Introduction
The treatment of patients with dry eye disease is based upon the severity of the patient’s disease and symptoms. In addition, since there are several factors that can contribute to dry eye symptoms, it is critical to address the underlying cause. Dry eye disease impacts patients’ vision, quality of life, productivity, and activities of daily living and also has economic costs including the cost of medical appointments, treatments, and procedures. , The goals of treating dry eye disease are to improve patients’ symptoms and quality of life, decrease inflammation, and prevent ocular surface damage. There have been several advances in treatment modalities in recent years that aim to decrease the effects of dry eye disease on patients’ lives.
A stepwise approach is recommended to determine the most appropriate treatment for patients based upon the severity of their dry eye disease. It is important for clinicians to consider each individual patient’s symptoms to create a comprehensive treatment plan. Specifically, clinicians should evaluate meibomian gland physiology, tear film lipid quality, meibomian gland status, and tear production, loss, and runoff. It is also essential to ensure communication with other medical specialists to address multifactorial causes of dry eye disease. In 2017, the DEWS II Management and Therapy report put forth an algorithm for staged management recommendations for dry eye disease. ( Table 11.1 ).
Step 1:
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| Step 2: If above options are inadequate consider
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| Step 3: If above options are inadequate consider
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| Step 4: If above options are inadequate consider
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a Potential variations within the disease spectrum are acknowledged to exist between patients and the management options listed above are not intended to be exclusive. The severity and etiology of the DED state will dictate the range and number of management options selected from one or more steps.
b One or more options concurrently within each category can be considered within that step of the dry eye disease state. Options within a category are not ranked according to importance and may be equally valid.
c It should be noted that the evidence available to support the various management options differs and will inevitably be lower for newer management options. Thus, each treatment option should be considered in accordance with the level of evidence available at the time management is instigated.
d The use of prescription drugs needs to be considered in the context of the individual patient presentation, and the relative level of evidence supporting their use for that specific indication, as this group of agents differs widely in mechanism of action.
Nonpharmacologic Treatments
Patient Education
In patients with dry eye disease, removing exacerbating factors should be advised (e.g., antihistamine, diuretic use, cigarette smoking, air drafts, ceiling fans, and low humidity environments). Patients can employ environmental interventions including using indoor humidifiers, air filters, or cleaners to ameliorate dry eye symptoms by increasing air moisture and reducing particulates in the air. Other conservative measures include but are not limited to the use of dry eye goggles, wrap-around sunglasses, and also limiting screen time.
Dietary Supplementation
Nutritional supplements that have antiinflammatory properties including essential fatty acids such as omega-3, linoleic acid (LA) and gamma-linoleic acids (GLAs) can be used in the management of ocular surface disease. Omega 3 fatty acids from patients’ diet or in the form of supplements have anti-inflammatory properties that may aid in treating DED. Omega 3 fatty acids are present in fish and green leafy vegetables. GLA and its precursor LA are used in chronic inflammatory disorders such as rheumatoid arthritis.
Several studies have shown a potential benefit for the use of omega-3 fatty acids for the treatment of dry eye. Miljanović et al. studied the association between dietary intake of n − 3 and n − 6 fatty acids and dry eye syndrome in the Women’s Health Study among 1546 subjects who reported a diagnosis of DES. Their study showed that patients who had higher dietary intake of n-3 fatty acids had a decreased incidence of dry eye syndrome. In another study, a randomized trial of 28.5 mg LA plus 15 mg GLA twice daily in addition to substitute tears showed a significant decrease in DES symptoms, lissamine green staining, and ocular surface inflammation in patients with aqueous deficient keratoconjunctivitis sicca. A prospective, double-blind randomized trial of 264 eyes of patients with dry eye who received one capsule (500 mg) twice daily of 325 mg EPA and 175 mg DHA for 3 months compared to placebo showed significant improvement in the omega-3 group in symptoms compared to placebo. In addition, the omega-3 group also showed a significant change in Schirmer’s test and TBUT values. A multicenter, prospective, interventional, double-masked study randomized 105 subjects to receive a total of 1680 mg of eicosapentaenoic acid/560 mg of docosahexaenoic acid (omega-3 group) or a control of 3136 mg of LA daily for 12 weeks. The study showed that consumption of reesterified omega-3 fatty acids showed significant reduction in tear osmolarity, omega-3 index levels, TBUT, MMP-9, and OSDI symptom scores compared to controls.
