In 2017, the Tear Film and Ocular Surface Society (TFOS) published the TFOS Dry Eye Workshop II (DEWS II) in The Ocular Surface.1-9 The objectives were to update the definition of dry eye disease (DED) established in DEWS I and critically review and integrate the substantial volume of literature on various aspects of DED, including risk factors, pathophysiology, management, and future therapies. Since the publication of DEWS II, the field of DED has grown considerably, with more than 8,000 studies added to the literature. This article highlights some of the significant advances since the publication of DEWS II and seeks to increase awareness of future interventions in DED treatment.<
Tear Film Homeostasis
At the core of the DEWS II definition of DED is the disruption of tear film homeostasis.1 Since 2017, clinicians’ awareness and understanding of the crucial role and visual impact of the tear film and ocular surface on postoperative outcomes have grown. In 2019, the ASCRS Cornea Clinical Committee published its now widely adopted novel preoperative ocular surface disease (OSD) diagnostic and treatment algorithm. This tool can help busy cataract and refractive surgeons with diagnosing and managing perioperative OSD.10
The factors contributing to tear film disruption are extensive; they encompass individual characteristics, the physical environment, and daily lifestyle decisions. A significant lifestyle factor highlighted in DEWS II, one that is increasingly prevalent in daily life, is the digital environment. The TFOS lifestyle report on the impact of the digital environment on the ocular surface explores how technology affects DED and digital eye strain.11 The digital environment is a crucial risk factor for DED. Studies have found that 78% to 97% of computer users experience poor tear film stability, leading to symptoms of DED.12,13 Research has also indicated that the increased use of digital devices correlates with lower scores on the Schirmer test. Talens-Estarelles et al demonstrated that, the greater the number of years an individual has used a computer and the longer the duration of use is, the more likely they are to have lower Schirmer test scores.14 This increased dryness is thought to result from a reduced blink rate and incomplete blinking, which increase the tear film’s susceptibility to evaporative and aqueous deficiency disruptions.15
Lifestyle and Environmental Factors
The COVID-19 pandemic significantly altered people’s lifestyles and introduced novel risk factors for DED, notably the use of face masks.16 Mask-associated DED had been identified before the pandemic and is believed to be caused when an improperly fitted mask directs airflow around the eyes.17 The widespread recommendation for mask usage during the pandemic led to an increase in the number of people presenting with first-time dry eye symptoms. A survey of 3,605 patients found that 18.3% experienced worsened dry eye symptoms while wearing masks.18 A prospective cohort study of 203 participants assessed dry eye symptoms in groups categorized by mask-wearing duration. It found that those wearing masks for less than 3 hours per day had significantly fewer dry eye symptoms than those wearing masks for 3 to 6 hours daily (P = .01).19
DEWS II recommended a stepwise approach to DED management, starting with patient education, dietary modifications, and lubricating eye drops and advancing to prescription medications, punctal plugs, and more sophisticated forms of treatment.9 Significant progress has been made in treatment methodologies since then.
Nutritional Interventions and Gut Microbiome
The evidence on omega-3 fatty acid supplementation has been mixed.20 Shortly after DEWS II was published, the Dry Eye Assessment and Management (DREAM) study found that omega-3 supplementation did not yield better outcomes compared to controls.21 Later, Downie et al conducted a Cochrane review of 34 studies involving 4,314 participants and concluded that there was low-certainty evidence that omega-3 supplements reduced dry eye symptoms compared to placebo but moderate-certainty evidence suggesting improvements in Schirmer scores and tear film breakup time.22 These findings indicate that omega-3 fatty acids might improve the physical indicators of dry eye rather than the symptoms.
In contrast, another meta-analysis including 17 trials with 3,363 patients reported improvements in both the symptoms and signs of DED with omega-3 supplementation.23 Moreover, the TFOS report on the digital environment and ocular surface identified oral omega-3 supplementation as a likely effective treatment for digital eye strain.11 Although further research into omega-3 fatty acids for DED is needed, other supplements such as turmeric and vitamin D3 have shown benefits for these patients.24
Emerging FDA-Approved Treatments in DED Management
Lacrifill (cross-linked hyaluronic acid derivative; Nordic Pharma).
