Tolerability of Current Treatments for Dry Eye Disease: A Review of Approved and Investigational Therapies

Abstract

Dry eye disease (DED) is a common, multifactorial ocular disease impacting 5% to 20% of people in Western countries and 45% to 70% in Asian countries. Despite the prevalence of DED and the number of treatment approaches available, signs and symptoms of the disease continue to limit the quality of life for many patients. Standard over-the-counter treatment approaches and behavior/environmental modifications may help some cases but more persistent forms often require pharmacological interventions. Approved and investigational pharmaceutical approaches attempt to treat the signs and symptoms of DED in different ways and tend to have varying tolerability among patients. While several pharmacological approaches are the standard for persistent and severe disease, mechanical options provide alternate treatment modalities that attempt to balance efficacy and comfort. Newer approaches target the causes of DED, utilizing novel delivery methods to minimize irritation and adverse events. Here, we review approved and investigational approaches to treating DED and compare patient tolerability.

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Introduction

Dry eye disease (DED), or keratoconjunctivitis sicca, is a common, multifactorial ocular disease impacting between 5% and 20% of people in Western countries and between 45% and 70% of people in Asian countries.^1,2 The pathophysiology of DED involves a cascade of inflammatory events that can be worsened by intrinsic factors such as age, sex, and autoimmune diseases.^1,3 Desiccating stress at the ocular surface and tear hyperosmolarity, which can be caused by extrinsic factors, activate mitogen-activated protein kinase signaling; upregulate nucleotide-binding domain, leucine-rich–containing family, pyrin domain–containing-3 (NLPR3) and toll-like receptor and oxidative stress pathways; and stimulate the secretion of cytokines, chemokines, and matrix metalloproteinases. This initiates a vicious inflammatory cycle that leads to disruption of the epithelial barrier, apoptosis of epithelial cells in the cornea and lacrimal gland cells, and T-cell infiltration. This loss of homeostasis in the cornea, conjunctiva, and lacrimal glands causes further instability of the tear film, which in turn triggers further inflammatory signaling.³ The loss of tear film homeostasis and accompanying ocular symptoms, including tear film instability and hyperosmolarity, ocular surface inflammation and damage, and neurosensory abnormalities, play etiologic roles in DED.⁴ The onset of DED may be influenced by many variables, including local ocular factors, systemic diseases, sociodemographic characteristics, environmental conditions, elective medications, and surgical procedures.⁵ Additionally, DED is cyclical, with symptom flares and inactive periods.⁶

There is no gold standard sign or symptom for diagnosing DED. Instead, a combination of questionnaires and evaluations are used to identify DED (Table 1). Symptoms of DED include ocular pain, burning, dryness, foreign body sensation, and visual disturbances.¹ Signs of DED include decreased noninvasive break-up time; elevated or a large interocular disparity in osmolarity; or positive ocular surface staining of the cornea, conjunctiva, or lid margin.⁴ Additionally, gentle expression of the meibomian glands and meibography may be used as assessment tools.⁷ These methods can determine the presence of meibomian gland dysfunction by assessing the quantity of meibum secreted as well as alterations in its lipid composition and its expressibility. Meibography also evaluates meibomian gland loss, demonstrated by gland dropout and changes in its length, thickness, and density.^8,9

Table 1.

Most Frequently Used Methods for Diagnosing DED

Evaluation	Purpose	Diagnostic Process
Tear film break-up time	Evaluation of time between complete blink and the first break in tear film	Sodium fluorescein dye applied to the eye. Tear film is observed under a slit lamp while the patient avoids blinking until dry spots develop. Cutoff below 10 seconds is consistent with DED
Tear meniscus assessment	Assessment of the inferior tear film meniscus height by slit lamp	Slit-lamp biomicroscopy can be used to measure the height of the tear meniscus. A short meniscus height is consistent with DED
Schirmer test	Measure of basic and reflex tearing	A Schirmer paper strip is folded and hooked over the lateral lid margin. Less than 5 mm to 10 mm of wetting after 5 minutes is consistent with DED
Phenol red test	Measures tear production	A phenol red dyed cotton thread is hooked over the temporal eyelid into the sulcus for 15 seconds as the patient rests with eyes closed. If wet, the thread will turn red. Values of less than 10 mm to 20 mm are considered deficient
Fluorescein staining	Assessment of corneal damage	A small volume of the stain is applied to the eye for 1 to 3 minutes. Observation of ≥5 spots is consistent with DED
Lissamine green staining	Assessment of conjunctival and lid margin damage	The stain is applied to the lid margin with ≥2-mm length consistent with DED
Conjunctival redness	Graded by slit-lamp evaluation for redness of hyperemia often observed in DED (but not specific to DED)	Subjectively graded by slit-lamp biomicroscopy, but positive results are not indicative of DED
Tear film osmolarity	Osmolarity values tend to increase with disease severity	Tear film osmolarity can be sampled and tested with a 308-mOsm/L threshold for mild/moderate disease and a 316-mOsm/L threshold indicative of more severe disease
Matrix metalloproteinases	Testing of matrix metalloproteinase-9 that may be elevated in disease	Can be sampled and assessed by point-of-care tests. Higher levels are consistent with DED
Blepharitis	Eyelid evaluation for anterior blepharitis and Demodex blepharitis	Visual examination that may be aided by tests for oil and crust deposits
Lid wiper epitheliopathy	Increased lid wiper staining associated with DED	Fluorescein or lissamine green stain can be applied to the lid wiper, with staining associated with damage to the region
Meibomian gland evaluation	Evaluation of the expressed meibum following application of digital pressure	Evaluation is performed by meibography, with meibomian function assessed by quantity (degree of meibomian gland loss determined by meibograde from 0 to 3, as well as length, thickness, and density of meibomian glands), meibum quality (increased thickness and lipid content of the meibum), and meibum expressibility8,9
Eyelid blink and closure	Assessment of incomplete closure of the eyelid	Visual assessment that can be supported by a microscope or camera to determine if the eye regularly closes all the way

Note: Data from Golden MI, Meyer JJ, Zeppieri M, Patel BC. Dry Eye Syndrome. Treasure Island, FL: StatPearls Publishing; 2024. Available from: https://www.ncbi.nlm.nih.gov/books/NBK470411/.¹⁰

Abbreviation: DED, dry eye disease.

According to the Tear Film and Ocular Surface Society Dry Eye Workshop II (TFOS DEWS II) report, the first step for staged management and treatment of DED involves educating the patient on the condition, its management, and its prognosis.⁴ Ocular lubricants, such as artificial tears, and lid hygiene/warm compresses can be used to relieve DED symptoms.⁴ Patients should modify the local environment and remove or change any potential aggravators of the disease.⁴ Changing or supplementing a diet with foods rich in omega-3, omega-6, and omega-7 polyunsaturated fatty acids has anti-inflammatory effects and may be associated with clinical improvement in DED, both independently and in addition to other therapies.^11–16 If these initial modifications do not improve the signs and symptoms of DED, over-the-counter and prescription medications may be used (Table 2).⁴

Table 2.

