Dry Eye Disease (Keratoconjunctivitis Sicca) Treatment & Management

Early detection and aggressive treatment of dry eye disease (DED), or keratoconjunctivitis sicca (KCS), may help prevent corneal ulcers and scarring. The frequency of follow-up care depends on the severity of the signs and symptoms.

Although supplemental lubrication is the mainstay of treatment for mild and moderate aqueous-deficient dry eye disease, any concomitant lid disease must also be treated. The use of topical cyclosporine has been shown to enhance the production of the aqueous component of the tear layer, as well as increase goblet cell density and decrease inflammatory tear cytokines. The use of oral omega-3 fatty acids has beneficial anti-inflammatory properties that aid in the production of tears. Numerous preparations of omega-3 fatty acids are available for point-of-service sales and provide pharmaceutical-grade, mercury-free sources of essential fatty acids known to improve ocular surface function. ^{[42, 43]}

Other forms of treatment include the use of plugs that block the puncta. Temporary punctal occlusion may be accomplished with collagen (dissolvable) or silicone (permanent) plugs; newer cross-linked collagen punctal plugs have a longer duration of action before dissolving, with labeling from 3-6 months postimplantation. If plugs are ineffective, electrocauterization of the inferior puncta may be performed in patients with severe dry eye disease, documented Schirmer tear test deficiency, and patent upper lid puncta. In some cases, other surgical options may be considered.

Environment-related issues that may exacerbate dry eye disease should be discussed; alternatives may be needed.

Treatment of very severe dry eye disease or dry eye disease associated with a connective tissue disorder (CTD), including Sjögren syndrome (SS), should be coordinated with an internist or a rheumatologist, as well as relevant dental and gynecologic consultants.

DEWS II treatment recommendations

The Management and Therapy Subcommittee of the Tear Film and Ocular Surface Society's Dry Eye Workshop II (TFOS DEWS II) have proposed an updated (2017) algorithm to approach the treatment of dry eye. The algorithm, adapted here from the published report, ^[44] is presented in a stepwise approach, beginning with low-risk, highly available interventions and progressing for cases of treatment failure or severe dry eye.

Step one is as follows:

• Educate the patient regarding the condition, management, and prognosis
• Modify the patient’s local environment
• Educate the patient on dietary modifications (including oral essential fatty acid supplementation)
• Identify any potentially etiologic systemic/topical medications and consider modification or elimination of offending agents
• Apply ocular lubricants (lipid-containing supplements in patients with MGD)
• Institute proper lid hygiene and apply warm compresses

Step two (used if the above options are inadequate) is as follows:

• Use of nonpreserved ocular lubricants to minimize preservative-induced toxicity
• Tea tree oil therapy to treat demodicosis, if present
• Tear conservation therapy (punctal occlusion, moisture chamber spectacles/goggles)
• Overnight treatments (eg, ointment or moisture chamber devices)
• In-office, physical heating and expression of the meibomian glands (including device-assisted therapies [eg, LipiFlow])
• In-office intense pulsed light therapy to treat MGD
• Prescription drug therapy (topical antibiotic with or without steroid applied to lid margins for anterior blepharitis, limited-duration topical corticosteroid, topical secretagogues, topical nonglucocorticoid immunomodulators (eg, cyclosporine), topical LFA-1 antagonists (eg, lifitegrast), oral macrolide or tetracycline antibiotics

Step three (used if the above options are inadequate) is as follows:

• Oral secretagogue therapy
• Application of autologous/allogeneic serum eye drops
• Therapeutic contact lenses (soft bandage lenses, rigid scleral lenses)

Step four (used if the above options are inadequate) is as follows:

• Longer-duration topical corticosteroid therapy
• Amniotic membrane grafting
• Surgical punctal occlusion
• Other surgical options (eg, salivary gland transplantation, tarsorrhaphy)

Agents that have been used to treat dry eye disease include the following:

• Artificial tear substitutes
• Gels, emulsions and ointments
• Anti-inflammatory agents - Topical cyclosporine, ^{[5, 6]} topical corticosteroids
• Topical or systemic omega-3 fatty acids: Omega-3 fatty acids inhibit the synthesis of lipid mediators and block the production of interleukin (IL)–1 and tumor necrosis factor alpha (TNF-α)
• Topical or systemic tetracyclines: Decrease MMP, collagenase, and phospholipase A2 activity and inhibit bacterial lipase with a resultant decrease in pro-inflammatory free fatty acids
• Secretagogues - Diquafosol (approved in Japan ^{[9, 10]} but not in the United States)
• Autologous or umbilical cord serum
• Systemic immunosuppressants
• Lymphocyte function-associated antigen 1 (LFA-1) antagonists

Lubricating supplements are the medications most commonly used to treat dry eye disease. If these agents are to be used more frequently than every 3 hours, preservative-free formulations are the treatment of choice. If a patient has SS, the use of systemic immunosuppressants should be considered.

Prescribe artificial tears, preferably preservative-free artificial tears, and a lubricating ointment. Mild dry eye disease can be treated with drops up to 4 times a day; more severe cases call for more aggressive treatment, such as drops 10-12 times a day. Thick artificial tear drops or gels can also be used in more severe cases, although these agents tend to blur the vision. Tear ointments can be used during the day, but they are generally reserved for bedtime use because of the poor vision after placement.

Cyclosporine

Cyclosporine is a neurokinin (NK)–1 and NK-2 receptor inhibitor that can down-regulate these signaling molecules. It improves goblet cell counts and reduces the numbers of inflammatory cells and cytokines in the conjunctiva. Another novel addition to the therapeutic armamentarium for dry eye disease is lifitegrast, which commonly is used in conjunction with cyclosporine to treat both aqueous tear deficiency and evaporative dry eye disease. 

The clinical trials that led to FDA approval of topical cyclosporine 0.05% emulsion for the treatment of moderate to severe dry eye disease demonstrated statistically significant tear production increases in treated patients compared to tear-only controls. In addition, these trials demonstrated that topical cyclosporine emulsion produced no detectable serum levels, reduced concomitant artificial tear use, reduced ocular surface goblet cell density and T-cell expression based on conjunctival biopsy analysis, and reduced inflammatory tear cytokine production based on tear analysis.

A randomized, double-masked, vehicle-controlled clinical study evaluated the efficacy and safety of two different concentrations of cyclosporine (1% and 0.05%) in aqueous solution compared with vehicle. At Day 21, noted as early in the trial, statistically significant improvement in four symptoms and three ocular signs were observed when cyclosporine 1% was administered, and equivalent improvement in three symptoms and three ocular signs was observed when cyclosporine 0.5% was used. ^[45]

Lifitegrast

Lifitegrast  is a small-molecule integrin antagonist that reduces ocular surface inflammation and T-cell activation by blocking the interaction of lymphocyte function-associated antigen 1 (LFA-1) with intracellular adhesion molecule 1 (ICAM-1). It is safe and effective and is FDA-approved for the treatment of dry eye disease. ^{[7, 8, 46]}

The first LFA-1 antagonist, lifitegrast ophthalmic (Xiidra), was approved by the FDA in July 2016 for treatment of the signs and symptoms of dry eye disease. Lifitegrast binds to the integrin lymphocyte function-associated antigen-1 (LFA-1), a cell surface protein bound on leukocytes, and blocks the interactions of LFA-1 with its cognate ligand intercellular adhesion molecule-1 (ICAM-1). ICAM-1 may be overexpressed in corneal and conjunctival tissues in dry eye disease; LFA-1/ICAM-1 interaction can contribute to the formation of an immunologic synapse, resulting in T-cell activation and migration to target tissues.