In contrast, other studies have not shown a benefit for omega-3 fatty acids in treating dry eye. The Dry Eye Assessment and Management trial, a large, multicenter, double-blind clinical trial sponsored by the National Eye Institute, compared the use of a daily oral dose of 3000 mg of fish-derived n-3 eicosapentaenoic and docosahexaenoic acids in 349 subjects to olive oil placebo in 186 subjects with moderate-to-severe dry eye disease. The study did not show significantly better outcomes after 12 months for the treatment group compared to placebo.
There is also evidence that vitamin D deficiency may be a risk factor for dry eye disease as it is associated with worse subjective symptoms, tear film dysfunction, and decreased tear production. Future studies are indicated to determine if vitamin D has a protective effect on the development of dry eye diseases and if supplementation could be beneficial.
Eyelid Hygiene
Warm compresses
The most common technique to relieve meibomian gland obstruction in evaporative dry eye is to apply heat to the eyelids and to physically manipulate the eyelids to express the contents of the meibomian glands. In patients with meibomian gland dysfunction (MGD), the lipid composition of the meibum, which is largely oil based, is altered causing an increased melting point with increased viscosity at lid temperature. Applying heat to the eyelids is thought to liquefy the lipids so they can be massaged out of the meibomian glands and secreted into the tear film with gentle pressure from a cotton swab or fingertip. , Warm compresses can be performed using a towel or cloth dipped in warm water or commercially available eyelid masks that are microwaveable. Studies have shown that the application of warm compresses increases the tear film lipid layer thickness within 5 min. ,
Cleaning eyelids
Daily home treatments also include cleaning the eyelashes with tear-free baby shampoo such as Johnson’s No More Tears (Johnson & Johnson, New Brunswick, NJ, USA) or using premedication scrubs or foams. Cleansers can be used to loosen oils and debris from the eyelids including premedicated wipes, such as OCuSOFT Lid Scrubs (OcuSOFT, Rosenberg, TX, USA) or Systane lid wipes (Alcon, Fort Worth, TX, USA). Foams can also be applied to the eyelid including TheraTears SteriLid (Akorn Pharmaceuticals, Lake Forest, IL, USA) or OCuSOFT foaming cleansers.
In patients with chronic blepharitis, approximately 29%–74% of cases are thought to be attributed to Demodex mites infestation of the eyelashes. , Tea tree oil has been found to be efficacious against Demodex. The product Cliradex and Cliradex Complete (Biotissue, Doral, FL, USA) utilizes terpinen-4-ol, which is considered the most effective ingredient against Demodex , and is used one to two times daily for symptoms, for a treatment course of at least 2 months. ,
Lubrication
Over-the-counter artificial tears are often the first line of pharmacotherapy for treating dry eye disease. , Artificial tears are used to replace and supplement patients’ natural tears to improve ocular hydration. As a result, treatment with artificial tears aims to reduce tear osmolarity and decrease evaporation to increase ocular lubrication. , Artificial tears alleviate symptoms of dry eye disease by improving lubrication between the eyelids and ocular surface, stabilizing the tear film, protecting corneal and conjunctival cells, decreasing evaporative loss, and improving wound healing.
A systematic review of 43 randomized control trials showed that artificial tears are a safe measure to treat dry eye symptoms. Treatment with artificial tears is considered to be effective in relieving symptoms and there has not been a significant difference in efficacy in comparing the different formulations. ,
Dry eye products include various chemical formulations with a range of osmolarity, viscosity, and pH. Artificial tears also vary in their electrolyte composition, the presence of preservatives and solutes. The major component of artificial tears is an aqueous base.
While products with increased viscosity have a longer retention time, they can lead to blurred vision and increase debris. Therefore, lower viscosity drops have better tolerability during the daytime, while higher viscosity formulations are often used at nighttime. Viscous enhancing agents help relieve symptoms in DED by enhancing tear retention, increasing goblet cell density, protecting the surface of the eye, increasing tear film thickness, and helping to restore corneal density. , Viscosity enhancing agents include carbomer 940 (polyacrylic acid), carboxymethyl cellulose (CMC), dextran, hyaluronic acid (HA), HP-guar, hydroxypropyl methylcellulose (HPMC), polyvinyl alcohol (PVA), polyvinylpyrrolidone (PVP), and polyethylene glycol.
