Personalized Management of Dry Eye Disease: From Pathophysiologic Mechanisms to Targeted Therapeutic Approaches

Dry eye disease (DED) is a prevalent, chronic condition diagnosed in about 16.4 million Americans, with an additional 6 million undiagnosed patients experiencing dry eye symptoms.1 The prevalence of DED increases with patient age. The burden of DED is multifactorial, leading to a considerable impact not only on visual function but also on activities of daily living, including personal and professional work and quality of life.2 The direct and indirect costs associated with DED are substantial.

The etiology of DED varies, and it may include evaporative, aqueous-deficient, and inflammatory aspects.2 Treatments are often individualized to the patient’s underlying pathophysiology and severity of presenting symptoms. Nonprescription treatment for DED includes over-the-counter (OTC) artificial tears, warm compresses, and lid hygiene procedures.3 Prescription therapies may act via several mechanisms, including relieving inflammation, increasing tear production, and decreasing tear evaporation.4

There are a variety of nonpharmacologic procedures, OTC treatments, prescription therapies, and devices available to improve DED symptoms.3 Patients may attempt several different therapies alone or in combination in a staged approach to obtain relief.2 The development of future pharmacotherapeutic agents may be helpful for patients with suboptimal responses to existing therapies.

Background and Role of Evaporation in DED Pathophysiology

The presentation of DED includes various possible signs and symptoms.5 The condition is typically classified into aqueous-deficient dry eye (ADDE), evaporative dry eye (EDE), or mixed presentation (ie, features of ADDE and EDE) subtypes.5 In ADDE, despite normal tear evaporation, reduced lacrimal secretion leads to tear hyperosmolarity.6 In EDE, despite normally functioning lacrimal glands, tear hyperosmolarity can be caused by excessive evaporation that is usually related to meibomian gland dysfunction (MGD).6,7 In addition, DED may have a mixed etiology in which both lacrimal and meibomian glands are impaired.7

Symptoms of DED include ocular dryness, irritation, tearing, burning, stinging, and blurred vision. Patients may also experience a foreign body sensation in the eye, itching, photophobia, redness, mucous discharge, increased blinking frequency, and eye fatigue.5 Symptoms tend to worsen throughout the day, and they may be exacerbated by low humidity, fans, and prolonged visual efforts such as those needed to read or use digital devices. The severity and duration of DED symptoms vary, as do disturbances in vision. DED is sight-threatening for only a small percentage of patients, but it may substantially impact quality of life and visual function during daily activities of living, such as social, physical, and workplace functioning (eg, driving, reading).5 DED also plays a role in comorbid eye conditions such as glaucoma—39% of patients with glaucoma also experience DED symptoms.8 In addition, DED must be addressed before cataract surgery, as the disease can impact keratometric readings and preoperative planning.9 Providers should attempt to identify the primary source of the disease and manage the chronic complications.6

The estimated economic impact of DED is substantial. The average annual indirect costs of its management are over $11,000 per patient and total more than $55 billion in the United States. These expenditures are added to the annual direct costs of over $700 per patient and more than $3.8 billion in the United States.10 Indirect costs may include lost work time and productivity, changes in type of work, reductions in quality of life, and impaired social, emotional, and physical functioning.5 Direct costs include office visits, in-office procedures, prescription and OTC medications, and specialized eyewear. Older age and female sex have been identified as risk factors for DED.

Two large, cross-sectional surveys demonstrated that the prevalence of DED in the US is 7.8% in women and 4.3% in men 50 years and older, and prevalence appears to increase with age.11,12 Results of a systematic review and meta-analysis found that the incidence of DED in young adults was 3.5%, but it increased to almost 7.8% in patients older than 68 years.13 Conditions associated with the development of DED include androgen hormone deficiencies; blink or eyelid abnormalities; systemic inflammatory diseases such as Sjogren syndrome, auto­immune thyroid disease, or rheumatoid arthritis; ocular surface diseases including herpes simplex virus keratitis; surgeries that disrupt the trigeminal afferent sensory nerves (eg, laser-assisted in situ keratomileusis, small incision lenticule extraction); and systemic conditions that disrupt the tear-stimulating efferent cholinergic nerves.5 The reduced blink rate that can occur with excessive screen time is also a risk factor for DED; therefore, DED may have a growing impact on younger populations due to modern lifestyle factors (eg, use of electronic devices with screens).5,14