- Type: Temporary ocular canalicular occlusion device
- Purpose: Enhances tear film stability and provides relief for dry eye disease (DED) symptoms by temporarily occluding the canalicular system
- FDA status: Approved in 2024
Cyclosporine ophthalmic solution 0.1% (Vevye, Harrow)
- Type: Prescription medication
- Purpose: Increases tear production with less irritation owing to a water-free, preservative-free formulation
- FDA status: Approved in May 2023
- Notable finding: In phase 3 trials, 71.6% of participants experienced clinically meaningful benefits.1-3
Perfluorohexyloctane ophthalmic solution (Miebo, Bausch + Lomb)
- Type: First prescription eye drop for evaporative DED
- Purpose: Forms a protective layer to reduce tear evaporation
- FDA status: Approved in May 2023
- Notable finding: Clinical improvement in dry eye symptoms at 4 weeks, with significant improvement at 2 and 8 weeks.4-6
Lotilaner ophthalmic solution 0.25% (Xdemvy, Tarsus Pharmaceuticals)
- Type: Treatment for anterior blepharitis due to Demodex infestation
- Purpose: Targets mites residing in the meibomian glands and lash follicles
- FDA status: Approved in July 2023
- Notable finding: Significant mite eradication and symptom improvement in the Saturn-1 trial7-10
Loteprednol etabonate ophthalmic suspension 0.25% (Eysuvis, Alcon)
- Type: First eye drop indicated for the short-term treatment of DED flares
- Purpose: Addresses sudden exacerbations in previously stable DED patients
- FDA status: Approved in October 2020
- Notable finding: Provided rapid relief from DED flare symptoms11
1. Agarwal P, Scherer D, Günther B, Rupenthal ID. Semifluorinated alkane-based systems for enhanced corneal penetration of poorly soluble drugs. Int J Pharm. 2018;538(1-2):119-129.
2. Sheppard JD, Wirta DL, McLaurin E, et al. A water-free 0.1% cyclosporine A solution for treatment of dry eye disease: results of the randomized phase 2B/3 ESSENCE Study. Cornea. 2021;40(10):1290-1297.
3. Akpek EK, Wirta DL, Downing JE, et al. Efficacy and safety of a water-free topical cyclosporine, 0.1%, solution for the treatment of moderate to severe dry eye disease: the ESSENCE-2 randomized clinical trial. JAMA Ophthalmol. 2023;141(5):459-466.
4. Sheppard JD, Evans DG, Protzko EE. A review of the first anti-evaporative prescription treatment for dry eye disease: perfluorohexyloctane ophthalmic solution. Am J Manag Care. 2023;29(14 suppl):S251-S259.
5. Vittitow J, Kissing R, DeCory H, Borchman D. In vitro inhibition of evaporation with perfluorohexyloctane, an eye drop for dry eye disease. Curr Ther Res Clin Exp. 2023;98:100704.
6. Sheppard JD, Kurata F, Epitropoulos AT, Krösser S, Vittitow JL; MOJAVE Study Group. NOV03 for signs and symptoms of dry eye disease associated with meibomian gland dysfunction: the randomized phase 3 MOJAVE study. Am J Ophthalmol. 2023;252:265-274.
7. Rhee MK, Yeu E, Barnett M, et al. Demodex blepharitis: a comprehensive review of the disease, current management, and emerging therapies. Eye Contact Lens. 2023;49(8):311-318.
8. Gonzalez-Salinas R, Karpecki P, Yeu E, et al. Safety and efficacy of lotilaner ophthalmic solution, 0.25% for the treatment of blepharitis due to Demodex infestation: a randomized, controlled, double-masked clinical trial. Cont Lens Anterior Eye. 2022;45(4):101492.
9. Yeu E, Wirta DL, Karpecki P, Baba SN, Holdbrook M; Saturn I Study Group. Lotilaner ophthalmic solution, 0.25%, for the treatment of Demodex blepharitis: results of a prospective, randomized, vehicle-controlled, double-masked, pivotal trial (Saturn-1). Cornea. 2023;42(4):435-443.
10. Gaddie IB, Donnenfeld ED, Karpecki P, et al. Lotilaner ophthalmic solution 0.25% for Demodex blepharitis: randomized, vehicle-controlled, multicenter, phase 3 trial (Saturn-2). Ophthalmology. 2023;130(10):1015-1023.