Some artificial tears products include preservatives including benzalkonium chloride (BAK), ethylenediaminetetraacetic acid (EDTA), and purite, which can be associated with toxicity and an allergic response. Preservatives are intended to prevent microbial growth. Artificial tears that contain preservatives should be used no more than 4–6 times daily. , Preservative-free drops are advised in patients that require frequent instillation of eye drops or who have preexisting corneal conditions. However, preservative-free preparations, which come in unit dose containers, are often more expensive and may be difficult to use for some patients. As such, the choice of an agent should be patient specific.
TheraTears and Bion Tears have an electrolyte profile similar to that of the natural tear film.
Ointments and gels have the advantage of providing lubrication to the ocular surface for a longer duration of time, thereby, extending relief for the patient; however, they blur vision and are usually used before bedtime.
Lacrisert (Bausch & Lomb, Rochester, NY, USA) is a water soluble, preservative-free, hydroxypropyl cellulose ophthalmic insert, used in patients with moderate-to-severe DED, that is placed in the inferior cul-de-sac beneath the base of the tarsus and dissolves over 12 h to improve lubrication of the eye ( Fig. 11.1 ). A multicenter center study showed that the inserts significantly improved clinical signs (e.g., keratitis, conjunctival staining, and tear volume) and reduced symptoms in patients with dry eye syndrome.
The lipid layer of the tear film controls the evaporation rate of tears. In patients with MGD, they have a deficiency of lipid in the tear film composition. Lipid-containing lubricants include eye drops, and lipid-containing sprays (formulations that contain liposomes). Lipid-containing eye drops, which are formulated as emulsions, are being used at an increased frequency as they are thought to prevent tear evaporation. Lee et al. conducted a systematic review of lipid-containing lubricants and concluded that most studies showed efficacy in improving signs of dry eye. Cationic oil-in-water (o/w) nanoemulsions are made of positively charged oil nanodroplets dispersed in water. Armane et al. showed Cationorm was well tolerated in patients with mild to moderate dry eye.
Punctal Plugs
The insertion of punctal plugs into the tear ducts (puncta) of the upper or lower eyelids aims to decrease the drainage of tears from the ocular surface to increase lubrication of the ocular surface. Punctal plugs, which include absorbable and nonabsorbable devices, can be placed at the level of the punctual opening or deeper within the canaliculus (either the vertical or horizontal canaliculus). , There is a large collection of punctal and canalicular plugs available in the market that are made of a range of materials including collagen, silicone, hydrogel, polydioxanone, and acrylic. Punctal occlusion can be utilized when combined with other dry eye treatments in patients refractory to topical lubricants alone. ,
Collagen-based plugs absorb in 1 to 16 weeks. Atelocollagen solution can be injected through the punctum, where it turns into a white-colored gel at body temperature. Succinylated collagen plugs and hypromellose 2% can also be used.
Punctal plugs have a range of designs but usually have a head on the top to enable removal of the plug and then a thin neck and cone-shaped base. Nonabsorbable plugs are often silicone-based which include the Freeman style plug (dumb-bell shaped punctal plug). Silicone plugs, which are available in a range of sizes, are often prescribed after a patient has reported symptomatic benefit from a collagen-based plug. , Punctal plugs can also be made of Teflon, hydroxyethyl methacrylate (HEMA), and polymethylmethacrylate (PMMA).
Canalicular plugs are temporary and usually rod shaped. The cylindrical SmartPlug is an intracanalicular plug made from a thermolabile polymer that changes its shape when inserted into the punctum. The FORM FIT (Oasis Medical, Glendora, CA, USA) vertical intracanalicular plug is made from an injectable hydrogel that expands after contacting the tear film into the shape of the canaliculus. The plug is inserted using a preloaded inserter. , Cyanoacrylate adhesives can also be used for temporary punctal occlusion. Thermosensitive acrylic canalicular plugs (Medennium Smart Plug) can also be used. Horizontal canalicular plugs exist in temporary or permanent forms. The Herrick canalicular plug is made of silicone and is described as having a “golf tee” shape.