There appears to be a higher proportion of DED due to EDE (often associated with MGD) compared to ADDE. In a study of 224 patients with DED, 50% had EDE, 14% had ADDE, and 36% were classified as having a mixed etiology.7 Meibomian gland dropout increases with increasing age, which correlates with a higher proportion of MGD-based DED in the older population, particularly those 50 years and older.6

Tear Film Instability and Evaporation Cycle

The pathophysiology of DED is complex and multifactorial. It involves disruption of tear film homeostasis leading to tear film instability, hyperosmolarity, and ocular surface inflammation and damage that perpetuates further tear film instability.6

The tear film includes a thicker mucoaqueous layer and a thinner outer lipid layer that protects against evaporation and helps spread the tear film over the ocular surface. The mucoaqueous layer is formed from components including aqueous basal tears produced by lacrimal glands and mucins secreted by conjunctival goblet cells; the stabilizing lipid layer is produced by the meibomian glands.15

Tear hyperosmolarity can trigger an inflammatory response to the ocular surface epithelial cells by activating inflammatory mediators and proteases; mediator activation combined with tear hyperosmolarity leads to goblet and epithelial cell loss. Epithelial injury, defective glycocalyx, and loss of tear volume and goblet cell mucin can lead to the frictional symptoms experienced by patients with DED. Tear hyperosmolarity and epithelial injury in DED also may stimulate corneal nerve endings, leading to discomfort and an increased blink rate and compensatory lacrimal tear secretion.6

Clinical Recommendations for DED Management

The American Academy of Ophthalmology (AAO) based its diagnostic recommendations on the Tear Film and Ocular Surface Society International Dry Eye Workshop II report.5,6 Many diseases may present with symptoms similar to DED, which may make diagnosis difficult.5 Symptoms that can overlap with other conditions include foreign body sensation, itching, irritation, and soreness. DED diagnosis should be based on assessing patient history, such as causative or exacerbating factors, history of prolonged visual efforts, and whether symptomatic relief with artificial tears is achieved. The diagnosis may then be supported by clinical examination and diagnostic tests. Examples of diagnostic tests that may be included in the workup for ocular surface disease include the Schirmer test of aqueous tear production, the fluorescein dye disappearance test (which measures the tear function index), the fluorescein tear break up time test, dye staining to assess ocular surface damage, and tear osmolarity testing. In addition to diagnostic tests, validated questionnaires such as the Ocular Surface Disease Index may be used. Specific to the AAO Preferred Practice Pattern guideline, DED severity classification places patients into mild, moderate, or severe disease categories, although overlapping characteristics may complicate classification.5

Goals of DED Treatment and Recommended Management Strategies

The main goal of DED management is to restore homeostasis of the ocular surface and tear film to break the damaging cycle of DED.6 Long-term goals include identifying and treating the causes of DED to address chronic complications and to manage symptoms. The AAO recommends a staged management approach to DED treatment. Patient education is critical for successful treatment, and it should include information about the condition, management, and prognosis.5

• Step 1 of the staged management approach includes patient education, environmental and dietary modifications, reduction or elimination of contributing medications, eyelid hygiene, and use of artificial tears and warm compresses.5 Several artificial tear formulations are available; however, agent selection depends on the etiology of DED.4 For example, for patients with MGD, lipid-containing artificial tear formulations are recommended. Some patients may experience more irritation when using artificial tear formulations that contain preservatives. As the severity of DED increases, topical agents with aqueous enhancement properties (eg, gels, emulsions, ointments) may be trialed.5
• Step 2 includes tear conservation approaches, overnight treatments, in-office expression of meibomian glands, and prescription medications that may include nasal sprays, oral antibiotics, and topical agents such as corticosteroids, secretagogues, antibiotics, nonglucocorticoid immunomodulatory drugs (eg, cyclosporine A [CsA]), lymphocyte function-associated antigen 1 (LFA)-1 antagonists (eg, lifitegrast), andperfluorohexyloctane.5
• Step 3 should be considered if previous treatments inadequately address signs and symptoms. It includes use of oral secretagogues, autologous/allogenic serum eye drops, platelet-rich plasma eye drops, blood-based products, and therapeutic contact lenses.5
• Step 4 includes treatment with topical corticosteroids for longer durations, amniotic membrane grafts, surgical punctal occlusion, and various other surgical procedures.5