11. Starr CE, Dana R, Pflugfelder SC, et al. Dry eye disease flares: a rapid evidence assessment. Ocul Surf. 2021;22:51-59.
Research is exploring the impact of nutrition on inflammatory mediators—recognized contributors to DED—via modifications in the gut microbiome. Investigations have shown alterations in the gut microbiome in patients with DED and Sjögren syndrome.25 A noteworthy study found that patients with Sjögren syndrome who underwent fecal transplants, which significantly altered their microbiome, reported relief from dry eye symptoms at 3 months.26 These findings are encouraging, but questions remain about the specific microbiome properties most advantageous for patients with DED and how to develop a safe, effective method for modifying gut flora.
Prescription Medications
Significant advances have been made in the second level of treatment proposed by DEWS II—prescription medication. Antiinflammatory modulators such as cyclosporine A (CsA) 0.05% (Restasis, Allergan/AbbVie) were observed to be a widely used treatment for DED in DEWS II.9 Since then, a Cochrane review on the efficacy of CsA 0.05% for dry eye patients found the evidence to be inconclusive. Although treatment with CsA 0.05% led to an increase in the number of conjunctival mucosal cells, no improvements in mucus secretion or associated tear film parameters were found. The review also highlighted a potential increase in adverse events, particularly a burning sensation associated with the topical application of cyclosporine.27 The conclusion was that more long-term studies are required.
Some limitations associated with CsA (both 0.05% and 0.09% [Cequa, Sun Ophthalmics]) emulsion might be mitigated by a new water-free and preservative-free CsA formulation dissolved in a semifluorinated alkane (Vevye, Harrow), which was recently approved by the FDA. Vevye contains CsA at a 0.1% concentration.28 Due to its higher concentration and distinct vehicle, Vevye might offer increased bioavailability and cause less irritation to the ocular surface.28 In a phase 2 clinical trial, treated patients experienced improvements in corneal staining and a faster onset of symptom improvement compared to those who received the 0.05% emulsion.29 A subsequent phase 3 randomized clinical trial, ESSENCE-2, corroborated these results. ESSENCE-2 involved 834 participants, and 71.6% of those in the CsA group experienced clinically meaningful benefits from treatment.30 Although the initial data are promising, further long-term efficacy studies are necessary. (For detailed information on recent FDA-approved treatments in DED management, see the sidebar.)
Innovations Targeting Evaporative DED
Some strategies for managing DED focus on evaporative dry eye, caused primarily by meibomian gland dysfunction, which affects the tear film’s lipid layer. The FDA recently approved the first prescription drop aimed at evaporative DED, perfluorohexyloctane (PFHO) ophthalmic solution (Miebo, Bausch + Lomb), a water- and preservative-free alkane liquid. The product targets excessive evaporation by forming a monolayer at the tear film air-liquid interface.31 Preliminary studies suggest that PFHO can enhance the tear film’s lipid layer by coating the eye for up to 6 hours.32 Early clinical results support PFHO’s use. The phase 3 randomized controlled GOBI trial of 597 patients showed a clinical improvement in dry eye symptoms at 4 weeks and a significant improvement at 2 and 8 weeks.33 The MOJAVE trial, which included 620 patients, reported similar safety and efficacy outcomes.34
Emerging Treatments for Anterior Blepharitis and DED Flares
Anterior blepharitis, often triggered by Demodex infestation, can cause various symptoms. The FDA recently approved lotilaner ophthalmic solution 0.25% (Xdemvy, Tarsus Pharmaceuticals). Targeting Demodex blepharitis, the drug reaches the meibomian glands and lash follicles where mites reside.35,36 Its effectiveness was demonstrated in the Saturn-1 trial, a randomized controlled study of 421 patients that showed significant mite eradication, collarette improvement, and complete cure at 43 days.37 The Saturn-2 trial supported the drug’s safety and efficacy, with more than 90% of participants tolerating the treatment and showing significant clinical improvement.38
The concept of a DED flare—a sudden exacerbation in a previously stable patient—emerged after publication of the DEWS II report.39 The FDA approved the first eye drop for the short-term treatment of a DED flare, loteprednol etabonate ophthalmic suspension 0.25% (Eysuvis, Alcon), in 2020.
Looking Ahead to DEWS III
This article highlights just a few advances in DED research since the publication of TFOS DEWS II, including the subsequent TFOS OSD lifestyle report. The field is evolving rapidly. The TFOS DEWS III Workshop has begun, promising further insights in about 3 years.
