Article

Dry Eye Disease Treatments: Pharmaceutical vs Procedural

A look at what’s available and the ideal patients

Dry eye disease (DED) is one of the most common disease presentations in ophthalmology and optometry, with a prevalence of up to 75% in some groups.1 The symptoms are diverse, but even when they are nonexistent, the disease remains a concern for doctors since, if left untreated, DED can progress, ultimately affecting the patient’s overall well-being in significant ways (e.g., decreased vision, discomfort, and pain).2 For this reason, it is incumbent upon all eyecare providers to be aware of the latest treatments. These treatments fall under two categories: pharmaceutical and procedural (see “In the Pipeline”).

PHARMACEUTICAL TREATMENTS

Pharmaceutical treatments for DED come in many forms, from over-the-counter options to prescription drops and individualized compounded products. Each of these treatments can be beneficial when used the in right patient.

→ Artificial tears. There is a broad variety of tear products, including tear replacement, viscosity-enhancing tears, lipid-containing products, ointments, and more. Lipid-containing products, for example, are intended to restore the tear film’s lipid layer, reducing tear evaporation.

→ Oral omega supplements. Essential fatty acids (EFAs) are termed “essential” because they are necessary for healthy metabolic processes to occur.3,4 Omega-3 EFAs and some omega-6 EFAs are recognized to have a broad range of systemic anti-inflammatory effects, including inhibiting the production of several key proinflammatory cytokines and preventing T-lymphocyte proliferation processes, which have been implicated in the pathogenesis of DED.3

→ Hypochlorous acid. Also known as HOCI, hypochlorous acid is a microcidal component of the innate immune system.5,6 It can kill bacteria, block bacterial-derived toxins, and blunt the effects of human cell-derived pro-inflammatory mediators.5,7,8 Research shows that bacterial load is more than 14x greater in blepharitis patients compared with controls,9,10 and hypochlorous acid solution may be helpful in decreasing the bacterial load on the lid margin, particularly in patients who have meibomian gland dysfunction (MGD) or ocular rosacea associated with blepharitis. Hypochlorous acid can be applied as a foam or on an impregnated gauze pad once or twice daily. In one study, hypochlorous acid decreased the bacterial load greater than 90%.9

Meibography showing meibomian gland drop out with structural gland changes.

→ Tea tree oil. Tea tree oil is a natural essential oil that exhibits antimicrobial, anti-inflammatory, antifungal, and antiviral properties,11 and it is toxic to Demodex.3,12 Demodex infestation of the eyelids and eyelashes can result in Demodex-associated blepharitis (DAB), marked by the presence of cylindrical dandruff at the base of the lashes. DAB has been implicated in a number of chronic disorders of the eyelids and ocular surface.13 Tea tree oil is typically administered as a foam or on an impregnated pad ­­— as is true with HOCI. It must be used as directed since exposure to high concentrations of tea tree oil can lead to a severe dermatitis of the eyelids.

Cassini surface qualifier demonstrating an unstable tear film with missing and bowed lines.

→ Immunomodulators. The prescription immunomodulating drugs are cyclosporine ophthalmic emulsion 0.05% (Restasis, Allergan), lifitegrast ophthalmic solution 5% (Xiidra, Novartis), and more recently, cyclosporine ophthalmic solution 0.09% formulated with nanomicelle technology (Promacta, Novartis). Preservative-free compounded cyclosporine 0.1% ophthalmic emulsion in chondroitin sulfate is also available.

→ Short-term steroids. Although controversial in some cases (e.g., glaucoma patients), short-term (less than one month) steroids have an important place in DED management, including as induction therapy with long-term pharmacologic agents and/or for the treatment of episodic flare-ups. Both loteprednol etabonate ophthalmic gel 0.38% (Lotemax SM, Bausch + Lomb) and fluorometholone acetate ophthalmic suspension 0.1% have been used to treat DED. Used off-label, the allergy drug loteprednol etabonate ophthalmic suspension 0.2% (Alrex, Bausch + Lomb) for seasonal allergic conjunctivitis is also prescribed for DED. More recently, a 0.4 mg dexamethasone ophthalmic insert (Dextensa, Ocular Therapeutix) was approved for the treatment of inflammation and pain following ophthalmic surgery. This intracanalicular insert, placed in the punctum, is designed to deliver preservative-free dexamethasone to the ocular surface for up to 30 days, while acting as a temporary plug to further improve a desiccated ocular surface.