List of Approved Treatments for DED in the US

Treatment	Category	Indication	Approval
CyclASol 0.1% ophthalmic solution (VEVYE)	CNI	Increase tear production	US 202317
Cyclosporine ophthalmic emulsion 0.05% (RESTASIS)	CNI	Increase tear production in patients where tear production is presumed to be suppressed due to ocular inflammation; BID6,18–20	US 2003
Cyclosporine ophthalmic solution 0.09% (CEQUA)	CNI	Increased tear production21–24	US 2018
iLux MGD treatment system	Thermomechanical	Application of localized heat and pressure to break up oil blockages in the meibomian glands	US 201625
iTear100	Electronic	Applied externally near the border of the nose and cheek	US 202026
KPI-121 0.25% ophthalmic nanoparticle suspension of loteprednol etabonate (EYSUVIS)	Corticosteroid	Short-term (up to 2 weeks) treatment of signs and symptoms of DED27	US 2020
Lifitegrast 5.0% ophthalmic solution (XIIDRA)	LFA-1/ICAM-1 inhibitor	Treatment of signs and symptoms of DED; BID28	US 201629,30
LipiFlow thermal pulsation system	Thermomechanical	Heat upper and lower eyelid while applying graded pulsatile pressure to the outer surface31	US 201632
MiBoFlo Thermoflo	Thermal	Consistent emissive heat to the meibomian glands33	US (FDA Class II with exemption)
Perfluorohexyloctane ophthalmic solution (MIEBO)	CNI	Reduces tear evaporation	US 2023
Sodium hyaluronate ophthalmic solution	Hyaluronic acid	Promotes corneal injury healing34	Japan 1995, US and EU OTC
TearCare System	Thermomechanical	Delivers precise heat and manual mechanical meibomian expression31	US (FDA Class II with exemption)
Varenicline (TYRVAYA [varenicline solution] 0.03 mg)	Cholinergic agonist	Treatment of signs and symptoms of DED; BID35,36	US 202137

Note: Data from CenterWatch - FDA Approved Drugs - Listings in Dry Eye Disease. Available from: https://www.centerwatch.com/directories/1067-fda-approved-drugs/topic/949-dry-eye-disease.³⁸

Abbreviations: BID, twice a day; CNI, calcineurin inhibitor; DED, dry eye disease; FDA, Food and Drug Administration; ICAM-1, intracellular adhesion molecule-1; LFA-1, lymphocyte function–associated antigen-1; MGD, meibomian gland disease; OTC, over the counter.

Many of the therapeutic options for DED have issues with tolerability (such as instillation-site burning or pain and blurred vision), which impacts the quality of life (QoL) for patients and may lead to decreased adherence.⁶ This review focuses on the tolerability profiles of the US Food and Drug Administration (FDA)-approved and investigational products designed to treat the underlying causes of DED and highlights the educational points that may improve patient adherence and outcomes.

Currently Approved Pharmacological Treatments for Dry Eye Disease

DED is classified by the TFOS DEWS II report into 3 subtypes: evaporative dry eye (EDE), the most common form; aqueous-deficient dry eye (ADDE); and a mixed form of DED when these 2 etiologies co-occur.⁴ ADDE is characterized by insufficient tear production by the lacrimal glands leading to a reduced aqueous component in the tear film, while EDE stems primarily from dysfunction of the meibomian glands that results in deficient secretion of the lipid component of the tear film.^4,39

All forms of DED can be treated with tear substitutes, topical lubricants, and anti-inflammatory drugs, including steroids and cyclosporine.^4,39,40 Therapeutic strategies specifically targeting EDE include enhanced lid hygiene using warm compresses, lid scrubs, and gentle massage for instance, and mechanical methods to unclog blocked meibomian glands, such as thermal pulsation (TPS), intense pulsed light (IPL), and meibomian gland probing.⁹ Additionally, antibiotics such as topical azithromycin or oral doxycycline can be used to treat EDE.^9,41 For the treatment of severe ADDE, secretagogues can be used to stimulate tear production by acting on the ocular surface receptors.⁴⁰

Treatment of DED involves a comprehensive approach of treating the underlying stressors/causes of the disease (if possible) by simple nonprescription therapies (lid cleansers, warm compresses, and nutraceuticals) before using more invasive/pharmacological treatments (Table 3).⁴² Because of the heterogeneity in the population of patients with DED and the variability in severity and character of the disease in these patients, there is no clearly delineated treatment regimen for DED. Instead, treatment of DED can involve multiple recommended therapeutic approaches that can be selected based on the nature and degree of the disease, as well as other individual factors.⁴ Initial treatments such as artificial tears provide short-term symptom relief by coating the corneal surface and creating an unbroken layer to protect the eye from desiccating stress and injury.^1,43 However, these treatments merely address symptoms of DED and have no direct effect on the underlying inflammation or mechanisms responsible for disease progression.

Table 3.