1. Craig JP, Nichols KK, Akpek EK, et al. TFOS DEWS II definition and classification report. Ocul Surf. 2017;15(3):276-283.
2. Sullivan DA, Rocha EM, Aragona P, et al. TFOS DEWS II sex, gender, and hormones report. Ocul Surf. 2017;15(3):284-333.
3. Stapleton F, Alves M, Bunya VY, et al. TFOS DEWS II epidemiology report. Ocul Surf. 2017;15(3):334-365.
4. Willcox MD Argüeso P, Georgiev GA, et al. TFOS DEWS II tear film report. Ocul Surf. 2017;15(3):366-403.
5. Belmonte C, Nichols JJ, Cox SM, et al. TFOS DEWS II pain and sensation report. Ocul Surf. 2017;15(3):404-437.
6. Bron AJ, Paiva CS, Chauhan SK, et al. TFOS DEWS II pathophysiology report. Ocul Surf. 2017;15(3):438-510.
7. Gomes JAP, Azar DT, Baudouin C, et al. TFOS DEWS II iatrogenic report. Ocul Surf. 2017;15(3):511-538.
8. Wolffsohn JS, Arita R, Chalmers R, et al. TFOS DEWS II diagnostic methodology report. Ocul Surf. 2017;15(3):539-574.
9. Jones L, Downie LE, Korb D, et al. TFOS DEWS II management and therapy report. Ocul Surf. 2017;15(3):575-628.
10. Starr CE, Gupta PK, Farid M, et al. An algorithm for the preoperative diagnosis and treatment of ocular surface disorders: a report by the ASCRS Cornea Clinical Committee. J Cataract Refract Surg. 2019;45(5):669-684.
11. Wolffsohn JS, Lingham G, Downie LE, et al. TFOS lifestyle: impact of the digital environment on the ocular surface. Ocul Surf. 2023;28:213-252.
12. Sánchez-Valerio MDR, Mohamed-Noriega K, Zamora-Ginez I, Baez Duarte BG, Vallejo-Ruiz V. Dry eye disease association with computer exposure time among subjects with computer vision syndrome. Clin Ophthalmol. 2020;14:4311-4317.
13. Uchino M, Yokoi N, Uchino Y, et al. Prevalence of dry eye disease and its risk factors in visual display terminal users: the Osaka study. Am J Ophthalmol. 2013;156(4):759-766.
14. Talens-Estarelles C, Sanchis-Jurado V, Esteve-Taboada JJ, Pons ÁM, García-Lázaro S. How do different digital displays affect the ocular surface? Optom Vis Sci. 2020;97(12):1070-1079.
15. Blehm C, Vishnu S, Khattak A, Mitra S, Yee RW. Computer vision syndrome: a review. Surv Ophthalmol. 2005;50(3):253-262.
16. Jones L, Efron N, Bandamwar K, et al. TFOS lifestyle: impact of contact lenses on the ocular surface. Ocul Surf. 2023;29:175-219.
17. Giannaccare G, Vaccaro S, Mancini A, Scorcia V. Dry eye in the COVID-19 era: how the measures for controlling pandemic might harm ocular surface. Graefes Arch Clin Exp Ophthalmol. 2020;258(11):2567-2568.
18. Boccardo L. Self-reported symptoms of mask-associated dry eye: a survey study of 3,605 people. Cont Lens Anterior Eye. 2022;45(2):101408.
19. Krolo I, Blazeka M, Merdzo I, Vrtar I, Sabol I, Petric-Vickovic I. Mask-associated dry eye during COVID-19 pandemic-how face masks contribute to dry eye disease symptoms. Med Arch. 2021;75(2):144-148.
20. Markoulli M, Ahmad S, Arcot J, et al. TFOS lifestyle: impact of nutrition on the ocular surface. Ocul Surf. 2023;29:226-271.
21. Dry Eye Assessment and Management Study Research Group; Asbell PA, Maguire MG, Pistilli M, et al. n-3 fatty acid supplementation for the treatment of dry eye disease. N Engl J Med. 2018;378(18):1681-1690.
