Summary
Dry eye disease is a condition with a global prevalence of  approximately 10%, characterized by visual disturbances and ocular discomfort which negatively impact quality of life. Current treatment options include administration of topical eye droplets. Recent studies have shown that the addition of omega-3 fatty acids to these eye droplets improves certain features of their effects.
 
Introduction
Dry eye disease (DED) is an umbrella term for inflammation at the ocular (eye) surface that causes visual disturbances and ocular discomfort. Two main presentations of DED exist, dry eyes as a result of reduced tear production and dry eyes as a result of increased evaporation of the tear film, also referred to as tear film break-up time. Tear film covers the ocular surface to keep the eyes hydrated and protect them against infection. To counter evaporation of this protective tear film, meibomian glands produce a lipid component called meibum, which reduces tear film evaporation. Typical clinical signs of DED are dysfunction of meibomian glands and a short tear film break-up time. A commonly used clinical classification of DED is the ocular surface disease index, that scales the severity of DED based on patient-reported symptoms. Though DED often occurs in idiopathic (without clear cause) form, wearing contact lenses is a common DED cause (also referred to as contact lens discomfort DED). Interestingly, a large study with 32470 women reported that the dietary intake of omega-3 fatty acids reduced the risk of developing DED in women aged 45 and older (Miljanović et al. 2005). This sparked interest in possible therapeutic effects of omega-3 fatty acids in reduction of DED symptoms. Yet, as discussed in the ‘Background’ section, DED clinical trials with omega-3 supplementation aimed to reduce DED symptom burden unexpectedly failed to deliver conclusive results. However, recent studies using a topical omega-3 delivery method have offered promising results, as described in the section ‘Research findings’.
 
Background
A number of clinical trials investigating the effects of oral omega-3 fatty acid supplementation in DED have been carried out, some of which reported opposing outcomes. These conflicting results are likely influenced by a small number of clinical trial participants, differences in supplement composition, differences in dietary habits and differences in exclusion criteria (such as DED severity). In order to resolve this, the Dry Eye Assessment and Management (DREAM) research group was formed, which set up a large clinical trial with 349 DED patients (‘N−3 Fatty Acid Supplementation for the Treatment of Dry Eye Disease’ 2018). DED patients of all subtypes received a daily supplementation containing either 3000mg omega-3 fatty acids or a placebo (olive oil) for one year, during which they continued to receive their current DED treatment. Surprisingly, no significant differences were found between groups, though both groups showed an improvement in DED signs and symptoms (likely as a result of their continued current treatment). Additionally, no treatment differences were found between DED subgroups, categorized based on severity of symptoms, EPA and DHA levels in red cells and ocular inflammation. These results were somewhat unexpected, as the dose of the omega-3 fatty acid supplementation that was given is the highest that is used in clinical trials. On this basis, the authors concluded that no case could be made for the inclusion of oral omega-3 supplementation in DED treatment.

Crucially, other omega-3 fatty acid delivery methods such as topical administration of (non-aqueous) eye drops are available, which might be more suitable in the context of DED. Non-aqueous eyedrops have a longer residual time on the ocular surface than aqueous eye drops. Therefore, omega-3 containing water-free eye drops might offer a better delivery of omega-3 fatty acids to the ocular surface, compared to oral supplementation. Here they can contribute their anti-inflammatory effect, but might also serve to counter tear film break up time. As discussed below, recent studies researching the effects of topical omega-3 fatty acid administration in the context of DED shine a new light on the role of omega-3 fatty acids in DED treatment.
 
Research findings
As meibomian gland dysfunction is a clinical sign of DED,  Hampel and colleagues set out to test the effects of DHA and EPA supplementation on inflammation markers in a human meibomian gland epithelial cell culture (Hampel et al. 2015). As inflammation markers can be great indicators of dysfunction, a measured decrease in these markers can be interpreted as a functional improvement. The authors reported that supplementation of human meibomian gland epithelial cells with omega-3 fatty acids DHA and EPA caused a decrease in inflammatory markers such as cytokines. Moreover, an increase of anti-inflammatory DHA metabolite RvD1 was found in these cells after supplementation. Therefore, it was concluded that DHA and EPA induce an anti-inflammatory effect in human meibomian gland epithelial cells, which may be beneficial in DED.

Investigating the suspected beneficial role of omega-3 fatty acids in DED, Fogagnolo and colleagues designed a clinical study with DED patients undergoing cataract surgery (Fogagnolo et al. 2020). Forty-five DED patients aged 66-82 undergoing cataract surgery were divided into two groups. For a period of 4 weeks, a group of 23 individuals self-administered eyedrops containing omega-3 fatty acids EPA and DHA) daily three times, the other group of 22 individuals did not administer any eye drops. At the 2 week point after the start of the study, all patients underwent cataract surgery, which often worsens DED symptoms DED severity and symptoms were assessed at the day of surgery, and 1 and 2 weeks after the surgery. It was found that compared to the control group, the patients in the omega-3 eyedrop group showed a an increased tear film breakup time at every DED assessment day. Moreover, the omega-3 group had a significantly better ocular surface disease index score than the control group at every time point. The authors concluded that the ocular surface of the omega-3 group was more protected and quickly restored from the cataract surgery.