Complications of punctal plugs include plug extrusion, infection (e.g., canaliculitis and dacryocystitis), canalicular migration of the plug, pyogenic granuloma, punctal and canalicular stenosis, biofilm formation, allergic reaction, and punctual enlargements. Infections are more common with intracanalicular options. , , Canalicular plugs have a higher risk of migration. ,
A systematic review of randomized controlled trials of collagen and silicone punctal plugs in patients with dry eye syndrome or aqueous tear deficiency was inconclusive in determining whether punctal plugs improve dry eye symptoms.
Prescription Drugs
Antiinflammatories
Cyclosporine
Cyclosporine (Restasis) helps to decrease inflammation in DED. The US Food and Drug Administration (FDA) approved the 0.05% solution of cyclosporine A (CsA) to increase tear production in patients with dry eye disease. , Cyclosporine is an anti-inflammatory agent that acts by entering T cells and binding to cyclophilins, which inhibits calcineurin, a calcium-dependent phosphatase, inhibiting nuclear factor of activated T cells, cytoplasmic 1 (NFATc1) dephosphorylation as shown in Fig. 11.2 . As a result, this reduces IL-2 levels and suppresses T-cell activation. , Cyclosporine has been shown to decrease IL-6 levels, reduce activated T lymphocytes, decrease the expression of inflammatory and apoptotic markers, and increase goblet cell numbers in the conjunctiva of patients with dry eye disease. Therefore, cyclosporine is thought to help to restore the homeostasis of the conjunctival epithelium.
In the United States, CsA 0.05% (Restasis and Restasis multidose, Allergan, Irvine CA), a homogenous emulsion of glycerin (2.2%), castor oil (1.25%), polysorbate 80 (1.00%), carbomer copolymer type A (0.05%), and purified water (up to 100%), is approved to increase tear production in patients with ocular inflammation. , Results from clinical trials show that noticeable improvement usually takes 3 months.
Chen et al. compared the efficacy and safety profile of topical cyclosporine 0.05% or vehicle twice daily for 8 weeks in a multicenter, randomized, double-blind, vehicle-controlled, parallel-group study of 223 dry eye patients. The study showed significant improvement in ocular dryness at week 8 foreign body sensation at weeks 4 and 8, corneal staining at weeks 4 and 8, and in the Schirmer test at week 4 compared to the vehicle. Overall, the study showed that cyclosporine 0.05% was effective and safe treatment for patients with moderate-to-severe dry eye. Additional studies have shown cyclosporine’s efficacy in patients with DED and Sjögren’s syndrome (SS).
Stevenson et al. reported on multicenter, double-masked, parallel-group, dose-response controlled trial of cyclosporine A (0.05%, 0.1%, 0.2%, and 0.04%) in 129 patients compared to the 33 patients who received the vehicle twice daily for 12 weeks. The study showed that CsA emulsions were all safe and well-tolerated and produced improvements in ocular signs and symptoms in patients with moderate-to-severe dry eye disease.
Sall et al. compared the efficacy and safety of CsA 0.05% and 0.1% compared to vehicle in patients with moderate-to-severe dry eye disease for 6 months in two multicenter, randomized clinical trials with a total of 877 patients. The study reported that compared to vehicle, both CsA formulations produced significantly greater improvements in corneal staining and categorized Schirmer values while CsA 0.05% also had a significant improvement in three subjective measures.
Baiza-Durán reported a multicenter, randomized, double-masked, vehicle controlled trial of CsA 0.1%, CsA 0.05%, or vehicle only including 183 patients followed for 98 days and showed that both formulations of cyclosporine A decreased complaints and improved signs in patients with moderate-to-severe dry eye disease, with CsA 0.1% outperforming the other groups.
Cequa (cyclosporine ophthalmic solution 0.09% (Sun Pharmaceuticals, Cranbury, NJ)) was approved by the US FDA to increase tear production in patients with dry eye disease. Cequa, also known as OTX-101, is a nanomicellar solution to enhance bioavailability of the drug to ocular tissues while decreasing systemic exposure. Goldberg et al. reported the results of a randomized, multicenter, vehicle-controlled, double-masked, phase 3 clinical trial of OTX-101 0.09% including 744 patients that showed significant increase of 10 mm of more in Schirmer test score at day 84 and significant improvements in corneal and conjunctival staining compared to the vehicle. Pooled analysis of randomized vehicle-controlled studies showed that OTX-101 twice daily led to significant improvements versus vehicle in corneal and conjunctival staining beginning at 4 weeks that were also seen up to 12 weeks and that the medication was well tolerated. , ,
Compounded cyclosporine-based formulations can be considered including Klarity-C (Imprimis Pharmaceuticals, San Diego, California), which is 0.1% CsA in a chondroitin sulfate emulsion. The possible advantages of using chondroitin sulfate as a lubricant include its antiinflammatory properties and it is thought to decrease corneal edema.
