Patient-Reported Dry Eye Treatment and Burden of Care.

OBJECTIVES: Dry eye is a common condition that can decrease the quality of life. This survey-based study of persons with dry eye investigated self-reported treatments (initial, current), out-of-pocket expenses, time spent on self-management, sources of care, and sources of information about their condition. METHODS: Online dry eye newsletters and support groups were emailed a link to an electronic survey asking members to participate. Survey respondents were not required to answer every question. RESULTS: In total, 639 persons with self-reported dry eye responded (86% women, 14% men [n=623]; mean ± SD age, 55 ± 14 years [n=595]). Artificial tears were the most reported intervention (76% initially, 71% currently). The median (interquartile range) out-of-pocket treatment cost annually was $500 ($200-$1,320 [n=506]). In addition, 55% (n=544) estimated 5 to 20 min daily on self-management; 22% spent an hour or more. Ophthalmologists provided most dry eye care (67%, n=520). Only 48% (n=524) reported that their primary source of dry eye information came from their eye care clinician. CONCLUSIONS: Artificial tears are the primary treatment for dry eye. Ophthalmologists provide most dry eye care, but half of patients report that their eye care provider is not their primary source of information. Almost one fourth of patients spend an hour or more daily on treatments.

Efficacy and Safety of Artificial Tears Containing Lipidure and Hypromellose for the Treatment of Moderate Dry Eye Disease in Contact Lens Wearers.

Background and Objectives: Dry eye disease (DED) affects 5-50% of the global population and deeply influences everyday life activities. This study compared the efficacy, tolerability, and safety of novel Respilac artificial tears containing lipidure and hypromellose (HPMC) with the widely used Nextal artificial tears, which are also HPMC-based, for the treatment of moderate DED in contact lenses (CL) wearers. Materials and Methods: In a prospective, single-center, randomized investigation, 30 patients aged ≥18 years, diagnosed with moderate DED, and wearing CL were randomly assigned to the Respilac (n = 15) or Nextal group (n = 15). Patients self-administrated one drop of Respilac or Nextal in both eyes three times daily for 21 days. Changes in the endpoint (visual analogue scale (VAS) score for ocular tolerability, symptom assessment in dry eye (SANDE) score, non-invasive first break-up time (NIF-BUT) results, tear analysis value, meibography results, and CL tolerability results were assessed, comparing treatment groups and time-point evaluations. Adverse events (AEs) were also recorded and evaluated. Results: VAS scores decreased with time (p < 0.001) in both groups, showing no statistically significant difference among them (p = 0.13). Improvements were also detected from screening to end-of-treatment, which were indicated by the SANDE scores for severity and frequency (p < 0.001) and by tear analysis results (p < 0.001) with no observed difference between the Nextal and Respilac arms. NIF-BUT, meibography, and CL tolerability values were shown to be non-significantly affected by treatment and time. There were no AEs detected in this study cohort. Conclusions: Respilac was confirmed to be effective, safe, and well-tolerated. Lipidure-based ophthalmic solution was shown not to be inferior to the currently used Nextal, however, showing improvements in DED symptoms. Within the existing literature, our study is one of the first to report that MPC plus HPMC-containing eye drops are an effective option for the treatment of moderate dry eye disease and desiccation damage prevention in contact lens wearers.

Autologous Serum Eye Drops for Dry Eye: Systematic Review.

BACKGROUND: Dry eye is a common condition with serious implications worldwide. The unique composition of autologous serum (AS) eye drops has been hypothesized as a possible treatment. OBJECTIVES: This study aimed to review the effectiveness and safety of AS. DATA SOURCES: We searched five databases and three registries up to September 30, 2022. STUDY ELIGIBILITY: We included randomized controlled trials (RCTs) comparing AS with artificial tears, saline, or placebo for participants with dry eye. STUDY APPRAISAL AND SYNTHESIS METHODS: We adhered to Cochrane methods for study selection, data extraction, risk-of-bias assessment, and synthesis. We used the Grading of Recommendations Assessment, Development and Evaluation framework to evaluate the certainty of evidence. RESULTS: We included six RCTs with 116 participants. Four trials compared AS with artificial tears. We found low-certainty evidence that AS may improve symptoms (0- to 100-point pain scale) after 2 weeks of treatment compared with saline (mean difference, -12.00; 95% confidence interval, -20.16 to -3.84; 1 RCT, 20 participants). Ocular surface outcomes (corneal staining, conjunctival staining, tear breakup time, Schirmer test) were inconclusive. Two trials compared AS with saline. Very low-certainty evidence suggested that Rose Bengal staining (0- to 9-point scale) may be slightly improved after 4 weeks of treatment compared with saline (mean difference, -0.60; 95% confidence interval, -1.11 to -0.09; 35 eyes). None of the trials reported outcomes of corneal topography, conjunctival biopsy, quality of life, economic outcomes, or adverse events. LIMITATIONS: We were unable to use all data because of unclear reporting. CONCLUSIONS: The effectiveness of AS is uncertain based on current data. Symptoms improved slightly with AS compared with artificial tears for 2 weeks. Staining scores improved slightly with AS compared with saline, with no benefit identified for other measures. IMPLICATIONS OF KEY FINDINGS: High-quality, large trials enrolling diverse participants with varying severity are needed. A core outcome set would allow for evidence-based treatment decisions consistent with current knowledge and patient values.

Update on Dry Eye Disease Treatment: Evidence From Randomized Controlled Trials.

