Luise considers ambiguous and “nowhere near as common” as chronic dry eye—an ester steroid such as loteprednol can be employed as a pulse topical steroid.
“As a general rule, pulsing topical steroids is better than using them long term in low-dose daily use, but even here there are exceptions,” Dr. de Luise said. One exception is when using very low-dose topical steroids at one drop a day for chronic recalcitrant herpes zoster keratouveitis. “If this one drop a day is summarily stopped, the inflammation recurs. Thus, this is a scenario where a taper down to a low daily dosage for a chronic period has scientific sense and can be a community standard for chronic recalcitrant HZ keratouveitis.”
Dr. Holland typically starts with loteprednol for induction therapy, followed by lifitegrast, shifting to cyclosporine if unresponsive to lifitegrast.
“I like loteprednol because it has a lower risk of elevating intraocular pressure, and I have not seen cataract formation with loteprednol in using it with patients over the years, even with long-term therapy,” he said. “It is an ester steroid, the only ester steroid that we have, which makes it safer than all the other steroids, which are ketone steroids.”
Dr. Holland also uses steroid pulses when dry eye flares, which he said occurs in the majority of patients. “Whether the patient has episodic flares and in the interval is relatively quiet or the patient is on maintenance therapy with an immunomodulator, they are going to have flares,” he said. “I like to use pulse therapy with steroids to cover these flares.”
Meanwhile, Dr. Pflugfelder will use a steroid pulse with cyclosporine, tapering to a stop after 1 month.
Patients going on short-course therapies of about 2 weeks don’t typically need a follow-up visit unless symptoms persist or flare; patients on maintenance therapy will typically be seen for follow up in a month to 6 weeks by Dr. Hovanesian, in 6 weeks by Dr. Holland. Treatment failure is rarely an issue—“Typically, steroids don’t fail,” Dr. Hovanesian said—but additional therapies or adjuncts such as punctal occlusion are considered depending on patient response.

Lifitegrast, cyclosporine combo?

Some patients report using both lifitegrast and cyclosporine together. Dr. Pflugfelder said that while there is no evidence to support this concept, he has patients who use both and think the combination is better than monotherapy.
“I don’t think there’s any real science behind whether that works,” Dr. Hovanesian said. “Both are T-cell inhibitors, so it’s hard to construct a logical argument that they would be highly additive to each other. Yet they are two drugs that work on the same disease, so it makes sense to try them together.”
Dr. de Luise said that the two drugs do work in different places and at different points in the inflammatory cascade: lifitegrast on the ICAM-LFA interaction, cyclosporine on calcineurin inhibition on newly hatched T-cells. “To the extent that the dry eye in a given patient is predominantly or totally related to inflammation (which is not always the case), there may be a synergistic benefit to using both medications,” he said. “However, in the real-world scenario, there may be insurance limitations, and using both may have to be paid out of pocket by that particular patient.”
Despite anecdotal reports, Dr. Holland doesn’t see a role for the combination. “If I were to add a second medication, I would rather not put them on two drugs that work on a similar pathway,” he said. “I would rather add a steroid as my second medication than a drug with a similar mechanism.”