Given that CsA may take 3 months for maximal effect, topical steroids have also been used before the initiation of long-term topical 0.05% cyclosporine as an induction agent and as an early maintenance agent to expedite relief of symptoms and improve ocular signs. , Side effects of topical cyclosporine include burning or stinging after instillation, conjunctival hyperemia, discharge, epiphora, eye pain, foreign body sensation, visual disturbance, or pruritus.
Lifitegrast
Lifitegrast (Xiidra), approved in July 2016, is the second topical antiinflammatory agent approved by the US FDA for treatment of the signs and symptoms of dry eye. , , Lifitegrast is a small lymphocyte function–associated antigen-1 (LFA-1) antagonist used to reduce inflammation and manage dry eye symptoms. The medication mimics the intercellular adhesion molecule-1 (ICAM-1) preventing the binding between ICAM-1 and lymphocyte functional–associated antigen-1 (LFA-1), inhibiting T-cell recruitment, activation, migration, and proinflammatory cytokine release. , , The mechanism of action of Lifitegrast is demonstrated in Figs. 11.3 and 11.4 . ,
Studies have indicated that topical lifitegrast may have rapid effect, long-term safety as well as improvement in the signs and symptoms of dry eye disease. Patients may experience mild instillation site irritation, pain and reaction, and dysgeusia. Lifitegrast is preservative free and comes in single-unit dose ampule.
The SONATA (Safety of a 5.0% concentration of lifitegrAst ophthalmic solution) study was a multicenter, randomized, prospective, double-masked, placebo-controlled phase 3 study of 331 participants who evaluated the 1-year safety of twice-daily lifitegrast compared to placebo as measured by treatment-emergent adverse events. The study showed that lifitegrast was safe and well tolerated.
Randomized control trials in the United States have evaluated the efficacy of lifitegrast: OPUS-1, OPUS-2, and OPUS-3. , , Holland et al. reported on OPUS-3 a phase III, 12 week, double-masked, multicenter study of 711 participants that compared lifitegrast 5.0% ophthalmic solution to placebo. The study showed that lifitegrast significantly improved patient reported symptoms of eye dryness (measured by the EDS, eye dryness score) and was well tolerated. Significant symptomatic improvement is reported to occur by 6 weeks and as early as 2 weeks (OPUS-2 and OPUS-3).
Lifitegrast has high aqueous solubility, quick absorption into ocular tissues, and systemic elimination.
Topical steroids
Topical corticosteroids target inflammatory pathways to improve symptoms in ocular surface disease. Short-term therapy with corticosteroids such as loteprednol 0.5% (Lotemax) can be used to decrease inflammation at the ocular surface. Topical corticosteroids bind to glucocorticoid receptors and modulate the expression of antiinflammatory and proinflammatory genes. NF-kB, which is a main transcription factor in inflammation, is suppressed by corticosteroids, which causes the suppression of proinflammatory mediators and induction of lymphocyte apoptosis. Several studies have shown short-term benefit of topical corticosteroids in managing dry eye disease.
Loteprednol etabonate ophthalmic 0.5% suspension was approved by the US FDA in March 1998 for the treatment of corticosteroid-responsive conditions. A randomized, double-masked placebo-controlled trial of loteprednol etabonate ophthalmic 0.5% suspension four times daily in 64 patients with keratoconjunctivitis sicca and delayed tear clearance showed significant benefit after 2 weeks compared to the vehicle group in patients with at least moderate clinical inflammation.