Summary of Efficacy for Approved and Investigational DED Treatments

Treatment	Dosage	Status/Phase	Efficacy	Publications	Most Common AEs (>5% of Patients)
Anakinra/EBI-005 (IL-1R antagonist)	5%	Phase 3	Reduced corneal fluorescein staining Reduced symptoms of DED Decreased need for artificial tears Increased visual acuity and number of expressible meibomian glands	Amparo et al JAMA Ophthalmol. 2013.44 NCT0199880245 NCT0240503946	Conjunctivitis
Bevacizumab (anti-VEGF)	0.05%	NA	Improved TBUT	Kasetsuwan et al PLoS One. 2020.47 TCTR2017102400248	NA*
CyclASol 0.1% ophthalmic solution (VEVYE)	Ophthalmic solution containing cyclosporine 0.1% (1 mg/mL)	US approved	Increase from baseline in Schirmer wetting Reduced corneal staining Reduced ocular surface epithelial lesions	Akpek et al JAMA Ophthamol. 2023.49 Sheppard et al Cornea. 2021.50 NCT0261766751 NCT0452312952	Instillation-site reactions
Cyclosporine ophthalmic emulsion 0.05% (RESTASIS)	Ophthalmic emulsion containing cyclosporine 0.5 mg/mL	US approved	Improved symptom relief Improved OSDI scores Prevented disease progression Reduced total ocular surface staining scores Increased mean Schirmer test scores Improved TBUT	Mah et al Clin Ophthalmol. 2012.6 Stonecipher et al Clin Ophthalmol. 2016.19 Rhee et al Ophthalmology. 2017.20	Instillation-site pain and burning, eye irritation
Cyclosporine ophthalmic solution 0.09% (CEQUA)	Ophthalmic solution containing cyclosporine 0.9 mg/mL	US approved	Significantly decreased ocular surface staining of both the cornea and conjunctiva (relative to vehicle control) Improved corneal staining Improved Schirmer test scores Improved conjunctival staining Improved proportion of clear central corneas	Weiss et al J Ocul Pharmacol Ther. 2019.22 Malhotra et al Cornea. 2019.23 Goldberg et al Ophthalmology. 2019.24	Conjunctival hyperemia, instillation-site pain
HU00701 and HU007	0.01% cyclosporin A + 3% trehalose and 0.02% cyclosporin A + 3% trehalose, respectively	Phase 3	Improved TBUT	Shin et al J Ocul Pharmacol Ther. 2021.53 NCT0438499154 NCT0574376455 NCT0346157556	NA*
KPI-121 0.25% ophthalmic nanoparticle suspension of loteprednol etabonate (EYSUVIS)	Ophthalmic suspension containing 2.5 mg/mL of loteprednol etabonate	US approved	Significant improvements in conjunctival hyperemia and ocular discomfort severity scores	Korenfeld et al Cornea. 2021.27	Instillation-site pain
Lacriprep	0.005% and 0.01%	Phase 1/2	Tear stabilization and tear viscosity regulation Stabilized meibomian gland secretions Lowered tear surface tension	Georgiev et al JBC. 2020.57 NCT0322644458	NA
Lifitegrast 5.0% ophthalmic solution (XIIDRA)	Ophthalmic solution containing lifitegrast 50 mg/mL	US approved	Improved eye dryness scores (visual analog score) Improved inferior corneal staining score	Holland et al Ophthalmology. 2017.28	Instillation-site irritation and reaction, dysgeusia
Perfluorohexyloctane ophthalmic solution (MIEBO)	100% perfluorohexyloctane as eye drops	US approved	Decreased total corneal fluorescein staining Improved dryness scores and symptom burden	Tauber et al Cornea. 2021.59 NCT0572377060 NCT0456732961 NCT0413979862 NCT0414022763	NA*
Varenicline (TYRVAYA [varenicline solution] 0.03 mg)	Nasal spray delivering 0.03 mg of varenicline in each spray (0.05 mL)	US approved	Decreased mean goblet cell area Improved tear film production Reduced eye dryness scores	Dieckmann et al Ophthalmol Ther. 2022.35 Wirta et al Cornea. 2022.36	Sneezing, nasal discomfort, cough, throat irritation, instillation-site irritation, dysesthesia pharynx
RCI; Acthar Gel	80 U/mL	Phase 4, approved for other indications	Decreased corneal fluorescein staining Decreased mean SANDE score Decreased erythema Decreased conjunctival lissamine green staining Decreased intraocular pressure	Toyos et al Ophthalmol Ther. 2022.64	Insomnia, headache, upper respiratory infection, dysfunctional uterine bleeding, injection-site reactions, heart palpitations, irritability, edema
OC-02	NA	Phase 2	Improved Schirmer test results Improved eye dryness scores Improved eye discomfort	Torkildsen et al Clin Ther. 2022.65 NCT0363346166 NCT0345239767	Cough and throat irritation, instillation-site irritation, nasopharyngitis, sneezing
OCS-02 (licaminlimab)	NA	Phase 2	Improved global ocular discomfort scores	Shettle et al Clin Ophthalmol. 2022.68 NCT0236551969	NA*
PL9643	NA	Phase 3	Improved corneal staining and ocular discomfort in moderate-to-severe disease70	NCT0520117071	NA
Rebamipide ophthalmic suspension (OPC-12759)	2% ophthalmic suspension	Japan approved; US phase 3	Improved fluorescein staining scores Improved lissamine green conjunctival staining score Improved TBUT Improved subjective ocular symptoms, including foreign body sensation, dryness, photophobia, eye pain, and blurred vision	Kinoshita et al Am J Ophthalmol. 2014.72 NCT0020198173 NCT0020195574 NCT0163213775 NCT0081832476	Nasopharyngitis, dysgeusia, conjunctival hemorrhage, allergic conjunctivitis, trichiasis
Recombinant human epidermal growth factor	10, 50, or 100 µg/mL	Phase 1	NA	Yoo et al Pharmaceuticals (Basel). 2022.77 NCT0521946178	Corneal erosion
Recombinant human nerve growth factor	4 or 20 µg/mL	Phase 2	Improved signs and symptoms of DED Improves ocular surface disease index scores Improves ocular damage Increases tear film production	Sacchetti et al Br J Ophthalmol. 2020.79 NCT0398236880	Abnormal sensation in eye, eye pain, eye irritation, eye pruritus, blurred vision, headache, foreign body sensation, photophobia, increased lacrimation, visual impairment, rhinitis
Reproxalap	0.25 and 0.5% ophthalmic solution	Phase 3	Improved SANDE frequency scores Improved ODS and OD4SQ (overall, dryness, grittiness, and burning scores) Improved Schirmer test scores Improved tear osmolarity Improved lissamine green total and staining scores	Clark et al J Ocul Pharmacol Ther. 2021.81 NCT0473539382 NCT0467435883	Instillation-site pain
SKQ1 (visomitin ophthalmic solution)	300 nM (181 ng/mL) for 24 h	Russia approved, US phase 3	ROS scavenger in the mitochondria, reducing inflammation in the eye	Wei et al Ophthalmol Ther. 2019.84 NCT0420602085 NCT0376473586	NA*
Tanfanercept	0.25% ophthalmic solution	Phase 3	Improved inferior corneal staining score and total corneal staining scores Improved Schirmer test results Improved TBUT	Dong et al Int Ophthalmol. 2022.87 NCT0510970288 NCT0384645389	Conjunctivitis, conjunctival redness
TRPM8 channel blockers	0.0014% or 0.003% ophthalmic solution	Phase 2b	Stimulated tear production	Chen et al PLoS One. 2016.90 Fakih et al Int J Mol Sci. 2020.91 Wirta et al Ocul Surf. 2022.92	Instillation-site burning or stinging

Note: *No AEs occurring in >5% of patients were reported.

Abbreviations: AE, adverse event; DED, dry eye disease; IL-1R, interleukin 1 receptor; NA, not applicable; OD4SQ, ocular discomfort and 4-symptom questionnaire; ODS, ocular discomfort scale; OSDI, ocular surface disease index; RCI, repository corticotropin injection; ROS, reactive oxygen species; SANDE, Symptom Assessment Questionnaire in Dry Eye; TBUT, tear break-up time; TRPM8, transient receptor potential cation channel subfamily M member 8; VEGF, vascular endothelial growth factor.

