The members of the Management and Therapy Subcommittee undertook an evidence-based review of current dry eye therapies and management options. Management options reviewed in detail included treatments for tear insufficiency and lid abnormalities, as well as anti-inflammatory medications, surgical approaches, dietary modifications, environmental considerations and complementary therapies. Following this extensive review it became clear that many of the treatments available for the management of dry eye disease lack the necessary Level 1 evidence to support their recommendation, often due to a lack of appropriate masking, randomization or controls and in some cases due to issues with selection bias or inadequate sample size. Reflecting on all available evidence, a staged management algorithm was derived that presents a step-wise approach to implementing the various management and therapeutic options according to disease severity. While this exercise indicated that differentiating between aqueous-deficient and evaporative dry eye disease was critical in selecting the most appropriate management strategy, it also highlighted challenges, based on the limited evidence currently available, in predicting relative benefits of specific management options, in managing the two dry eye disease subtypes. Further evidence is required to support the introduction, and continued use, of many of the treatment options currently available to manage dry eye disease, as well as to inform appropriate treatment starting points and understand treatment specificity in relation to dry eye disease subtype.

TFOS DEWS II Management and Therapy Report

Background
Over the counter (OTC) artificial tears historically have been the first line of treatment for dry eye syndrome and dry eye-related conditions like contact lens discomfort, yet currently we know little regarding the overall efficacy of individual, commercially available artificial tears. This review provides a much needed meta-analytical look at all randomized and quasi-randomized clinical trials that have analyzed head-to-head comparisons of OTC artificial tears.

Objectives
To evaluate the effectiveness and toxicity of OTC artificial tear applications in the treatment of dry eye syndrome compared with another class of OTC artificial tears, no treatment, or placebo.

Search methods
We searched CENTRAL (which contains the Cochrane Eyes and Vision Trials Register) (2015, Issue 12), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE (January 1946 to December 2015), EMBASE (January 1980 to December 2015), Latin American and Caribbean Health Sciences (LILACS) (January 1982 to December 2015), the ISRCTN registry (www.isrctn.com/editAdvancedSearch), ClinicalTrials.gov (www.clinicaltrials.gov), the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en) and the US Food and Drugs Administration (FDA) website (www.fda.gov). We did not use any date or language restrictions in the electronic searches for trials. We last searched the electronic databases on 4 December 2015. We searched reference lists of included trials for any additional trials not identified by the electronic searches.

Selection criteria
This review includes randomized controlled trials with adult participants who were diagnosed with dry eye, regardless of race and gender. We included trials in which the age of participants was not reported, and clinical trials comparing OTC artificial tears with another class of OTC artificial tears, placebo, or no treatment. This review did not consider head-to-head comparisons of artificial tears with another type of dry-eye therapy.

Data collection and analysis
We followed the standard methodological procedures expected by Cochrane. Two authors independently screened the search results, reviewed full-text copies for eligibility, examined risk of bias, and extracted data. We performed meta-analysis for trials that compared similar interventions and reported comparable outcomes with sufficient data. We summarized all other included trial results in the text.

Main results
We included 43 randomized controlled trials (3497 participants with dry eye). Due to the heterogeneity of study characteristics among the included trials with respect to types of diagnostic criteria, interventions, comparisons, and measurements taken, our ability to perform meta-analyses was limited. The review found that, in general, there was uncertainty whether different OTC artificial tears provide similar relief of signs and symptoms when compared with each other or placebo. Nevertheless, we found that 0.2% polyacrylic acid-based artificial tears were consistently more effective at treating dry eye symptoms than 1.4% polyvinyl alcohol-based artificial tears in two trials assessing this comparison (175 participants). All other included artificial tears produced contradictory between-group results or found no between-group differences. Our review also found that OTC artificial tears may be generally safe, but not without adverse events. Overall, we assessed the quality of evidence as low due to high risks of bias among included trials and poor reporting of outcome measures which were insufficient for quantitative analysis. Furthermore, we identified an additional 18 potentially eligible trials that were reported only in clinical trial registers with no associated results or publications. These trials reportedly enrolled 2079 total participants for whom no data are available. Such lack of reporting of trial results represents a high risk of publication bias.

Authors' conclusions
OTC artificial tears may be safe and effective means for treating dry eye syndrome; the literature indicates that the majority of OTC artificial tears may have similar efficacies. This conclusion could be greatly skewed by the inconsistencies in study designs and inconsistencies in reporting trial results. Additional research is therefore needed before we can draw robust conclusions about the effectiveness of individual OTC artificial tear formulations.