New formulations

Existing anti-inflammatory agents are evolving through new formulations.
“I’m excited about a new clinical trial on loteprednol 0.25%, which is under the study name of KPI-121 [Kala Pharmaceuticals],” Dr. Holland said. “This technology is a nanoparticle suspension that has a mucous-penetrating property, so it penetrates the ocular surface well, and therefore, you can lower the concentration and get a better effect.”
Inveltys, a 1% formulation using the proprietary AMPPLIFY mucus-penetrating particle drug delivery technology (Kala Pharmaceuticals) described by Dr. Holland, has already been approved by the FDA as the only twice-daily ocular corticosteroid for the treatment of inflammation and pain after ocular surgery.
A solution form of cyclosporine 0.09% is FDA-approved and available as Cequa (Sun Pharma). Another cyclosporine solution formulation, CyclASol 0.1% (Novaliq), is in Phase 3 clinical trials.
The FDA-approved Cequa is 0.09% cyclosporine encapsulated in nanomicelles and stored in solution, delivered via classic dropperette. It’s a more potent concentration, and the micelle encapsulation allows greater tissue penetration—“so we need to get comfortable with its tolerability in the eye,” Dr. Hovanesian said.
“Theoretically, the increased concentration and the formulation in solution of Cequa, which is a solution of the historically highly insoluble molecule cyclosporine, should create increased bioavailability and thus an increased patient response,” Dr. de Luise said.
Meanwhile, “CyclASol is interesting because it is not a water-based drop,” Dr. Hovanesian said. Rather, the 0.1% concentration is delivered in a perfluorocarbon liquid, so “it is probably better tolerated than any other formulation of this drug on the eye,” he said.
“That said, cyclosporine is intrinsically irritating, and dry eye disease is often a heterogenous group of both aqueous deficient dry eye disease and evaporative dry eye disease, so it remains to be seen how effective these formulations will be as usage and experience by the ophthalmic community increases,” Dr. de Luise noted.
As such, it remains to be seen how these new formulations will influence standard drug therapies. “I will evaluate the new cyclosporines and based on clinical response decide if I change my treatment paradigm or not,” Dr. Holland said.
Dr. de Luise cited additional therapies in the pipeline: iontophoresis anti-inflammatories from EyeGate Pharma; perfluorooctane non-steroidal anti-inflammatories from Novaliq, which is exciting, he said, because there are no currently approved strategies for evaporative eye disease due to meibomian gland dysfunction; and an aldehyde trap for use as an anti-inflammatory from Aldeyra Therapeutics. Meanwhile, Dr. Holland is looking out for RGN-259, a thymosin beta-4-based sterile and preservative eye drop being developed by RegeneRx for dry eye and neurotrophic keratitis, currently in Phase 3 trials.
There are still some gaps to fill. “There is need of an anti-inflammatory to inhibit corneal neovascularization and one to inhibit inflammation-induced conjunctival fibrosis as occurs in mucus membrane pemphigoid and Stevens- Johnson syndrome,” Dr. Pflugfelder said.
All this highlights the fascinating complexity of the ocular surface, and so also ocular surface disease and management. “As we talk about it, you can see that dry eye is a complicated disease,” Dr. Hovanesian said. “In its simplest form, when treating dry eye, first you need to quiet down inflammation.”
While clinicians should then go on to identify and treat the underlying causes of any given patient’s condition, anti-inflammatory therapeutics remain an essential component of ocular surface management.

At a glance

• Anti-inflammatory agents currently in use are steroids and immunomodulators, while NSAIDs have fallen out of favor due to the risk of scleral and corneal melts.
• While there is no “one-size-fits-all” regimen, steroids are best for immediate relief and so are often used to initiate treatment.
• Newer formulations of existing agents offer better drug penetration and improved tolerance, but experience is currently limited.

Contact information

de Luise
: vdeluisemd@gmail.com
Holland: eholland@holprovision.com
Hovanesian: jhovanesian@harvardeye.com
Pflugfelder: stevenp@bcm.edu

About the doctors

Vincent de Luise, MD
Assistant clinical professor of ophthalmology
Yale University School of Medicine
New Haven, Connecticut

Edward Holland, MD
Director of Cornea Services
Cincinnati Eye Institute

John Hovanesian, MD
Harvard Eye Associates
Laguna Hills, California

Stephen Pflugfelder, MD
James and Margaret Elkins Chair in Ophthalmology
Baylor College of Medicine

Financial interests

de Luise
: None
Holland: Kala Pharmaceuticals, Novartis, Takeda, Senju
Hovanesian: Alcon, Allergan, BlephEx, Johnson & Johnson Vision, Sun Pharmaceutical, Novaliq, Shire, Eyevance
Pflugfelder: Shire, Allergan, Senju

Anti-inflammatory therapeutics for ocular surface management Anti-inflammatory therapeutics for ocular surface management
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