EYSUVIS (loteprednol etabonate ophthalmic suspension 0.25%) (Kala Pharmaceuticals Inc., Watertown, MA) was approved by the US FDA in 2020 for the short-term treatment of the signs and symptoms of dry eye disease. The medication is to be used four times daily for up to 2 weeks. EYSUVIS, also referred to as KPI-121, is an ophthalmic nanoparticle suspension of loteprednol etabonate that is formulated with a mucus-penetrating particle (MPP) technology to enhance ocular drug delivery. Specifically, MPP aims to prevent mucous binding and decrease mucous-driven clearance to improve ocular surface drug delivery. Korenfeld et al. reported on the results of four trials (one phase 2 and three phase 3 multicenter, randomized, double-masked, vehicle controlled trials) for a total of 2871 subjects. The results showed that the medication was safe and well tolerated when taken four times daily for 2–4 weeks with a low incidence of adverse events.
A single-center, double-masked, randomized, vehicle-controlled clinical trial of 21 patients who received topical 0.1% fluorometholone (FML) compared to 19 patients who received topical polyvinyl alcohol group for 22 days in dry eye disease patients showed that the FML group had significant improvement in corneal and conjunctival staining, hyperemia, and TBUT compared to placebo. The study also showed that FML prevented ocular surface worsening in patients exposed to desiccating stress.
Topical methylprednisolone and dexamethasone have been studied in dry eye disease. ,
Risks of corticosteroid therapy include elevation of intraocular pressure and long-term use may lead to the development of cataracts. Topical steroids can delay wound healing and cause corneal and scleral thinning. Topical steroids are contraindicated in patients with viral, mycobacterial, or fungal infections of the cornea and conjunctiva.
Antibiotics
Tetracyclines
Oral tetracyclines including doxycycline and minocycline, which block protein synthesis by inhibiting the binding of aminoacyl-tRNA to the mRNA-ribosome complex, have antibacterial and antiinflammatory properties. Tetracyclines inhibit the production or bacterial lipases in order to improve the lipid profile of meibomian oils. Tetracyclines reduce the activity of collagenases, phospholipases, and matrix metalloproteinases. In addition, they block angiogenesis and suppress the production of IL-1 and TNF-α in the corneal epithelium, reducing meibomian lipid breakdown products.
Tetracycline and its analogues are used to treat diseases associated with dry eye disease including blepharitis, MGD, and acne rosacea. MGD is often associated with evaporative dry eye disease.
Rosacea is an inflammatory disorder, which has been associated with MGD, blepharitis and Demodex. Ocular rosacea is characterized by meibomian gland inflammation and inspissation, conjunctival hyperemia, and lid margin telangiectasia, frequently leading to dry eyes. , ,
Several small studies have shown that tetracyclines may decrease symptoms and hyperemia in rosacea. A comparative study of doxycycline 100 mg/day and tetracycline hydrochloride 1 g/day for the management of subjective symptoms of ocular rosacea in 24 patients showed that at 6 weeks all but one patient had symptomatic improvement. A prospective study of 39 patients with cutaneous rosacea with ocular involvement who were given doxycycline 100 mg daily for 12 weeks showed improvement in ocular disease and increase in tear break-up time. Määtä et al. showed that matrix metalloproteinase 8 (MMP-8) levels and activation were increased in tear fluid samples in 22 patients with ocular rosacea compared to 22 controls, which decreased after treatment with oral doxycycline at both 4 and 8 weeks.
Blepharitis, a common ocular surface disorder, which involves inflammation of the eyelids can be managed with tetracyclines. A randomized, double-masked, placebo-controlled partial crossover trial studied topical fusidic acid gel and oxytetracycline in patients with symptomatic chronic blepharitis with and without rosacea. Fifty percent of patients with blepharitis and associated rosacea were symptomatically improved by oxytetracycline alone.
MGD, a type of posterior blepharitis, is caused by structural changes or dysfunction of the meibomian glands. A prospective open-label observational clinical trial demonstrated that topical therapy with azithromycin and oral therapy with doxycycline improved signs and symptoms of MGD and associated dry eyes and also reconstituted lipid properties of meibomian gland secretion. A prospective randomized clinical trial of 60 patients with stage 3 or 4 MGD after 1 and 2 months of oral minocycline 50 mg and artificial tears compared to artificial tears alone showed statistically significant improvement in all clinical signs and symptoms measured. There were also significant reductions in IL-6, IL-1ẞ, IL-17α, TNF-α, and IL12p70 after 2 months of treatment. Aronowicz also showed that tetracyclines may be efficacious in treating meibomianitis.