/pdf/over-the-counter-otc-artificial-tear-drops-for-dry-eye-48paxdm3x5.pdf

Over the counter (OTC) artificial tear drops for dry eye syndrome

Biomarkers provide a powerful and dynamic approach to improve our understanding of the mechanisms underlying ocular diseases with applications in diagnosis, disease modulation or for predicting and monitoring of clinical response to treatment. Defined as measurable indicator of normal or pathological processes, biomarker evaluation has been used extensively in drug development within clinical settings to better comprehend effectiveness of treatment in ocular diseases. Biomarkers in the eye have the advantage of access to multiple ocular matrices via minimally invasive methods. Repeat sampling for biomarker assessment has enabled reproducible objective measures of disease process or biological responses to a drug treatment. This review describes the usage of biomarkers with respect to four commonly sampled ocular matrices in clinic: tears, conjunctiva, aqueous humor and vitreous. Issues that affect the evaluation of biomarkers are discussed along with opportunities to leverage biomarkers such that ultimately, they can be used for customized targeted therapy.

/pdf/review-of-biomarkers-in-ocular-matrices-challenges-and-3j0be5w4fa.pdf

Review of Biomarkers in Ocular Matrices: Challenges and Opportunities.

Components of the ocular surface synergistically contribute to maintaining and protecting a smooth refractive layer to facilitate the optimal transmission of light At the air–water interface, the tear film lipid layer (TFLL), a mixture of lipids and proteins, plays a key role in tear surface tension and is important for the physiological hydration of the ocular surface and for ocular homeostasis Alterations in tear fluid rheology, differences in lipid composition, or downregulation of specific tear proteins are found in most types of ocular surface disease, including dry eye disease (DED) Artificial tears have long been a first line of treatment in DED and aim to replace or supplement tears More recently, lipid-containing eye drops have been developed to more closely mimic the combination of aqueous and lipid layers of the TFLL Over the last 2 decades, our understanding of the nature and importance of lipids in the tear film in health and disease has increased substantially The aim of this 

Relevance of Lipid-Based Products in the Management of Dry Eye Disease.

Dry eye disease (DED) is the most common ocular surface disease, characterized by insufficient production and/or instability of the tear film. Tear substitutes are usually the first line of treatment for patients with DED. Despite the large variety of tear substitutes available on the market, few studies have been performed to compare their performance. There is a need to better understand the specific mechanical and pharmacological roles of each ingredient composing the different formulations. In this review, we describe the main categories of ingredients composing tear substitutes (e.g., viscosity-enhancing agents, electrolytes, osmo-protectants, antioxidants, lipids, surfactants and preservatives) as well as their effects on the ocular surface, and we provide insight into how certain components of tear substitutes may promote corneal wound healing, and/or counteract inflammation. Based on these considerations, we propose an approach to select the most appropriate tear substitute formulations according to the predominant etiological causes of DED.

/pdf/artificial-tears-biological-role-of-their-ingredients-in-the-3voqk0iz.pdf

Artificial Tears: Biological Role of Their Ingredients in the Management of Dry Eye Disease

PURPOSE To evaluate the ability of Systane(®) Balance (SYSB) administered four times per day for 4 weeks to increase noninvasive tear film break-up time (NITFBUT) over baseline compared with a saline (SAL) control in patients with lipid-deficient dry eye (DE). PATIENTS AND METHODS Patients aged ≥18 years with DE and evidence of meibomian gland dysfunction (ie, abnormal gland expression and missing meibomian glands) were included in this randomized, parallel-group, controlled, investigator-masked comparison study. Patients were randomized to SYSB or SAL four times daily for 4 weeks. The primary efficacy variable was mean change in NITFBUT from baseline at week 4. Ocular surface staining, goblet cell density, and meibomian gland expression were also assessed. Safety assessments included adverse events (AEs), best-corrected visual acuity, and ocular signs. RESULTS A total of 49 patients received study treatments (SYSB, n=25; SAL, n=24). Most patients were women (67.4%) and Caucasian (63.3%); mean ± standard deviation (SD) age was 44±19 years. DE characteristics at baseline were similar between groups. After 4 weeks of treatment, the mean ± SD NITFBUT increase from baseline was significantly greater with SYSB (2.83±0.74 seconds) compared with SAL (0.66±0.55 seconds; P<0.001, t-test). Improvements in conjunctival and corneal staining, percentage of patients with increased goblet cell density, and meibomian gland expression were also observed with 4 weeks of SYSB over SAL. No AEs were reported for either treatment group; best-corrected visual acuity and ocular signs remained stable or improved compared with baseline. CONCLUSION SYSB restored tear film stability, improved ocular surface healing, and improved meibomian gland functionality after 4 weeks of use in patients with lipid-deficient DE. No AEs were reported with either SYSB or SAL.

https://www.dovepress.com/getfile.php?fileID=22551

Effects of Systane(®) Balance on noninvasive tear film break-up time in patients with lipid-deficient dry eye.