Although low-dose topical steroids may help to improve a patient’s symptoms, we must counsel patients on appropriate follow-up and potential side effects during treatment. Thus, the patient should be compliant with the treatment plan with no history of steroid response glaucoma.

IN THE PIPELINE

The following two pharmaceutical items are in the pipeline for the treatment of dry eye disease.

  1. Lipid layer stabilizer. The investigational drug NOV03 (Novaliq, Bausch Health, Inc.) is 100% perfluorohexyloctane. It is intended to stabilize the lipid layer and penetrate the meibomian glands. NOV03 uses water-free technology to prevent tear evaporation, restore tear film balance, and potentially dissolve thickened meibum.
  2. Loteprednol etabonate 0.25% with mucus-penetrating particle drug delivery. This drug is under investigation for the treatment of dry eye disease flare-ups.

→ Topical azithromycin. This drug, applied directly to the lid margins, can be a valuable option, particularly when MGD occurs in association with rosacea since the therapy is believed to have anti-inflammatory action, as well as properties that help to control bacterial flora.3

→ Recombinant human nerve growth factor (rhNGF) cenegermin-bkbj ophthalmic solution 0.002%. This drug (Oxervate, Dompé) is the first FDA-approved treatment for neurotrophic keratitis. Due to its orphan drug designation, it was given priority review for this rare and serious ocular surface disease presentation.

→ Oral tetracycline analogues. Doxycycline and minocycline are commonly considered for MGD. The reason is that it is hypothesized that a decrease in bacteria-producing lipolytic exoenzymes and inhibition of lipase production, with resultant decrease in meibomian lipid breakdown products, may contribute to an improvement in clinical parameters, such as irritation, redness, and foreign body sensation in MGD and anterior blepharitis associated with DED.3 Additionally, these agents have anti-inflammatory properties, with one study showing a significant reduction in matrix metalloproteinase 9 (MMP-9), a DED biomarker, in individuals who have rosacea following treatment with oral doxycycline.3,14

→ Amniotic cytokine extract. Amniotic-derived extract solutions contain combinations of cytokines, growth factors, and inhibitors of enzymes involved in tissue remodeling (MMPs).15-17 As such, a compounding pharmacy has formulated a cryopreserved eye drop of amniotic cytokine extract, which has been shown to contain soluble mediators that stimulate healing and reduce inflammation.15

Warped and irregular placido disc mires confirming tear film instability.

→ Amniotic fluid. Amniotic fluid contains electrolytes, growth factors, carbohydrates, lipids, proteins, amino acids, lactate, pyruvate, enzymes, and hormones.18,19 The presence of these multiple growth factors can promote cell growth and the regeneration of healthy collagens that help to promote healing.19 At least one compounding pharmacy has commercialized an amniotic fluid eyedrop, which is dosed one to four times daily for DED symptoms.19

→ Topical testosterone. Androgens have been found to upregulate genes involved in lipid metabolic pathways and downregulate those related to keratinization in human meibomian gland epithelial cells.19 For this reason, DED patients may be treated with compounded topical testosterone drops, with the goal of improving the quality of meibomian gland secretions and reducing ocular discomfort.19

→ Autologous serum. Autologous serum tears are an extremely effective treatment for many patients who have not responded fully to commercially available treatment options. They have been so effective in our severe patients (those requiring prescription medication) that we have now begun offering this option to patients who have less severe symptomatology.19 Many of the biochemical characteristics of autologous serum are similar to those of human tears, which likely contribute to enhanced corneal epithelial wound healing.19 Autologous serum was also found to inhibit the release of inflammatory cytokines and to increase the number of goblet cells and mucin expression in the conjunctiva.19