Differing management strategies regarding agent choice exist.6 Using the AAO staged management approach, if a patient does not respond to a given level of treatment, they progress to the next management level. Previous therapies could be continued as new agents are added, or they may be discontinued depending on patient tolerability. Within this stepped approach, the AAO offers caveats of basing the choice of prescription medication on the patient’s specific presentation and disease severity and involving shared decision-making between the provider and patient.5

Mechanism of Action in Prescription Treatments

EDE, ADDE, and mixed DED may all be treated with tear substitutes, topical lubricants, and topical anti-inflammatory medications (eg, cyclosporine, corticosteroids). Patients may require a multimodal approach due to various causative factors and symptoms. For example, patients without inflammation are unlikely to benefit from topical anti-inflammatory agents. Initial treatments (eg, artificial tears) provide symptomatic relief by coating the corneal surface; however, they do not address the underlying pathophysiology of DED.4

As a patient progresses to moderate DED, recommended treatment includes prescription therapy with topical corticosteroids, CsA, lifitegrast, varenicline, and perfluorohexyloctane.5 Therapeutic agents have varied benefits and limitations (Table 1).4,16-22 Topical cortico­steroid anti-inflammatory eye drops may be prescribed for short-term management, but long-term use is not recommended due to adverse events (AEs) including increased intraocular pressure, glaucoma, and cataracts.4 Topical CsA is a calcineurin inhibitor that decreases cell-mediated inflammation and allows restoration of the ocular surface; this treatment may result in increased tear production and improved DED symptoms. Lifitegrast is a small-molecule LFA-1 antagonist that reduces inflammation via inhibition of T-cell activation.4,21

Perfluorohexyloctane ophthalmic solution spreads across the ocular surface and acts as an anti-evaporative agent.4,23 Varenicline solution is a small-molecule nicotinic acetylcholine receptor partial agonist that binds to the trigeminal nerve, resulting in increased tear production through autonomic nerve stimulation.4

Future Directions in DED Management

Several agents are currently being developed to manage DED (Table 2).4,24-34 These investigational agents address various pathophysiologic mechanisms of DED, including reduced tear production, MGD, and mucin deficiency.24 In addition, several agents being developed address ocular inflammation via different mechanisms.4 Novel therapeutic approaches include growth factors that may lead to healing.4

Gaps in the Current Guidelines

Current International Statistical Classification of Diseases, Tenth Revision, (ICD-10) codes include billing information for DED of the left, right, or both eyes and subcategories of other specific diseases leading to DED, such as Sjogren syndrome or punctate keratitis.5 However, ICD-10 codes lack subcategories for classifying ADDE, EDE, or mixed etiology and do not reflect DED severity; this is out of sync with current AAO guidelines that base treatment recommendations on disease severity and prior treatment failure.

Additionally, DED lacks well-defined, clinically meaningful outcomes that correlate with symptoms.35 Standardization of outcome measures that are well defined may improve the comparative efficacy of investigational agents. Future research opportunities that may enhance evidence-based algorithms for treatment include head-to-head clinical trials, use of combination therapies, and real-world evidence on matching the therapeutic mechanism of action to the etiology of DED.

Conclusion

DED is a prevalent, chronic condition affecting millions of Americans. DED often results from a complex interplay between the ocular surface and glands that secrete tear components. Subsequent excessive evaporation or insufficient aqueous tear production leads to a vicious cycle of tear film instability and resulting ocular surface inflammation and damage. Various artificial tear formulations are available to manage DED symptoms; however, they do not address the root cause of DED. The recommended use of topical therapeutic agents follows a stepped approach. However, variability in individual symptoms, disease etiology, and patient response may require a patient-centered treatment strategy that involves shared decision-making. Further, DED’s multifactorial pathophysiology and variability in patient response necessitates thoughtful formulary building. Future research addressing the multifaceted etiology and symptomatology of DED may inform therapeutic approaches.