Purpose Squamous metaplasia in dry eye disease (DED) manifesting as the loss of conjunctival goblet cells results in reduced mucin secretion and tear film instability. The objective of this study was to evaluate the efficacy of a polyethylene glycol-propylene glycol/hydroxypropyl-guar (PEG-PG/HP-guar) artificial tear formulation in reducing the squamous metaplasia in patients with DED using conjunctival impression cytology (CIC). Methods In this Phase IV, single-arm, open-label study, DED patients (aged ≥18 years) with a corneal staining sum score ≥3 and tear film break-up time (TFBUT) <7 s self-administered the PEG-PG/HP-guar artificial tears, 3 times a day for a period of 90 days. The primary end point was the change from baseline in goblet cell density (Nelson's CIC grading score) over the treatment period. Other end points were change in the corneal and conjunctival staining scores, and TFBUT. Statistical evaluation was performed using a paired t-test. Results In total, 49 patients (n=98 eyes) completed the study. Compared with baseline, there was a significant reduction in the mean CIC scores (ie, improvement in goblet cell density) at Days 30, 60, and 90 (1.6±0.5 vs 1.2±0.5, 0.9±0.5, and 0.8±0.5; P<0.0001). At Day 90, 22% of eyes demonstrated squamous metaplasia Grade 0 (ie, normal epithelium). Similar improvements were observed in the corneal staining scores (5.7 vs 3.1, 1.1, and 0.5; P<0.0001), conjunctival staining scores (5.5 vs 3.6, 1.6, and 0.9; P<0.0001), and TFBUT (4.8 vs 5.8, 6.3, and 6.8 s; P<0.0001) at Days 30, 60, and 90, respectively. Conclusion In this study, treatment with PEG-PG/HP-guar artificial tears for 90 days decreased CIC score, reduced corneal and conjunctival staining, and increased TFBUT in patients with DED. These results suggest that PEG-PG/HP-guar artificial tears can improve the ocular surface health and reverse the changes induced by squamous metaplasia in DED.

/pdf/efficacy-of-polyethylene-glycol-propylene-glycol-based-43kegdh5mj.pdf

Efficacy of polyethylene glycol–propylene glycol-based lubricant eye drops in reducing squamous metaplasia in patients with dry eye disease

A novel ophthalmic latanoprost 0.005% nanoemulsion: a cytotoxicity study

The dry eye is a complex multifactor illness of the tear film and of the ocular surface characterized by symptoms of discomfort, vision alterations, and instability of the pre-corneal tear film which may bring about potential damage on the ocular surface. Instability of the film will produce increasing osmolarity of the tear film which will trigger epithelium osmotic lesions and inflammation. As these changes take place on the ocular surface, neurophysiologic mechanisms of homeostasis will be altered which will complicate the process even further with the cropping of vicious physiopathologic circuits.

/pdf/hyperosmolarity-of-the-tear-film-in-the-dry-eye-3d498lrd2o.pdf

Hyperosmolarity of the Tear Film in the Dry Eye

Purpose To evaluate the cytotoxicity of a new Latanoprost Benzalkonium chloride (BAK)-free nanoemulsion and to compare it with a Latanoprost solution containing BAK. Methods Normal Human Conjunctival epithelial cells (IOBA-NHC) were incubated for 15, 30, and 60 minutes with 1:6 dilutions of either latanoprost solution containing BAK (LSc), (latanoprost 0.005%, BAK 0.02%, Xalatan, Pfizer) or latanoprost nanoemulsion (LNe), (latanoprost 0.005%, potassium sorbate 0.18%; Louten Emulsion, POEN). Cytotoxicity was determined by MTT assay. Cell death was measured by flow cytometry using annexin V-FITC and propidium iodide. Results Cytotoxicity evaluation: the values of cell viability and proliferation obtained from cells exposed to LNe were between 80 and 90% relative to control group, whereas values obtained from cells exposed to LSc were around 30% relative to control group at all study times (p < 0.05 at 15 and 30 minutes; p < 0.01 at 60 minutes). Cell death evaluation: the percentage of viability was significantly lower in cells exposed to LSc compared with those incubated with LNe at all study times (p < 0.05 at 15 and 30 minutes; p < 0.01 at 60 minutes). Viability of cells exposed to LNe was higher than 90% at all study times, whereas there was a time-dependent decrease in cells exposed to Lsc. The percentage of viable cells in the LNe group was comparable to the viability of control group (93.1%) at all study times. No statistical differences between groups reached in early apoptotic cells. A significant increase of late apoptosis and necrosis cells were observed at all study times for those incubated with Lsc (p < 0.05; p < 0.01 at 30 and 60 minutes). Conclusions The new latanoprost nanoemulsion is significantly less cytotoxic on human conjunctival cells than LSc. It suggests that the new formulation could be gentler on the eye surface than currently available BAK preserved latanoprost solutions, with levels of cytotoxicity equivalent to control. 

Cytotoxicity evaluation of a novel latanoporst 0.005% nanoemulsion

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