→ Platelet-rich plasma. Platelets are a reservoir of biologically active growth factors that can potentially be used to treat ocular surface disorders.19 Many different preparations have been studied, several of which have demonstrated improvement in the signs and/or symptoms of DED in patients who have exhausted all other treatments.19

→ Oral gabapentin. Gabapentinoids are first-line agents in the treatment of chronic neuropathic pain outside the eye,19 and more recently, gabapentin has been shown to be effective in severe DED patients who have neuropathic ocular pain.19

PROCEDURAL TREATMENTS

As is the case with pharmaceutical treatments for DED, procedural treatments are diverse and target varied causes of chronic conditions. Each of the following has demonstrated efficacy when used in the right patient.

→ Heated masks. Warm compresses have long been considered a mainstay treatment for MGD,20-22 with several studies showing greater tear film stability and increased tear film lipid layer thickness following treatment of patients who have MGD.23-26 The application of heat to the meibomian glands is thought to soften meibum viscosity, improve secretion and, thus, increase tear lipid layer thickness.25,27,28

→ Punctal occlusion. Any condition that would benefit from aqueous retention on the ocular surface is a reasonable indication for punctal occlusion, by way of either cautery or plugs.19 However, managing evaporative DED with occlusion is controversial when ocular surface inflammation exists because limiting tear outflow could prolong the presence of proinflammatory cytokines on the ocular surface.19 Punctal occlusion, once MMP-9 biomarkers are negative, can be helpful under conditions in which the patient is experiencing a deficiency in aqueous production since the punctal plug will help the patient to retain any natural tears for longer.

→ Manual gland expression. Gland expression is both diagnostic and therapeutic in patients who have MGD. That said, it may have limited utility as a standalone treatment without prior gland heating (e.g., heat masks or gland/lid heating devices), due to the inherent discomfort of the procedure.

OPD III axial map demonstrating an unstable tear film.

→ Mechanical warming and evacuation. Several new technologies exist in this category for patients who have MGD. Some devices offer the dual benefits of warming, along with compression or pulsation to evacuate the meibomian glands. Others can be used in an open-eye environment to facilitate the benefits of blinking during treatment.

→ Intense pulsed light. Intense-pulsed light is a drug-free, drop-free light-based treatment that targets the root cause of MGD — inflammation.29-31 It closes off abnormal blood vessels that perpetuate the inflammation since they leak proinflammatory mediators.32,33

→ Intraductal probing. The availability of specialized probes for optimal safety, and the related economy and outcomes generated,3 make this approach reasonable to perform in select cases of MGD. That said, because of the invasive nature of the procedure, there are concerns of damage to the ductal system, leading many to consider this treatment only after conventional treatments have failed. Nevertheless, there is a very low risk overall of such damage.

→ Neurostimulation. Normal tear production can be stimulated via the nasolacrimal reflex by self-delivering electrical currents to the anterior ethmoidal nerve. The method, which has been commercialized, has shown to effectively improve both the signs and symptoms of DED.3

→ Mechanical cleansing and exfoliation. Removing excess bacteria, biofilm, and toxins from the lids is an essential part of ocular wellness. Therefore, it is important to advise DED sufferers about the tools and techniques that can help to simplify lid hygiene. Lid wipes are available in ready-to-use, moistened, and pre-treated towelettes. An oscillating soft-tip design for at-home use gently stimulates the meibomian glands by removing built-up biofilm from the lid margin. To supplement a patient’s daily lid hygiene regimen, an in-of-fice microblepharoexfoliation system uses a medical grade microsponge to remove scurf and debris from the eyelids, while concurrently exfoliating the lash base.

→ Scleral lenses. Fitting scleral lenses is becoming an increasingly common solution for the management of more advanced DED that does not respond to traditional treatments. The effectiveness of the treatment is likely due to the repository of tears between the lens and the ocular surface. However, advanced custom-designed prosthetic options may provide additional benefits, such as improved comfort and stabilization of vision, even in the most severe cases.34

→ Sutureless amniotic membrane. Amniotic membranes have anti-inflammatory, antifibrotic, antivascularization, and antiscarring effects, in addition to an ability to enhance epithelial healing.35 Cryopreserved amniotic membrane grafts, fastened to an ophthalmic conformer, are easy to insert in a clinical setting. As such, these self-retaining biologic corneal bandages are becoming more widely used in the treatment of ocular surface disease.35 Freeze-dried amniotic membranes are also available for the treatment of neurotrophic defects and other ocular surface issues.