Established side effects of tetracyclines include gastrointestinal effects and photosensitivity.
Topical azithromycin
Azithromycin is a macrolide antibiotic, which has strong anti-inflammatory properties and good coverage against gram-negative microorganisms. Topical azithromycin is considered a safe treatment for lid margin disease and MGD. Azithromycin inhibits the production of TNF-alpha, IL-1beta, IL-8, RANTES (Regulated on Activation, Normal T Cell Expressed and Secreted), and MMP (MMP-1, MMP-3, and MMP-9) by inhibiting nuclear factor-kappaB activation in corneal epithelial cells.
A study of 26 subjects with moderate-to-severe blepharitis who received azithromycin 1% ophthalmic solution for 4 weeks without warm compresses showed that topical azithromycin use was associated with significant improvement in several signs and symptoms of blepharitis. Luchs et al. conducted an open-label study of 21 patients with posterior blepharitis that showed that topical azithromycin 1% combined with warm compresses showed significant improvement in ocular signs and symptoms compared to warm compresses alone.
In patients with blepharoconjunctivitis, erythromycin ointment can also be considered.
Oral azithromycin
Studies have shown that oral azithromycin may be beneficial in the treatment of MGD and can provide a treatment alternative in patients unable to take other oral antibiotics. In particular, azithromycin may be beneficial in patients with MGD who also have rosacea due to its antiinflammatory properties. Side effects of systemic azithromycin include diarrhea, nausea, and vomiting.
Blood Products
Autologous and/or Allogenic Serum Drops
Autologous serum, which is devoid of blood’s cellular components and clotting factors, has been shown to provide relief in symptoms and improvement of the ocular surface of DES in patients with severe ocular surface disease refractory to standard treatments. , Autologous serum eye drops are made from a patient’s own blood by segregating the serum from cellular components. An advantage of serum is that it has several biochemical similarities to natural tears. , In addition, it contains epitheliotropic and antimicrobial factors that are beneficial for corneal nutrition, growth, and development. The topical use of serum was originally used to treat severe ocular surface diseases from SS, Stevens–Johnson syndrome, and chemical burns. , It is now also used to treat dry eyes after keratorefractive surgeries, recurrent erosions, persistent epithelial defects, neurotrophic keratopathy, chemical injuries, and superior limbic keratoconjunctivitis.
Several clinical trials and case series investigating autologous serum conclude that it can be efficacious in the treatment of signs and symptoms of DED. Mondy et al. showed that among 77 patients with dry eye and corneal epithelial defects, there were significant improvements in the symptoms frequency of dryness, ocular pain, and grittiness at 2 and 12 months. A systematic Cochrane review reviewed five studies that compared autologous serum to artificial tears or saline showed that eye drops containing autologous serum may have short-term benefits at improving dry eye symptoms but that further studies are needed to evaluate long-term effects.
Autologous serum eye drops are compounded from the patient’s own serum. There is variability in the methods of preparation, storage, and administration. After blood is drawn and forms a clot, the supernatant is centrifuged to separate the serum from the solid components. The serum is then decanted and can be diluted to a specific concentration. Autologous serum is usually administered at a 20% concentration although higher concentrations (50%–100%) have been used. ,
Serum tear preparation has rarely been associated with the risk of infection and microbial contamination (seen after extended use >30 days). Autologous serum should be stored at 4°C for less than a month and then can be stored for up to 3 months at −20°C. To prevent risk of viral transmission to others, it is advised that the donor be tested for blood-borne illnesses (e.g., human immunodeficiency virus (HIV), hepatitis B virus (HBV), hepatitis C virus (HVC), syphilis). ,
Autologous serum may be cost prohibitive for patients. It also requires patients to provide blood samples at least every 3 months. In addition, the production of autologous serum is regulated by national laws that vary between countries. , In the United States, the Center for Biologics Evaluation and Research (CBER) of the FDA is responsible for the regulation of blood components and its derivatives.
Allogenic serum may be used in patients with active inflammation, anemia, or other contraindications; however, allogenic serum may induce an immune response.
Eye–Platelet-Rich Plasma and Plasma Rich in Growth Factors
Platelet preparations have been used to treat ocular surface disease, including platelet-rich plasma (PRP), plasma rich in growth factors (PRGFs), and platelet lysate. The advantage of platelet preparations is that they contain an increased concentration of growth factor.