A wide range of artificial tear formulations are commercially available and are commonly based on cellulose derivatives, povidone, polyvinyl alcohol, carbomers, or hyaluronic acid. The type of patients’ tear film deficiency can guide the selection of artificial tear formulations based on the type of lubricant they contain, which can be aqueous or lipid based.^39,93 For instance, in patients with meibomian gland dysfunction, lipid-containing artificial tears are recommended.⁹³ However, artificial tears or ocular lubricants may include preservatives or excipients like benzalkonium chloride that cause irritation and ultimately worsen DED.^39,94,95 For patients with severe DED, autologous serum eyedrops are indicated.⁹³ These are derived from a patient’s own serum, which has a similar composition and biochemical properties as tears and contains growth factors and inflammatory substances that promote epithelial healing.⁹⁶

When therapeutic strategies using simple nonprescription therapies and artificial tears are not sufficient to address symptoms of DED, alternative approaches involving prescription treatments can be adopted. Among these available prescription therapies are topical corticosteroids, which improve the signs and symptoms of DED but are relatively unsuitable for long-term use due to the associated side effects of prolonged exposure, including elevated intraocular pressure (IOP), glaucoma, and cataracts.^1,6,97–99 EYSUVIS (0.25% loteprednol etabonate ophthalmic suspension; Alcon Laboratories, Inc, Fort Worth, TX, USA) is a topical corticosteroid approved by the US FDA in 2020 for short-term (2 week) treatment of the signs and symptoms of DED.^100,101 Loteprednol uses mucus-penetrating particle technology to improve ocular drug delivery and reduce DED flares by modulating the proinflammatory signaling mediated by the glucocorticoid receptor.^27,102,103 Across 4 clinical studies (one phase 2 and three phase 3 studies), 1430 patients with DED treated with loteprednol 4 times a day for 2 weeks demonstrated significant improvements in conjunctival hyperemia and ocular discomfort severity scores.^27,102 Additionally, 12.9% (185/1430) of loteprednol-treated patients reported an adverse event (AE) with 8.5% (121/1430) reporting a treatment-related AE. The most frequently occurring treatment-emergent AE (TEAE) was instillation-site pain (5.2%).²⁷ Although the majority of AEs were mild to moderate in severity, 0.6% (8/1430) of patients reported a severe AE, including instillation-site pain. Mean IOP values were similar in patients treated with loteprednol and vehicle, and 0.6% of patients in the loteprednol treatment group experienced an IOP measurement of ≥21 mm Hg in 1 or both eyes compared to 0.3% of patients in the vehicle treatment group.²⁷

For patients suffering from chronic DED, several pharmacological treatment options that are better suited for long-term treatment are available. These include anti-inflammatory agents such as topical cyclosporine or lifitegrast, the cholinergic agonist varenicline, the immunomodulatory hormonal treatment repository corticotropin injection (RCI), or the perfluorohexyloctane ophthalmic solution MIEBO.^{17,18,21,29,37,104–106}

Cyclosporine A (CsA) is a calcineurin inhibitor that mitigates the immune response and is indicated for transplantation, rheumatoid arthritis, psoriasis, and amyotrophic lateral sclerosis.¹⁰⁷ Topical CsA reduces the expression of interleukin-2 and its receptors in T cells, which decreases their proliferation, inhibits cell-mediated inflammatory pathways in the eye (inhibiting calcineurin), and helps restore the ocular surface.^1,43,108 As a result, continued use of topical CsA may increase tear production and reduce the signs and symptoms of DED.²² Approved CsA formulations in the US include cyclosporine ophthalmic solution 0.09% (CEQUA; Sun Pharmaceutical Industries, Inc., Princeton, NJ, USA; referred to as OTX-101 0.09%), cyclosporine ophthalmic solution 0.05% (RESTASIS; Allergan, Inc., Irvine, CA, USA), and CyclASol 0.1% ophthalmic solution (VEVYE; Novaliq GmbH, Heidelberg, Germany; Table 2).^17,18,21,109 The first generic form of RESTASIS, cyclosporine ophthalmic emulsion 0.05% single-use vials, was approved by the US FDA in 2022 (Viatris, Inc., Canonsburg, PA, USA).¹¹⁰ An additional formulation, cyclosporine ophthalmic emulsion 0.1% (Verkazia; Santen Pharmaceutical Co., Ltd, Emeryville, CA, USA), is approved by the US FDA for vernal keratoconjunctivitis, a rare ocular allergy condition.¹⁰⁴ OTX-101 0.09% (cyclosporine solution) is a nanomicellar, clear aqueous solution of CsA approved by the US FDA in August 2018 for keratoconjunctivitis sicca.^21,22 Cyclosporine ophthalmic emulsion 0.05% was approved by the US FDA in 2003 for DED.¹¹¹ CyclASol 0.1% ophthalmic solution is a clear, topical, water-free ophthalmic solution of CsA in a novel, semifluorinated alkane (SFA)-based EyeSol technology vehicle, using the SFA perfluorobutylpentane. CyclASol increases bioavailability of CsA while avoiding the use of oils, surfactants, and preservatives.^50,112

All 3 formulations of cyclosporine approved by the US FDA demonstrated efficacy in treating DED symptoms compared to vehicle. In a pooled analysis of a phase 2b/3 and a phase 3 study assessing the efficacy and safety of OTX-101 0.09% compared to vehicle, the primary endpoint of a ≥10-mm increase from baseline in Schirmer test scores at Day 84 was met. Patients treated with OTX-101 0.09% experienced a significant increase in tear production compared to vehicle-treated patients (16.6% of eyes vs 9.0% of eyes, respectively; P <0.0001), as well as a significantly greater change from baseline in total corneal fluorescein staining for all common post-baseline time points (Day 28, 56, and 84; P ≤0.0013).²³ In a phase 4 open-label study evaluating cyclosporine ophthalmic emulsion 0.05%, patients had significantly decreased total ocular surface and corneal staining scores after 6 months of treatment with cyclosporine 0.05% (P <0.001). Patients also experienced a significant increase in mean average eye Schirmer test scores from 5.3 mm at baseline to 8.7 mm at the 6-month time point (P = 0.010).¹⁹ In the phase 2b/3 ESSENCE study assessing the efficacy and safety of CyclASol 0.1%, the primary endpoint was met, with a statistically greater improvement from baseline in total corneal fluorescein staining in patients treated with CyclASol compared to vehicle at Week 4 (P = 0.0002). There was no significant difference in a >10-mm increase from baseline in Schirmer test scores between patients treated with CyclASol 0.1% and vehicle.⁵⁰