→ Surgical procedures. These are mandatory for DED treatment in cases of lid malposition with secondary exposure and tear film destabilization. Conjunctival chalasis, for example, can be addressed with a variety of techniques, including artificial tears, over-the-counter lubricant drops, warm compresses, and other prescription-strength drops for DED, or it can be handled with a more novel in-office-based high-frequency radiowave electrosurgery approach.

Case Study: young man

An Ever-growing Toolbox

The increasing list of pharmaceutical and procedural options for the treatment of DED makes it easier to tailor treatment to each patient’s unique presentation. CP

References

  1. Craig JP, Nelson JD, Azar DT, et al. TFOS DEWS II Report Executive Summary. Ocul Surf. 2017;15(4):802-812.
  2. Matossian C, McDonald M, Donaldson KE, Nichols KK, MacIver S, Gupta PK. Dry dye disease: consideration for women’s health. J Womens Health (Larchmt). 2019;28(4):502-514.
  3. Jones L, Downie LE, Korb D, et al. TFOS DEWS II Management and Therapy Report. Ocul Surf. 2017;15(3):575-628.
  4. Simopoulos AP. Omega-6/omega-3 essential fatty acids: biological effects. World Rev Nutr Diet. 2009;99:1-16.
  5. Kabat AG, Sowka JW. New blepharitis treatments. Rev Optom. 2014;10:80-81.
  6. Wang L, Bassiri M, Najafi R, et al. Hypochlorous acid as a potential wound care agent: part I. Stabilized hypochlorous acid: a component of the inorganic armamentarium of innate immunity. J Burns Wounds. 2007;6:e5.
  7. Gray MJ, Wholey WY, Jakob U. Bacterial responses to reactive chlorine species. Annu Rev Microbiol. 2013;67:141-160.
  8. Ono T, Yamashita K, Murayama T, Sato T. Microbicidal effect of weak acid hypochlorous solution on various microorganisms. Biocontrol Sci. 2012;17(3):129-133.
  9. Stroman DW, Mintun K, Epstein AB, et al. Reduction in bacterial load using hypochlorous acid hygiene solution on ocular skin. Clin Ophthalmol. 2017;11:707-714.
  10. Bezza Benkaouha I, Le Brun C, Pisella PJ, Chandenier J, Lanotte P. Bacterial flora in blepharitis. J Fr Ophthalmol. 2015;38(8):723-728.
  11. Carson CF, Hammer KA, Riley TV. Melaleuca alternifolia (Tea Tree) oil: a review of antimicrobial and other medicinal properties. Clin Microbiol Rev. 2006 Jan;19(1):50-62.
  12. Gao YY, Di Pascuale MA, Li W, et al. Br J Ophthalmol. 2005 Nov;89(11):1468-1473.
  13. Gao YY, Di Pascuale MA, Li W, et al. High prevalence of Demodex in eyelashes with cylindrical dandruff. Invest Ophthalmol Vis Sci. 2005;46(9):3089-3094.
  14. Määttä M, Kari O, Tervahartiala T, et al. Tear fluid levels of MMP-8 are elevated in ocular rosacea--treatment effect of oral doxycycline. Graefes Arch Clin Exp Ophthalmol. 2006;244(8):957-962.
  15. Yeu E, Goldberg DF, Mah FS, et al. Safety and efficacy of amniotic cytokine extract in the treatment of dry eye disease. Clin Ophthalmol. 2019;13:887-894.
  16. Steed DL, Trumpower C, Duffy D. Amnion-derived cellular cytokine solution. Eplasty. 2008;8:157-165.
  17. Franz MG, Payne WG, Xing L, et al. The use of amnion-derived cellular cytokine solution to improve healing in acute and chronic wounds. Eplasty. 2008;8:188-199.
  18. Rennie K, Gruslin A, Hengstschläger M, et al. Applications of amniotic membrane and fluid in stem cell biology and regenerative medicine. Stem Cells Int. 2012;2012:721538.