REFERENCES

1. Farrand KF, Fridman M, Stillman IÖ, Schaumberg DA. Prevalence of diagnosed dry eye disease in the United States among adults aged 18 years and older. Am J Ophthalmol. 2017;182:90-98. doi:10.1016/j.ajo.2017.06.033
2. O’Neil EC, Henderson M, Massaro-Giordano M, Bunya VY. Advances in dry eye disease treatment. Curr Opin Ophthalmol. 2019;30(3):166-178. doi:10.1097/ICU.0000000000000569
3. Jones L, Downie LE, Korb D, et al. TFOS DEWS II management and therapy report. Ocul Surf. 2017;15(3):575-628. doi:10.1016/j.jtos.2017.05.006
4. Gupta PK, Toyos R, Sheppard JD, et al. Tolerability of current treatments for dry eye disease: a review of approved and investigational therapies. Clin Ophthalmol. 2024;18:2283-2302. doi:10.2147/OPTH.S465143
5. Amescua G, Ahmad S, Cheung AY, et al; American Academy of Ophthalmology Preferred Practice Pattern Cornea/External Disease Panel. Dry eye syndrome preferred practice pattern. Ophthalmology. 2024;131(4):P1-P49. doi:10.1016/j.ophtha.2023.12.041
6. Craig JP, Nelson JD, Azar DT, et al. TFOS DEWS II report executive summary. Ocul Surf. 2017;15(4):802-812. doi:10.1016/j.jtos.2017.08.003
7. Lemp MA, Crews LA, Bron AJ, Foulks GN, Sullivan BD. Distribution of aqueous-deficient and evaporative dry eye in a clinic-based patient cohort: a retrospective study. Cornea. 2012;31(5):472-478. doi:10.1097/ICO.0b013e318225415a
8. Chan CCK, Crowston JG, Tan R, Marin M, Charles S. et al. Burden of ocular surface disease in patients with glaucoma from Australia. Asia Pac J Ophthalmol (Phila). 2013;2:79-87. doi:10.1097/APO.0b013e31828372c2
9. Venkateswaran N, Luna RD, Gupta PK. Ocular surface optimization before cataract surgery. Saudi J Ophthalmol. 2022;36(2):142-148. doi:10.4103/sjopt.sjopt_190_21
10. Yu J, Asche CV, Fairchild CJ. The economic burden of dry eye disease in the United States: a decision tree analysis. Cornea. 2011;30:379-387. doi:10.1097/ICO.0b013e3181f7f363
11. Schaumberg DA, Sullivan DA, Buring JE, Dana MR. Prevalence of dry eye syndrome among US women. Am J Ophthalmol. 2003;136:318-326. doi:10.1016/s0002-9394(03)00218-6
12. Schaumberg DA, Dana R, Buring JE, Sullivan DA. Prevalence of dry eye disease among US men: estimates from the physicians’ health studies. Arch Ophthalmol. 2009;127:763-768. doi:10.1001/archophthalmol.2009.103
13. McCann P, Abraham AG, Mukhopadhyay A, et al. Prevalence and incidence of dry eye and meibomian gland dysfunction in the United States: a systematic review and meta-analysis. JAMA Ophthalmol. 2022;140:1181-1192. doi:10.1001/jamaophthalmol.2022.4394
14. Modern technology and a multi-screen lifestyle viewed as important factors in rising prevalence of dry eye disease. News release. PR Newswire. October 17, 2016. Accessed May 15, 2025. https://www.prnewswire.com/news-releases/modern-technology-and-a-multi-screen-lifestyle-viewed-as-important-factors-in-rising-prevalence-of-dry-eye-disease-597289311.html
15. Willcox MDP, Argüeso P, Georgiev GA, et al. TFOS DEWS II tear film report. Ocul Surf. 2017;15(3):366-403. doi:10.1016/j.jtos.2017.03.006
16. Cequa. Prescribing information. Sun Ophthalmics; 2022. Accessed May 15, 2025. https://www.cequa.com/CequaPI.pdf
17. Eysuvis. Prescribing information. Alcon; 2023. Accessed May 15, 2025. https://www.eysuvis-ecp.com/pdf/prescribing-information.pdf
18. Restasis. Prescribing information. AbbVie; 2024. Accessed May 15, 2025. https://www.rxabbvie.com/pdf/restasis_pi.pdf
19. Tyrvaya. Prescribing information. Viatris; 2024. Accessed May 15, 2025. https://www.tyrvaya-pro.com/files/prescribing-information.pdf
20. Vevye. Prescribing information. Harrow; 2024. Accessed May 15, 2025. https://vevye.nyc3.cdn.digitaloceanspaces.com/files/Vevye-PI-05-24-1.pdf