Overall, these formulations of cyclosporine were well tolerated with mild AEs. In a phase 2b/3 and phase 3 study, TEAEs for patients receiving OTX-101 0.09% (n = 523) were mostly mild to moderate and resolved without treatment.²³ There were no clinically significant changes from baseline in visual acuity or IOP.²³ The most common AE in the OTX-101 0.09% arm was instillation-site pain, experienced by 24.2% of patients.²⁴ The most common ocular TEAEs included conjunctival hyperemia (30/372 [8.1%]), blepharitis (5/372 [1.3%]), eye irritation (3/372 [0.8%]), eye pruritus (1/372 [0.3%]), and foreign body sensation (1/372 [0.3%]). There were no ocular-related serious AEs (SAEs) reported.²⁴ In four phase 2 and 3, multicenter, randomized, controlled clinical studies (n = 1200), the most commonly reported AE was ocular burning (204/1200 [17%]).^18,113 Other commonly reported AEs include conjunctival hyperemia, discharge, epiphora, eye pain, foreign body sensation, pruritis, stinging, and visual disturbances (blurring).¹⁸ An open-label phase 4 study found similar safety events, with the most commonly reported ocular AEs including instillation-site burn (3/40 [7.5%]), instillation-site pain (3/40 [7.5%]), and eye irritation (2/40 [5%]), with 1 patient experiencing a treatment-related nonocular TEAE (headache).¹⁹ In a phase 2b/3 study, patients receiving CyclASol had similar proportions of ocular TEAEs (20/162 [12.3%]) vs patients receiving vehicle (14/166 [8.4%]).⁵⁰ The most frequently occurring ocular TEAEs were reduced visual acuity (CyclASol, 5/162 [3.1%]; vehicle, 3/166 [1.8%]), instillation-site pain (CyclASol, 4/162 [2.5%]; vehicle, 2/166 [1.2%]), and blurred vision (CyclASol, 2/162 [1.2%]; vehicle, 4/166 [2.4%]).⁵⁰ A second phase 3 study demonstrated similar safety profiles and proportions of TEAEs further supporting the use of CyclASol for DED.⁴⁹

Beyond the various CsA formulations, there are several other approved pharmacological treatments for chronic DED. Lifitegrast ophthalmic solution 5.0% (XIIDRA; Bausch & Lomb, Laval, Canada) is a small-molecule lymphocyte function–associated antigen 1 (LFA-1) antagonist approved for the treatment of signs and symptoms of DED.^29,114 Lifitegrast is thought to reduce inflammation in DED by preventing T-cell activation and recruitment through the inhibition of interactions between LFA-1 and the adhesion receptor intercellular adhesion molecule 1.¹¹⁴ In the confirmatory OPUS-3 studies (N = 711),²⁸ patients receiving lifitegrast had a greater mean improvement from baseline at Day 42 for itching, foreign body sensation, and eye discomfort than those receiving vehicle.²⁸ In a pooled analysis of 5 trials, most TEAEs were mild to moderate, with 1% of lifitegrast-treated patients reporting severe ocular TEAEs vs 0.4% receiving vehicle.¹¹⁵ The drop comfort score identified worse scores over the first 3 minutes postinstillation followed by improvements thereafter, persisting to subsequent visits.^28,116 The most frequently reported ocular TEAEs included irritation, reaction, and pain at the instillation site; there were no serious ocular TEAEs.¹¹⁵ Dysgeusia was the most common nonocular TEAE, reported by 14.5% (186/1287) of patients.¹¹⁵ Overall, 1.6% of patients reported a serious nonocular TEAE; however, none were believed to be related to the randomized treatment.¹¹⁵ Ninety patients (7%) receiving lifitegrast discontinued the trials.¹¹⁵ In the SONATA study, approximately twice as many patients receiving lifitegrast had decreased visual acuity compared to patients receiving vehicle per patient reporting, though changes through Day 360 were minimal (as assessed by 0.7 logarithm of the minimum angle of resolution best corrected visual acuity).¹¹⁷ Fewer patients in the lifitegrast group used artificial tears after Day 14, though use of artificial tears correlated to increased TEAEs.¹¹⁷

Varenicline solution 0.03 mg (TYRVAYA; Oyster Point Pharma Inc., Princeton, NJ, USA) is a small-molecule nicotinic acetylcholine (nACh) receptor partial agonist that targets and binds free nerve endings in the nasociliary and maxillary branches of the trigeminal nerve (via the nasal cavity).^35,37 The binding of varenicline to nACh receptors activates the trigeminal parasympathetic pathway, which is thought to increase tear production by stimulating the autonomic nerves of the cells in the lacrimal functional unit.^35,37 In a phase 2 study (n = 12), there were no ocular TEAEs, and the nonocular TEAEs were nonserious and mild in severity.³⁵ Additionally, the incidence of ocular TEAEs for patients treated with varenicline solution (16.5%; n = 260) was consistent with the incidence reported for patients receiving vehicle (16.3%; n = 251; ONSET-2). Sneezing was the most common TEAE, occurring in 82% of patients across the ONSET-1, ONSET-2 (phase 3), and MYSTIC (phase 2) studies.^118,119 Across all 3 studies, there were no SAEs resulting in study discontinuation.^36,118–120

RCI (Acthar Gel; Mallinckrodt Pharmaceuticals, Hampton, NJ, USA) is a mixture of porcine adrenocorticotropic hormone analogs and pituitary peptides that bind to and activate melanocortin receptors throughout the body, including those located on the cells of the retina, and is believed to exert immunomodulatory effects on B cells, T cells, and macrophages.^64,121 RCI is currently approved for severe, acute, and chronic allergic and inflammatory processes involving the eye.¹⁰⁶ In a phase 4 pilot study (N = 15) for DED, RCI was generally effective and well tolerated, with no ocular AEs reported and 2 patients discontinuing due to other AEs.⁶⁴

MIEBO (perfluorohexyloctane ophthalmic solution) consisting of inert and anhydrous SFA (Bausch & Lomb, Vaughan, Canada) is a preservative-free ophthalmic solution that rapidly spreads across the ocular surface due to its low surface/interfacial tension and interacts with the lipophilic portion of the tear film, preventing evaporation. It is a recently approved treatment option for DED.^59,105 In a phase 3 study, 54 patients reported 122 TEAEs; the number of patients reporting at least 1 TEAE was similar between the treatment groups.¹²² The most common ocular TEAEs were blurred vision, eye irritation, and eye pain.¹²² Four patients reported SAEs, and 3 patients discontinued the study due to an AE.¹²²

Mechanical Interventions

Nonpharmacological approaches to treating DED focus on promoting tear secretion and mobilization of meibum via thermal, light, mechanical, electrical, and combinatorial stimulation methods (Table 4). Mechanical stimulation may improve blood flow to the eye, which can promote tear secretion and improve dry eye symptoms.^123,124 Thermal applications use heat, often in combination with pulsation/vibration, to soften and express meibum.⁸⁴ Alternatively, external nasal nerve stimulation may be used to restore the activity of the lacrimal functional unit.¹²⁵ In a study of an external nerve stimulator, patients experienced notable improvements 30 days after treatment in Schirmer test and ocular surface disease index scores. Overall, 9 of 101 (9%) patients reported AEs, with 2 mild AEs related to the study device. The most commonly reported AEs were sneezing and dizziness.¹²⁵ There were no neurologic AEs or damage to the skin.¹²⁵ One patient reported nasal pain but remained in the study.¹²⁵

Table 4.