  19. Murri MS, Moshirfar M, Birdsong OC, Ronquillo YC, Ding Y, Hoopes PC. Amniotic membrane extract and eye drops: a review of literature and clinical application. Clin Ophthalmol. 2018;12:1105-1112.
  20. Opitz DL, Harthan JS, Fromstein SR, Hauswirth SG, Diagnosis and management of meibomian gland dysfunction: optometrists’ perspective. Clin Optom. 2015;7:59-69.
  21. Qiao J, Yan X. Emerging treatment options for meibomian gland dysfunction. Clin Ophthalmol. 2013;7:1797-1803.
  22. Villani E, Garoli E, Canton V, Pichi F, Nucci P, Ratiglia R. Evaluation of a novel eyelid-warming device in meibomian gland dysfunction unresponsive to traditional warm compress treatment: an in vivo confocal study. Int Ophthalmol. 2015;35(3):319-323.
  23. Arita R, Morishige N, Shirakawa R, Sato Y, Amano S. Effects of eyelid warming devices on tear film parameters in normal subjects and patients with meibomian gland dysfunction. Ocul Surf. 2015;13(4):321-330.
  24. Wang MT, Jaitley Z, Lord SM, Craig JP. Comparison of self-applied heat therapy for meibomian gland dysfunction. Optom Vis Sci. 2015;92(9):e321-e326.
  25. Olson MC, Korb DR, Greiner JV. Increase in tear film lipid layer thickness following treatment with warm compresses in patients with meibomian gland dysfunction. Eye Contact Lens. 2003;29(2):96-99.
  26. Goto E, Monden Y, Takano Y, Mori A, Shimmura S, Shimazaki J, Tsubota K. Treatment of non-inflamed obstructive meibomian gland dysfunction by an infrared warm compression device. Br J Ophthalmol. 2002;86(12):1403-1407.
  27. Geerling G, Tauber J, Baudouin C, et al. The international workshop on meibomian gland dysfunction: report of the subcommittee on management and treatment of meibomian gland dysfunction. Invest Ophthalmol Vis Sci. 2011;52(4):2050-2064.
  28. Goto E, Endo K, Suzuki A, et al. Improvement of tear stability following warm compression in patients with meibomian gland dysfunction. Adv Exp Med Biol. 2002;506(Pt B):1149-1152.
  29. Liu R, Rong B, Tu P, et al. Analysis of cytokine levels in tears and clinical correlations after intense pulsed light treating meibomian gland dysfunction. Am J Ophthalmol. 2017;183:81-90.
  30. Yin Y, Liu N, Gong L, Song N. Changes in the meibomian gland after exposure to intense pulsed light in meibomian gland dysfunction (MGD) patients. Curr Eye Res. 2018;43(3):308-313.
  31. Sambhi RS, Sambhi GDS, Mather R, Malvankar-Mehta MS. Intense pulsed light therapy with meibomian gland expression for dry eye disease. Can J Ophthalmol. 2020 Jan 13. pii: S0008-4182(19)30971-8. doi: 10.1016/j.jcjo.2019.11.009. [Epub ahead of print]
  32. Kassir R, Kolluru A, Kassir M. Intense pulsed light for the treatment of rosacea and telangiectasias. J Cosmet Laser Ther. 2011;13(5):216-222.
  33. Papageorgiou P, Clayton W, Norwood S, Chopra S, Rustin M. Treatment of rosacea with intense pulsed light: significant improvement and long-lasting results. Br J Dermatol. 2008;159(3):628-632.
  34. Nguyen MTB, Thakrar V, Chan CC. EyePrintPRO therapeutic scleral contact lens: indications and outcomes. Can J Ophthalmol. 2018;53(1):66-70.
  35. Suri K, Kosker M, Raber IM, et al. Sutureless amniotic membrane ProKera for ocular surface disorders: short-term results. Eye Contact Lens. 2013;39(5):341-347.