22. Downie LE, Ng SM, Lindsley KB, Akpek EK. Omega-3 and omega-6 polyunsaturated fatty acids for dry eye disease. Cochrane Database Syst Rev. 2019;12(12):CD011016.
23. Giannaccare G, Pellegrini M, Sebastiani S, et al. Efficacy of omega-3 fatty acid supplementation for treatment of dry eye disease: a meta-analysis of randomized clinical trials. Cornea. 2019;38(5):565-573.
24. Radkar P, Lakshmanan PS, Mary JJ, Chaudhary S, Durairaj SK. A novel multi-ingredient supplement reduces inflammation of the eye and improves production and quality of tears in humans. Ophthalmol Ther. 2021;10(3):581-599.
25. Moon J, Choi SH, Yoon CH, Kim MK. Gut dysbiosis is prevailing in Sjögren’s syndrome and is related to dry eye severity. PLoS One. 2020;15(2):e0229029.
26. Watane A, Cavuoto KM, Rojas M, et al. Fecal microbial transplant in individuals with immune-mediated dry eye. Am J Ophthalmol. 2022;233:90-100.
27. Topical cyclosporine A therapy for dry eye syndrome. Cochrane Database Syst Rev. 2019;9(9):CD010051.
28. Agarwal P, Scherer D, Günther B, Rupenthal ID. Semifluorinated alkane-based systems for enhanced corneal penetration of poorly soluble drugs. Int J Pharm. 2018;538(1-2):119-129.
29. Sheppard JD, Wirta DL, McLaurin E, et al. A water-free 0.1% cyclosporine A solution for treatment of dry eye disease: results of the randomized phase 2B/3 ESSENCE Study. Cornea. 2021;40(10):1290-1297.
30. Akpek EK, Wirta DL, Downing JE, et al. Efficacy and safety of a water-free topical cyclosporine, 0.1%, solution for the treatment of moderate to severe dry eye disease: the ESSENCE-2 randomized clinical trial. JAMA Ophthalmol. 2023;141(5):459-466.
31. Sheppard JD, Evans DG, Protzko EE. A review of the first anti-evaporative prescription treatment for dry eye disease: perfluorohexyloctane ophthalmic solution. Am J Manag Care. 2023;29(14 suppl):S251-S259.
32. Vittitow J, Kissing R, DeCory H, Borchman D. In vitro inhibition of evaporation with perfluorohexyloctane, an eye drop for dry eye disease. Curr Ther Res Clin Exp. 2023;98:100704.
33. Tauber J, Berdy GJ, Wirta DL, Krösser S, Vittitow JL; GOBI Study Group. NOV03 for dry eye disease associated with meibomian gland dysfunction: results of the randomized phase 3 GOBI study. Ophthalmology. 2023;130(5):516-524.
34. Sheppard JD, Kurata F, Epitropoulos AT, Krösser S, Vittitow JL; MOJAVE Study Group. NOV03 for signs and symptoms of dry eye disease associated with meibomian gland dysfunction: the randomized phase 3 MOJAVE study. Am J Ophthalmol. 2023;252:265-274.
35. Rhee MK, Yeu E, Barnett M, et al. Demodex blepharitis: a comprehensive review of the disease, current management, and emerging therapies. Eye Contact Lens. 2023;49(8):311-318.
36. Gonzalez-Salinas R, Karpecki P, Yeu E, et al. Safety and efficacy of lotilaner ophthalmic solution, 0.25% for the treatment of blepharitis due to Demodex infestation: a randomized, controlled, double-masked clinical trial. Cont Lens Anterior Eye. 2022;45(4):101492.
37. Yeu E, Wirta DL, Karpecki P, Baba SN, Holdbrook M; Saturn I Study Group. Lotilaner ophthalmic solution, 0.25%, for the treatment of Demodex blepharitis: results of a prospective, randomized, vehicle-controlled, double-masked, pivotal trial (Saturn-1). Cornea. 2023;42(4):435-443.
38. Gaddie IB, Donnenfeld ED, Karpecki P, et al. Lotilaner ophthalmic solution 0.25% for Demodex blepharitis: randomized, vehicle-controlled, multicenter, phase 3 trial (Saturn-2). Ophthalmology. 2023;130(10):1015-1023.
39. Starr CE, Dana R, Pflugfelder SC, et al. Dry eye disease flares: a rapid evidence assessment. Ocul Surf. 2021;22:51-59.