21. Xiidra. Prescribing information. Bausch + Lomb; 2023. Accessed May 15, 2025.https://www.xiidra-ecp.com/globalassets/pdf/packageinserts/pharma/xiidra-prescribing-information.pdf
22. Miebo. Prescribing information. Bausch + Lomb; 2023. Accessed May 15, 2025. https://pi.bausch.com/globalassets/pdf/packageinserts/pharma/miebo-
    package-insert.pdf
23. Schmidl D, Bata AM, Szegedi S, et al. Influence of perfluorohexyloctane eye drops on tear film thickness in patients with mild to moderate dry eye disease: a randomized controlled clinical trial. J Ocul Pharmacol Ther. 2020;36(3):154-161. doi:10.1089/jop.2019.0092
24. Sheppard JD, Nichols KK. Dry eye disease associated with meibomian gland dysfunction: focus on tear film characteristics and the therapeutic landscape. Ophthalmol Ther. 2023;12(3)1397-1418. doi:10.1007/s40123-023-00669-1
25. Tauber J, Laurie GW, Parsons EC, Odrich MG; Lacripep Study Group. Lacripep for the treatment of primary Sjogren-associated ocular surface disease: results of the first-in-human study. Cornea. 2023;42(7):847-857. doi:10.1097/ICO.0000000000003091
26. Toyos M, Toyos R, Jodoin B, Bunch R. Results from a prospective, open-label, phase 4 pilot study of repository corticotropin injection for moderate and severe dry eye disease. Ophthalmol Ther. 2022;11(3):1231-1240. doi:10.1007/s40123-022-00501-2
27. Evans D, Kenyon K, Ousler G, et al. Efficacy and safety of the melanocortin pan-agonist PL9643 in a phase 2 study of patients with dry eye disease. J Ocul Pharmacol Ther. 2023;39(9):600-610. doi:10.1089/jop.2023.0056
28. Shettle L, McLaurin E, Martel J, Seaman JW 3rd, Weissgerber G. Topical anti-TNFα agent licaminlimab (OCS-02) relieves persistent ocular discomfort in severe dry eye disease: a randomized phase II study. Clin Ophthalmol. 2022;16:2167-2177. doi:10.2147/OPTH.S366836
29. Kinoshita S, Awamura S, Oshiden K, Nakamichi N, Suzuki H, Yokoi N; Rebamipide Ophthalmic Suspension Phase II Study Group. Rebamipide (OPC-12759) in the treatment of dry eye: a randomized, double-masked, multicenter, placebo-controlled phase II study. Ophthalmology. 2012;119(12):2471-2478. doi:10.1016/j.ophtha.2012.06.052
30. Yoo H, Yoon S, Jang IJ, et al. Safety, tolerability, and serum/tear pharmacokinetics of human recombinant epidermal growth factor eyedrops in healthy subjects. Pharmaceuticals (Basel). 2022;15(11):1312. doi:10.3390/ph15111312
31. Clark D, Sheppard J, Brady TC. A randomized double-masked phase 2a trial to evaluate activity and safety of topical ocular reproxalap, a novel RASP inhibitor, in dry eye disease. J Ocul Pharmacol Ther. 2021;37(4):193-199. doi:10.1089/jop.2020.0087
32. Wirta DL, Senchyna M, Lewis AE, et al. A randomized, vehicle-controlled, phase 2b study of two concentrations of the TRPM8 receptor agonist AR-15512 in the treatment of dry eye disease (COMET-1). Ocul Surf. 2022;26:166-173. doi:10.1016/j.jtos.2022.08.003
33. Dong Y, Wang S, Cong L, et al. TNF-α inhibitor tanfanercept (HBM9036) improves signs and symptoms of dry eye in a phase 2 trial in the controlled adverse environment in China. Int Ophthalmol. 2022;42(8):2459-2472. doi:10.1007/s10792-022-02245-1
34. Torkildsen GL, Pattar GR, Jerkins G, Striffler K, Nau J. Efficacy and safety of single-dose OC-02 (simpinicline solution) nasal spray on signs and symptoms of dry eye disease: the PEARL phase II randomized trial. Clin Ther. 2022;44(9):1178-1186. doi:10.1016/j.clinthera.2022.07.006
35. Hirabayashi KJ, Akpek EK, Ahmad S. Outcome measures to assess dry eye severity: a review. Ocul Immunol Inflamm. 2022;30(2):282-289. doi:10.1080/09273948.2022.2027461