A recent study by Jacobi and collaborators investigated the effects of eyedrops containing DHA derived from algae on DED symptoms in adults (Jacobi et al. 2022). During a period of 8 weeks, 33 DED patients aged >18 were treated with non-aqueous eye drops containing perfluorohexyloctane, a semifluorinated alkane, and 0.2% DHA for 4 times per day. DED symptom assessment using clinical tests and the ocular surface disease index were conducted at the start and end of the 8 week period. Comparing the baseline to endpoint measurements, the authors reported that both meibomian gland dysfunction and tear film break up time was improved. Furthermore, subjective symptoms reported by patients improved after the 8 week treatment period.

Collaborating with scientists that contributed to the 2022 publication of Jacobi et al., Kaercher and colleagues set up a similar study to investigate the role of omega-3 fatty acids in DED (Kaercher et al. 2022).  They set out to compare eyedrops containing omega-3 fatty acids DHA and EPA to povidone-containing eyedrops, an artificial tear drop. For a period of 12 weeks, DED patients aged 37-68 took either omega-3 containing eye drops (37 patients) or povidone-containing eyedrops (39 patients). At week 0, 4, and 12, the tear film break up time and the ocular surface disease index were used to assess improvements in DED burden. Both groups showed significant improvements compared to the start of the study. Though non-significant, most secondary efficacy endpoints such as patient-reported symptom intensity were subject to greater improvements in the omega-3 group compared to the povidone group. Furthermore, the povidone group showed a decrease in symptom improvement at 12 weeks, whereas the omega-3 group maintained a steady improvement of DED symptoms throughout the study. The authors concluded that the omega-3 containing eyedrops are safe for use in DED and help in reducing DED symptom burden.
 
Conclusion
Around two decades ago, a large study reported that dietary intake of omega-3 fatty acids EPA and DHA protected against risk of developing DED in women aged 45 and over. This sparked interest in therapeutic implementation of omega-3 fatty acids as a way to reduce DED or DED symptom burden. Yet, as discussed above, the benefits of omega-3 fatty acids in the treatment of dry eye disease seems to be dependent on their method of delivery. A large study conducted by the Dry Eye Assessment and Management research group did not find any beneficial effect of long term and high-dose omega-3 supplementation for reducing DED signs and symptoms. However, treatment of human meibomian gland epithelial cells with omega-3 fatty acids EPA and DHA caused a reduction in markers of inflammation. Correspondingly, studies investigating the topical administration of eye drops containing omega-3 fatty acids in DED patients have yielded positive results. Taken together, omega-3 fatty acids such as DHA may improve the efficacy of eye drops to counter meibomian gland dysfunction, increase tear production, and improve tear film break up time. Finally, though oral supplementation with omega-3 fatty acids is unlikely to aid in DED symptom reduction, sufficient dietary intake of omega-3 fatty acids may aid in reducing the risk of DED development.
 
References
Fogagnolo, Paolo, Eleonora Favuzza, Daniele Marchina, Michela Cennamo, Roberto Vignapiano, Chiara Quisisana, Luca Rossetti, and Rita Mencucci. 2020. ‘New Therapeutic Strategy and Innovative Lubricating Ophthalmic Solution in Minimizing Dry Eye Disease Associated with Cataract Surgery: A Randomized, Prospective Study’. Advances in Therapy 37 (4): 1664–74. https://doi.org/10.1007/s12325-020-01288-z.
 
Hampel, Ulrike, Magret Krüger, Carolina Kunnen, Fabian Garreis, Mark Willcox, and Friedrich Paulsen. 2015. ‘In Vitro Effects of Docosahexaenoic and Eicosapentaenoic Acid on Human Meibomian Gland Epithelial Cells’. Experimental Eye Research 140 (November): 139–48.  https://doi.org/10.1016/j.exer.2015.08.024.
 
Jacobi, Christina, Simone Angstmann-Mehr, Anja Lange, and Thomas Kaercher. 2022. ‘A Water-Free Omega-3 Fatty Acid Eye Drop Formulation for the Treatment of Evaporative Dry Eye Disease: A Prospective, Multicenter Noninterventional Study’. Journal of Ocular Pharmacology and Therapeutics 38 (5): 348–53. https://doi.org/10.1089/jop.2021.0102.
 
Kaercher, Thomas, Elisabeth M. Messmer, Thomas Berninger, Klaudia K. Huber-van der Velden, Raphaela Geiger, Pauline Cipriano-Bonvin, and Christina Jacobi. 2022. ‘Topical Omega-3 Polyunsaturated Fatty Acids for the Treatment of Dry Eye – Results from a Pilot Randomized Controlled Masked-Observer Study’. Clinical Ophthalmology 16 (December): 4021–31. https://doi.org/10.2147/OPTH.S388294.
 
Miljanović, Biljana, Komal A Trivedi, M Reza Dana, Jeffery P Gilbard, Julie E Buring, and Debra A Schaumberg. 2005. ‘Relation between Dietary N−3 and N−6 Fatty Acids and Clinically Diagnosed Dry Eye Syndrome in Women2’. The American Journal of Clinical Nutrition 82 (4): 887–93. https://doi.org/10.1093/ajcn/82.4.887.
 
‘N−3 Fatty Acid Supplementation for the Treatment of Dry Eye Disease’. 2018. New England Journal of Medicine 378 (18): 1681–90. https://doi.org/10.1056/NEJMoa1709691.