Summary of Nonpharmacological Interventions for Dry Eye Disease

Treatment	Mechanism
Activa mask	Device uses heating and vibration to melt the meibum inside the glands and simultaneously squeezes them126
Acupuncture	Regulates ion channel movement and improves blood nourishment123
Broadband light + IPL	Modified IPL protocol uses optimized light wavelengths to treat DED127
EyeGiene eye lipid mobilization	Lowers meibum viscosity to improve oil gland function; vibration induces shear thinning to liquify and mobilize meibum128
Systane iLux MGD treatment system	Handheld device with disposable tips that contain 2 eyelid pads; 1 pad slides beneath the eyelid and makes contact with the inner surface while the other applies pressure on the outer surface84
IPL	Xenon flashlamp emits wavelengths of light between 400 and 1200 nm that induce closing of abnormal blood vessels129
iTear	External application and external nasal nerve stimulation restores the lacrimal functional unit125
LipiFlow thermal pulsation system	Softens and squeezes out stagnated meibum by heating the inner surface of the eyelids in addition to rhythmic compressions to the outer surface of the eyelid84
Low-level light therapy	Specifically utilizes red-light wavelengths to allow for atraumatic and athermal cellular photobioactivation130
MiBo Thermoflo	Computer and probe apply thermoelectricity in addition to manual pressure131
Rexon-Eye	Electrical stimulation leads to the metabolism and natural regeneration of cells, resulting in reactivation of lacrimal and meibomian glands132
TearCare	Sterile single-use flexible eyelid devices gently adhere to the contours of the patient’s eyelids and apply low heat84,133

Abbreviations: DED, dry eye disease; IPL, intense pulsed light; MGD, meibomian gland dysfunction.

IPL induces closing of abnormal blood vessels, a feature often prevalent in meibomian gland dysfunction.¹²⁹ However, wavelengths emitted by IPL and those absorbed by the pigmented iris overlap, leaving patients at risk of permanent eye damage from IPL without proper eye protection.¹³⁴ In a retrospective, noncomparative, interventional case series, IPL was generally well tolerated. There were no SAEs reported among the 88 patients involved. In total, 4 (8.9%) patients experienced AEs with 1 patient discontinuing the study. The AEs reported included moderate allergic conjunctivitis, moderate blepharitis (both deemed to be unrelated to the study), moderate bacterial conjunctivitis, and mild skin pain. No patients experienced systemic AEs.¹³⁵

Low-level light therapy (LLLT) specifically uses red-light wavelengths, and this allows for atraumatic and athermal cellular photobioactivation.¹³⁶ The red-light wavelength causes photonic interference allowing therapeutic levels of light to penetrate the skin to repair damaged cells and improve cell function.¹³⁶ An evaluation using light-emitting diode-based LLLT in 20 patients found no SAEs.¹³⁷ Electrotherapy delivers electrical stimulation to the biological tissue believed to stimulate metabolism and natural regeneration.¹³² Treatment with electrotherapy improved ocular surface disease index scores, noninvasive tear break-up time scores, and normalized tear meniscus height values.¹³² No AEs were noted in the study, and patients were reportedly comfortable during the procedure.¹³²

Punctual plugs, also called lacrimal plugs, are small devices made of silicone or collagen that can be used to treat patients with severe ADDE. Punctual plugs increase tear retention on the ocular surface by occluding tear ducts, which leads to delayed tear drainage.⁹³ In a retrospective study examining the use of silicone punctual plugs between 1996 and 2000 in 153 patients and 203 eyes, including 127 eyes with DED, symptoms improved in 73.9% of eyes at 4 ± 2 weeks’ follow-up. Additionally, mean corneal fluorescein staining scores, which assess the viability of the epithelium, significantly decreased at 4 ± 2 weeks’ follow-up (P <0.01), indicating an improvement in ocular surface disease with punctual plugs.^138,139 The most common complication associated with the use of punctual plug is loss of the plug.⁹³

Although mechanical approaches are well tolerated, cost, availability, and reproducibility tend to create substantial access burdens, and the symptom relief experienced after in-office treatment tends to decline over time, limiting long-term tolerability for patients.^84,131,140 In addition to the in-office treatments, patients may perceive maintenance protocols as tedious and time consuming, which can lead to poor adherence and tolerability.¹⁴⁰

Pharmacological Treatments in Development for Dry Eye Disease

In addition to the currently approved treatments for DED, there are other options in development. Ectoine eye drops are being evaluated to improve drug delivery and efficacy. Ectoine creates a protective hydration shell around proteins and biomolecules due to a strong binding capacity with water.¹⁴¹ In a systematic review of 16 studies in sensitive patient groups (ie, <18 years or after surgery), a limited number of AEs were reported and no SAEs were reported.¹⁴¹ Similarly, HU00701 and HU007 (0.01% CsA + 3% trehalose and 0.02% CsA + 3% trehalose; respectively; Huons Co., Ltd., Gyeonggi-do, Republic of Korea) are 2 new formulations of CsA in development.⁵³ Similar to previous formulations of CsA, the inclusion of trehalose is intended to limit desiccation.¹⁴² Although a clinical study evaluating CsA with trehalose did not identify improved corneal staining, the treatment was deemed to be safe and well tolerated.^53,143 In total, 8 patients reported AEs, including infection, eye disorder, general disorders and administration site conditions, and musculoskeletal and connective tissue disorders. The rates were consistent among the treatment, vehicle, and control groups.⁵³ Additionally, AZR-MD-001 (Azura Ophthalmics; Tel Aviv, Israel), an ointment containing selenium sulfide, diminishes the aberrant production of keratin that clogs the meibomian glands by inhibiting the growth and development of keratinocytes. This inhibition of keratinocytes leads to a reduction in the differentiation of epidermal cells and the production of corneocytes.¹⁴⁴ Results from a phase 2 trial show improvements in dry eye symptoms at 3 months, though 15 out of 23 AZR-MD-001-treated patients (across 3 dosage groups) reported at least 1 ocular TEAE.¹²