Approval of lifitegrast was based on four phase 3 trials (n >2500), OPUS-1, OPUS-2, OPUS-3, and one long-term (1-year) phase 3 safety study (SONATA). ^{[7, 8, 46, 47, 48]} Lifitegrast improved inferior corneal staining score (ICSS) in the OPUS-1 and OPUS-3 studies. ^{[47, 48]} Ocular safety and tolerability were similar to those of placebo. ^[7]

Loteprednol

Loteprednol etabonate is an analog of prednisolone acetate. After ocular administration, it is converted to inactive metabolites rapidly by the cellular esterases and therefore has relatively less risk for systemic side effects. Given its high anti-inflammatory efficacy and improved safety profile, loteprednol of a variety of concentrations has been used in reducing post-operative ocular inflammations and treating seasonal allergic conjunctivitis. Studies have also found that loteprednol etabonate 0.5% provided short-term rapid relief for dry eye signs and symptoms in patients with mild-to-moderate DED who are about to start cyclosporine therapy. ^[49]

The FDA has now also approved a formuation of loteprednol etabonate specifically for short-term relief of DED symptoms up to 2 weeks. Loteprednol 0.25% ophthalmic suspension (eyesuvis) uses nanoparticle technology to enhance the ocular delivery of the medication. ^[50]  In a report of four randomized, vehicle-controlled and double-masked studies, loteprednol 0.25% was found to have good safety profile and was well-tolerated. It is associated with low incidences of significant IOP elevation (0.6% in the medication group vs 0.2% in the control group). The most common adverse event is instillation site pain. ^[51]

Varenicline Nasal Spray

Varenicline is a selective nicotinic acetylcholine receptor agonist. Oral varenicline form has been used commonly as a medication that help in smoking cessation with established safety profile. The nasal spray form is administered in the nasal cavity and reacts with the nicotinic acetylcholine receptors present on the trigeminal nerve in the nasal cavity and stimulates the lacrimal functional units that produce tears. In the ONSET-2 study, a phase 3 randomized study, statistically significantly higher percentages of participants who received twice-daily varenicline nasal spray of 0.6mg/mL or 1.2mg/mL achieved a 10-mm improvement in Schirmer's test relative to the control group. The medication was also relatively well tolerated in the study, with the most common ocular and non-ocular adverse effects being conjunctival hyperemia and transient sneezing, respectively. Other common adverse effects reported included instillation site irritation (nasal), cough, and throat irritation. ^[52] This varenicline nasal spray received FDA approval in October 2021 as a treatment for signs and symptoms of DED. It is the only nasal spray approved for treatment for DED and may serve as an important tool in patients with DED who do not achieve adequate relief with frequent administration of artificial tears. 

Other Pharmacological Treatments

In a 2012 study, diquafosol and sodium hyaluronate showed similar efficacy in improving fluorescein staining scores of dry eye patients and diquafosol was superior in improving rose bengal staining scores. There was no significant difference between groups in adverse event rates. ^[53]

In-Office Procedures

Several in-office procedures are available for the treatment of dry eye disease, including the following:

• Vectored thermal pulsation (LipiFlow)
• Meibomian gland probing (Maskin probe or hyfrecator probe)
• Meibomian gland liquefaction and expression (MiBo ThermoFlo, TearCare System)
• Intense pulsed light therapy
• Intranasal tear neurostimulator (TrueTear)
• Lid-margin scrubbing (BlephEx)

Intranasal Tear Neurostimulator

Intranasal tear neurostimulation is a novel approach to the treatment of dry eyes. ^[54] The use of neurostimulation was first introduced for the treatment of dry eye disease by Kossler et al in 2015. ^[55] Intranasal tear neurostimulation works via an external, nonimplantable device to stimulate the nasal mucosa and activate the nasolacrimal reflex to increase tear production and improve tear film homeostasis. Stimulation of the nasal mucosa activates the afferent branch of the nasolacrimal reflex, whereby the anterior ethmoidal nerve relays a signal to the superior salivary nucleus in the pons. The efferent branch is then activated as the parasympathetic nerves of CN VII travel to the pterygopalatine ganglion and exit via the inferior orbital fissure as the zygomaticotemporal nerve, which innervates several components of the lacrimal functional unit. Activation of the main and accessory lacrimal glands, as well as conjunctival goblet cells and meibomian glands by the stimulated zygomaticotemporal nerve, results in increased tear production and enhances tear film homeostasis.