PRP is prepared from whole blood that is collected in the presence of a 3.2% sodium citrate anticoagulant solution, which is then centrifuged to isolate a platelet-enriched supernatant plasma. The PRP is divided into 3–4 mL aliquots and can be stored at 4°C for 1 week or a −20°C for an extended period. The growth factors present in PRP are thought to activate macrophages, induce cell repair and angiogenesis. In addition, these products, unlike serum drops, do not contain leukocytes that may increase levels of proinflammatory cytokines. Alio et al. showed PRP was associated with improvement in dry eye symptoms and signs in 368 patients with moderate-to-severe dry eye at 6 week follow-up.
PRGF is prepared by collecting whole blood in tubes containing 3.8% sodium citrate and then centrifuging the tubes using a soft spin at 460 × g at room temperature for 8 min. After the plasma supernatant is isolated, platelets are activated using 22.8 mM calcium chloride, which generates a fibrin clot and growth factors are released via platelet activation and degranulation. The growth factor–rich supernatant serum is filtered and is then diluted with 0.9% sodium chloride down to 20%. The product can be stored at 4°C for up to 1 week and then at −20°C for longer periods. The drops are administered four times a day. PRGFs have also been shown to lead to symptom improvement in patients with moderate-to-severe dry eye.
Platelet lysate has also been shown to be efficacious in the treatment of ocular graft-versus-host disease.
Eyelid Procedures
Several in-office procedures can be utilized in patients with evaporative dry eye in the setting of MGD.
Intense Pulsed Light
Intense pulsed light (IPL) utilizes high-intensity light sources, which emit light extending from visible (515 nm) to the infrared spectrum (1200 nm), which is absorbed by the skin tissue and then converted to destructive heat. Wavelengths can be customized for different targets. It is used in dermatology for the removal of hypertrichosis, benign cavernous hemangiomas, benign venous malformations, telangiectasia, pigmented lesions, acne rosacea, photo damaged skin, and port wine stain. ,
A third-generation IPL device for periocular use is commercially available for treating severe MGD after being refractory to other therapies. In 2021, the US FDA approved the Lumenis IPL device (Lumenis, Yokneam, Israel) for improving signs of DED from MGD. A randomized, double-masked, placebo-controlled trial evaluating IPL as a therapy for MGD showed a significant improvement in lipid layer grade, noninvasive tear break-up time, and in visual analogue symptoms scores from baseline with 86% of 28 subjects noting reduced symptoms in the treated eye by 45 days. A 30-month retrospective study of IPL and gland expression for treatment of DED caused by MGD showed 93% of 91 patients reported posttreatment satisfaction in regard to dry eye symptoms. A retrospective study of 35 patients with refractory dry eye treated with IPL and meibomian gland expression (MGX) showed significant reduction in Standard Patient Evaluation of Eye Dryness 2 (SPEED2) symptom survey scores and increase in meibomian gland evaluations (MGD) in the left eye after a minimum follow-up of 6 months. A multicenter cohort study of 100 patients with MGD and dry eye who underwent IPL (with an average of four sessions) showed a significant decrease in lid margin edema, facial telangiectasia, lid margin vascularity, meibum viscosity, and OSDI score. There was also a significant increase in the measured oil flow score and TBUT. A prospective study of IPL combined with MGX in 40 patients with moderate-to-severe MGD showed reduction in number and severity of symptoms and signs of dry eye after 15 weeks.
It is important to note that IPL cannot be used in patients with a Fitzpatrick score greater than 4, the upper eyelid cannot be directly treated and the procedure can be cost prohibitive for some patients.
Vectored thermal pulsation (LipiFlow)
Lipiflow Vectored thermal pulsation system (TearScience, Morrisville, NC, USA) clears blockages in the meibomian glands of patients with MGD by heating the glands to therapeutic levels of 42.5°C by applying localized heat to both inner eyelid surfaces (insulating the eye) while pulsating pressure is also applied to the outer eyelids through an inflatable air bladder. The procedure takes 12 min. Studies have shown vectoral thermal pulsation can lead to sustained improvements in objective and subjective measures of dry eye disease. , Fig. 11.5 shows the Lipiflow device.