Building on the success of varenicline nasal spray, OC-02 (simpinicline solution; Viatris, Inc., Canonsburg, PA, USA) is a highly selective nACh receptor agonist. OC-02 stimulates nACh receptors on the trigeminal parasympathetic nerve in the nasal cavity to induce tear production.⁶⁵ In a phase 2 study, 52% (64/123) of the patients receiving OC-02 reported a TEAE, with most of those incidents being nonocular and mild to moderate in severity (1 patient did present with a severe TEAE, but this was considered unrelated to the study).⁶⁵ The ocular TEAEs included eye pruritis (1 patient) and keratitis (1 patient).⁶⁵

Other novel pharmacological approaches focus on treating the mechanisms responsible for DED. Growth factors such as epidermal growth factor (EGF) or neural growth factor (NGF) are involved in many phases of growth and development and have been touted as having potential efficacy in the treatment of DED. Epidermal growth factor is a growth factor secreted from the lacrimal glands and is involved in corneal healing, suggesting a potential therapeutic role in DED.^77,145 Treatment with recombinant human EGF eye drops (Daewoong Bio Inc., Seoul, Korea) was generally well tolerated with 10/36 patients in the treatment group reporting TEAEs. All reported TEAEs were mild and transient and there were no SAEs.⁷⁷ Similarly, NGF plays a crucial role in modulating the central and peripheral nervous system, including the visual system.⁷⁹ After treatment with recombinant human NGF eye drops (Dompé Farmaceutici S.p.A, Milan, Italy), 1 patient experienced an SAE considered unrelated to treatment but did not discontinue the study. One patient discontinued the study due to an AE of bacterial conjunctivitis.⁷⁹ In the study, 29 of 40 patients experienced at least 1 AE, and 11 patients had at least 1 treatment-related AE.⁷⁹ All of the AEs experienced were considered to be mild to moderate in severity, though 1 patient discontinued the treatment due to an AE.⁷⁹ In general, no safety concerns emerged from this trial, with no increases in IOP or decreases in best corrected visual acuity observed and symptoms improving among those investigated on the visual analog scale.⁷⁹

Reproxalap (Aldeyra Therapeutics, Inc., Lexington, MA, USA), tanfanercept (Harbour BioMed [Guangzhou] Co. Ltd., Natick, MA, USA), imatinib mesylate, (Novartis, Basel, Switzerland), licaminlimab (Novartis, Basel, Switzerland), bevacizumab (Genentech Inc., San Francisco, CA, USA), and PL9643 (Palatin Technologies, Inc., Cranbury, NJ, USA) target specific pathways in DED pathogenesis and are designed to limit the inflammatory response. Reproxalap, a reactive aldehyde species (RASP) inhibitor, is a small-molecule inhibitor engineered to block RASP signaling.⁸¹ RASP are molecules that exert proinflammatory effects by binding thiol and amino groups on receptors and kinases, thereby activating cytokines and pro-histaminic factors. The proinflammatory cascade modulated by RASP also produces inflammatory molecules such as tumor necrosis factor alpha (TNF-α) and cyclooxygenase-2, and causes cell necrosis, apoptosis, and DNA damage. Notably, levels of malondialdehyde, a common form of RASP, are elevated in patients with DED. RASP signaling inhibition by reproxalap prevents the activation of nuclear factor-κ B (NF-κB), scavenger receptor A, and inflammasomes, leading to decreased levels of cytokines and histamines.¹⁴⁶ A preliminary trial noted improvements as early as 1 week after treatment initiation; however, there were 47 ocular TEAEs in 51 patients.⁸¹ Forty-two of the TEAEs involved ocular discomfort or pain upon instillation, but all TEAEs were transient and self-limiting.⁸¹ Similarly, tanfanercept is a molecularly engineered TNF receptor 1 fragment eye drop formulation designed to inhibit TNF-α signaling to reduce inflammation.⁸⁷ One study reported equal numbers of TEAEs in tanfanercept and placebo groups; however, ocular AEs were more prevalent in the tanfanercept group with conjunctivitis and conjunctival redness being the most frequently reported.⁸⁷ Imatinib mesylate is a tyrosine kinase inhibitor that preclinically is a potent discoidin domain receptor 1 inhibitor.¹⁴⁷ In preclinical studies, imatinib reduced damage to the ocular surface and reduced accumulation of inflammatory cells, restoring structure of the conjunctival epithelium.¹⁴⁷ In a preliminary clinical study in healthy individuals (N = 32), 4 TEAEs were reported, 3 in the imatinib mesylate groups and 1 in the placebo group; all TEAEs were mild to moderate in severity and recovered without sequelae, and there were no SAEs.¹⁴⁷ Licaminlimab is a single-chain antibody fragment that binds and neutralizes TNF-α.⁶⁸ Treatment-emergent adverse events were reported in similar numbers between the treatment group (19%) and the control group (14%).⁶⁸ In the licaminlimab group, dry eye and eye pruritus were the most commonly reported TEAEs and were not reported in the control group.⁶⁸ Bevacizumab (anti–vascular endothelial growth factor A [VEGF-A]) is a monoclonal antibody targeting the inflammatory response through the intended modulation of VEGF-A. Through inhibition of VEGF-A, bevacizumab may attenuate the inflammatory response, with preliminary results showing the treatment to be well tolerated (no safety events reported).⁴⁷ PL9643 is a melanocortin receptor pan-agonist designed to attenuate inflammation mediated by macrophages, antigen presenting cells, and antigen-specific T cells through modulation of the melanocortin system.¹⁴⁸ There are no reported drug-related ocular AEs or SAEs in early safety and tolerability studies.⁷⁰

Future therapeutic approaches are currently being investigated in preclinical models for the treatment of DED. One of these approaches involve the use of new delivery systems for improved bioavailability and prolonged drug exposure such as nanotechnology-based systems, hydrogels, and drug-eluting contact lenses.^149–151 Other strategies use regenerative medicine in an attempt to regenerate lacrimal glands by means including stem cells, allogeneic transplantation, and bioengineering.¹⁵⁰