Several clinical trials have been conducted on the use of intranasal tear neurostimulation for the treatment of dry eye disease. This treatment modality has been shown to be safe with consistent use over 3 to 6 months and improves dry eye symptoms and tear production;  may also improve corneal and conjunctival staining. ^{[56, 57]} The device for tear neurostimulation has been shown to be superior to sham treatment. ^[58]

The TrueTear intranasal tear neurostimulator is FDA-approved for the treatment of dry eye disease. The current recommendation is to use the stimulator for 1 to 3 minutes 2 to 4 times daily and not to exceed 10 applications in a 24-hour period. The device is generally well tolerated, with the most common adverse effects including epistaxis and, occasionally, pain.

Eye Protection

Specially made glasses known as moisture chamber spectacles, which wrap around the eyes to retain moisture and protect against irritants, may be helpful in some cases of dry eye disease.

Contact lenses may also be helpful; these are available in the following types:

• Silicone rubber lenses
• Gas permeable scleral-bearing hard contact lenses with or without fenestration
• Highly oxygen-permeable lenses (overnight wear)
• Cryopreserved sutureless amniotic membrane is available as a 5- to 10-day contact lens ^[59]

Punctal plugs are often employed in the treatment of dry eye disease. Available types include the following:

• Absorbable plugs - These plugs are made of collagen or polymers and either dissolve by themselves or may be removed by saline irrigation; occlusion duration ranges from 7-180 days
• Nonabsorbable plugs - These plugs are made of silicone; two main categories of silicone plugs are available for dry eye, capped punctal plugs and intracanalicular plugs
• Thermoplastic plugs (eg, SmartPLUG; Medennium, Irvine, CA) – These plugs are made of a thermosensitive, hydrophobic acrylic polymer that changes from a rigid solid to a soft, cohesive gel when its temperature changes from room temperature to body temperature
• Hydrogel plugs (eg Oasis Form Fit; Sigma Pharmaceuticals, Monticello, IA)

A study by Mataftsi et al found that punctal plugs offer an effective and safe treatment for children with persistent symptoms and should be considered. ^[60]

In a study of punctal occlusion surgery using a high heat-energy–releasing cautery device to treat severe dry eye disease and recurrent punctal plug extrusion, Ohba et al concluded that the device was associated with a low recanalization rate and demonstrated improvements in ocular surface wetness and visual acuity. ^[61]

In patients with dry eyes, close the puncta. If plugs are not available or are repeatedly lost, cautery or hyfrecation is indicated for permanent closure, beginning with the lower puncta and proceeding to the upper if necessary.

Surgical treatment of dry eye disease is reserved for very severe cases in which ulceration or impending perforation of the sterile corneal ulcer occurs.

Surgical options include the following:

• Sealing of the perforation or descemetocele with corneal cyanoacrylate tissue adhesive
• Corneal or corneoscleral patching for an impending or frank perforation
• Lateral tarsorrhaphy - Temporary tarsorrhaphy (50%) is indicated in patients with dry eye disease secondary to exposure keratitis after facial nerve paralysis and after trigeminal nerve lesions that give rise to dry eye disease secondary to loss of corneal sensation
• Conjunctival flap
• Conjunctivoplasty excision of symptomatic conjunctivochalasis
• Surgical cautery occlusion of the lacrimal drainage system ^[62]
• Mucous membrane grafting
• Salivary gland duct transposition
• Amniotic membrane transplantation or amniotic membrane contact lens therapy
• Prosthetic replacement of the ocular surface ecosystem (PROSE) lens therapy