Dry Eye Disease and Demodex Blepharitis

A common contributor to DED is Demodex blepharitis (DB), with upwards of 60% of DED patients with meibomian gland dysfunction also having DB. The Demodex mites are a normal part of the lid flora and are the most prevalent ectoparasite on the human skin.¹⁵² Demodex brevis are linked with symptomatic meibomian gland dysfunction where they can cause blockage of the orifice. Excreta from these mites can further contribute to the blockage and incite an inflammatory response, which can lead to filling, swelling, and enlargement of the meibomian gland.¹⁵² Importantly, DED can be both a cause and an effect of blepharitis, as the tear film helps provide resistance to infection.³⁹ Diagnosis of DB is driven by signs rather than symptoms due to the overlap with many other ocular conditions.¹⁵² As a result, DB is often under or misdiagnosed.¹⁵² Treatment of DB can include IPL, LLLT, tea tree oil, manuka honey, lid hygiene, ivermectin plus (0.1% ivermectin/1% melatonin), and the US FDA-approved ophthalmic drug TP-03, a lotilaner 0.025% ophthalmic solution (XDEMVY; Tarsus Pharmaceuticals, Inc., Irvine, CA, USA).^152–157 With the high incidence of DB and observed frequency of other underlying conditions, it is important to consider and effectively treat DB to maximize outcomes and help patients better tolerate their DED treatment.¹⁵⁸

Patient Education to Help Increase Tolerability of Dry Eye Disease Treatments

Due to the cyclic nature of DED, patients frequently discontinue treatment due to intolerance, perceived lack of effect, or a perceived resolution of signs/symptoms.¹⁵⁹ There continues to be dissatisfaction with the time to onset of effect of treatments, and patient education and awareness of this prolonged time may overcome adherence issues.¹⁵⁹ In a retrospective analysis of cyclosporine ophthalmic emulsion 0.05% studies, patients previously discontinuing topical CsA most frequently did so as a result of burning/stinging.⁶ Upon continuation of cyclosporine ophthalmic emulsion 0.05%, patients were educated on dry eye and topical CsA.⁶ Reinitiation of the study led to a clinical benefit in a majority (80%) of patients, though 2 patients discontinued the study within 4 weeks due to the burning sensation.⁶ These findings further suggest that patient education on treatment expectations and the need for continued treatment should focus on topics including disease signs and symptoms, prognosis and management, time to onset of therapy effects, proper use of the medication and the treatment regimen, and common ocular side effects, their transient nature, and how to manage them.¹⁵⁹ Patient education on how early discontinuation can limit QoL and the importance of adhering to the treatment regimen, even when temporary relief is achieved, is necessary for improved treatment tolerability.¹⁵⁹

Conclusion

In moving beyond artificial tears, treatments for DED focus on the multitude of complex mechanisms that may be implicated in the disease. The persistent burden on the patient and impact DED has on QoL facilitate further evaluation of increasingly effective and well-tolerated treatments. Although currently approved treatments have improved outcomes, AEs and poor tolerability mean these therapeutic options are not suitable for all patients. However, new treatments or regimens with improved AE profiles are becoming increasingly more tolerable. Additionally, educating patients on the nature of the disease as well as tools to mitigate potential treatment-related AEs will encourage patient adherence and lead to improved treatment outcomes.

Funding Statement

Medical writing and editorial support and manuscript submission were funded by Sun Pharma.

Abbreviations

ADDE, Aqueous-deficient dry eye; AE, Adverse event; BID, Twice a day; CsA, Cyclosporine A; DB, Demodex blepharitis; DED, Dry eye disease; EDE, Evaporative dry eye; EGF, Epidermal growth factor; FDA, Food and Drug Administration; IOP, Intraocular pressure; IPL, Intense pulsed light; LFA-1, Lymphocyte function–associated antigen 1; LLLT, Low-level light therapy; nACh, Nicotinic acetylcholine; NGF, Neural growth factor; NLRP3, Nucleotide-binding domain, leucine-rich–containing family, pyrin domain–containing-3; QoL, Quality of life; RASP, Reactive aldehyde species; RCI, Repository corticotropin injection; SAE, Serious adverse event; SFA, Semifluorinated alkane; TEAE, Treatment-emergent adverse event; TFOS DEWS II, Tear Film and Ocular Surface Society Dry Eye Workshop II; TNF, Tumor necrosis factor; TNF-α, Tumor necrosis factor alpha; TPS, Thermal pulsation; VEGF-A, Vascular endothelial growth factor A.

Data Sharing Statement

Data sharing is not applicable to this article, as no data sets were generated or analyzed during the current study.

Ethics Approval and Informed Consent

This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising, or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Disclosure

PG is a consultant to Allergan, Alcon, Aurea, Bausch & Lomb, Johnson & Johnson Vision, Kala Pharmaceuticals, Novartis, Ocular Science, RegGenRxTree, Shire, Sight Sciences, Tarsus, TearLab, TearScience, and Zeiss. JS reports personal fees from Allergan, Alcon, Avedro, Bausch & Lomb, Claris Bio, Clementia Pharma, Dompé, EyeDetec, EyeGate, Lacrisciences, Novartis, Ocular Therapeutix, Science Based Health, Senju, Shire, Sun Pharma, TearLab, TearScience, Tissue Tech, Topcon, and TopiVert; and other fees from Alcon/Novartis, Kala Pharmaceuticals, Novaliq, Noveome, Ocular Therapeutix, Shire, TearLab, and Visus. MT reports consultant fees from Bausch & Lomb, Eyevance, Iridex, Mallinckrodt, Dompé, Sun Pharma, and Zeiss; speaker fees from Bausch & Lomb, Lumenis, Mallinkrodt, Shire, Sun Pharma, and Zeiss; research fees from Alcon, Allysta, Amber Ophthalmics, Bausch & Lomb, DigiSight, Dompé, Farmaceutici, Glaukos, Iridex, Kala Pharmaceuticals, Lumibird, Lumenis, Magellan, Mallinckrodt, MIXTO Lasering, Novartis, Ocular Tech, Oculos, Opternative, Ray, ReVitaLid, Recordati, Shire, Sun Pharma, Sylentis, and Zeiss; and miscellaneous fees from MIXTO Lasering. RT reports speaking fees from Mallinckrodt, Zeiss, Sun Pharma, and Oyster Point; consulting fees from Zeiss, Sun Pharma, and Oyster Point; and research fees from Mallinckrodt. FSM is the chief medical advisor at Kala Pharmaceuticals; reports consulting fees from Alcon, Allergan, Aldeyra, Aperta, Azura, Bausch & Lomb, Dermavent, Kiora, Iview, Johnson & Johnson Vision, Novartis, NuLids, and SightSciences; and research support from Thea, Sun Pharma, Viatris/Oyster Point, Tarsus, Mallinckrodt, Dompé, and YuYu. PT is part of the speaker bureau for Sun Pharma, Viatris Pharmaceuticals, and Lumenis; and is a faculty member for Johnson & Johnson Vision Institute, outside the submitted work. DH reports a patent “Ophthalmic Specialty Instrument for Treating Meibomian Gland Dysfunction” pending; and he is a key opinion leader for Lumenis speaking on OptiLight and OptiPlus & receiving compensation for this work. The authors report no other conflicts of interest in this work.