ABSTRACT: Although the ultimate goal of dry eye disease (DED) management is to restore the ocular surface and tear film homeostasis and address any accompanying symptoms, addressing this is not an easy task. Despite the wide range of current treatment modalities targeting multiple aspects of DED, the available DED management literature is quite heterogeneous, rendering evaluation or comparison of treatment outcomes hard or almost impossible. There is still a shortage of well-designed, large-scale, nonsponsored, randomized, controlled trials (RCTs) evaluating long-term safety and efficacy of many targeted therapies individually or used in combination, in the treatment of identified subgroups of patients with DED. This review focuses on the treatment modalities in DED management and aims to reveal the current evidence available as deduced from the outcomes of RCTs.

A Critical Appraisal of the Physicochemical Properties and Biological Effects of Artificial Tear Ingredients and Formulations.

Dry eye disease is among the most prevalent diseases affecting the ocular surface. Artificial tears remain the cornerstone therapy for its management. There are currently a wide variety of marketed artificial tears available to choose from. These artificial tears differ significantly in their composition and formulation. This article reviews the physicochemical and biological properties of artificial tear components and how these characteristics determine their use and efficacy in the management of dry eye. Furthermore, this article also discusses the various formulations of artificial tears such as macro and nanoemulsion and the type of preservatives present in them.

[Viral Conjunctivitis: Findings, Therapy, and Prophylaxis]. / Virale Bindehautentzündungen: Befunde, Therapie und Prophylaxe.

Viral conjunctivitis is one of the most common acute eye diseases. The fall and winter months are known to be the main season for viral infections which is also reflected in the ophthalmological outpatient clinics. Viral conjunctivitis is often accompanied by symptoms of the upper and lower respiratory tract, fever, chills, arthralgia or skin lesions. The spectrum of pathogens comprises DNA viruses such as Adeno-, Herpes simplex and Molluscum contagiosum as well as RNA viruses. Symptoms caused by pandemic pathogens such as SARS-CoV-2 and mpox viruses can also cause ocular manifestation. Viral conjunctivitis is often self-limiting leaving no residual symptoms, however an ophthalmologist should be consulted if there are inflammatory symptoms of the anterior eye accompanied by visual disturbance. It is particularly important to recognize the affection of corneal or even intraocular structures early to initiate an adequate and effective therapy. Affection of the cornea, vitreus or retina can result in temporary or permanent impairment of the field of vision and visual acuity. The diagnosis is usually made without further tests on the basis of the typical clinical presentation. Rapid tests or PCR diagnostics are also available for confirmation. In most patients the treatment is symptomatically with artificial tears and antibiotic eye drops in cases accompanied by secondary bacterial infections, not prophylactically. If the cornea or other ocular structures are affected by certain viruses, local as well as systemic virostatic therapy is initiated. The most important prophylactic measure is meticulous and consistent hygiene.

Efficacy and Safety of OC-01 (Varenicline Solution) Nasal Spray on Signs and Symptoms of Dry Eye Disease: The ONSET-2 Phase 3 Randomized Trial.

PURPOSE: To evaluate the efficacy and safety of OC-01 (varenicline solution) nasal spray for treatment of patients with dry eye disease. DESIGN: Randomized, multicenter, double-masked, vehicle-controlled, phase 3 study. PARTICIPANTS: Adults 22 years of age or older with a diagnosis of dry eye disease, artificial tear use, Ocular Surface Disease Index score of 23 or more, and Schirmer test score (STS) of 10 mm or less. Eligibility was not restricted by eye dryness score (EDS). METHODS: Patients (N = 758) were randomized in a 1:1:1 ratio to twice-daily treatment with 50-µl intranasal spray in each nostril of OC-01 0.03 mg (n = 260), OC-01 0.06 mg (n = 246), or vehicle (control; n = 252) for 4 weeks (ClinicalTrials.gov identifier, NCT04036292). MAIN OUTCOME MEASURES: The primary efficacy end point was the percentage of patients achieving a 10-mm improvement or more in STS at week 4. Secondary end points included change from baseline to week 4 in STS and EDS in a controlled adverse environment (CAE) chamber and in the clinic. Treatment-emergent adverse events (TEAEs) were assessed. RESULTS: A statistically significantly greater percentage of patients achieved the primary end point in both OC-01 treatment groups compared with the vehicle group (OC-01 0.03 mg, 47.3%; OC-01 0.06 mg, 49.2%; vehicle, 27.8%; P < 0.0001 for both doses). Change from baseline in STS at week 4 was statistically significantly greater for patients receiving OC-01 than vehicle (P < 0.0001 for both doses). Eye dryness score assessed at week 4 improved with OC-01 treatment compared with vehicle, although the difference was not significant for EDS measured in the CAE chamber and showed (nominal) significance in the clinic. Overall, 86.5% of patients (654/756) reported at least 1 TEAE during the treatment period; most were mild, nonocular (sneezing, cough, throat irritation, and instillation site irritation) and were reported by fewer patients in the vehicle group than in the OC-01 treatment groups (OC-01 0.03 mg, 97.3%; OC-01 0.06 mg, 99.2%; vehicle, 57%). CONCLUSIONS: OC-01 nasal spray was well tolerated and showed a clinically meaningful effect on signs and symptoms of dry eye disease.

Topical pharmacologic interventions versus placebo for epidemic keratoconjunctivitis.

BACKGROUND: Viruses cause about 80% of all cases of acute conjunctivitis. Human adenoviruses are believed to account for 65% to 90% of cases of viral conjunctivitis, or 20% to 75% of all causes of infectious keratoconjunctivitis worldwide. Epidemic keratoconjunctivitis (EKC) is a highly contagious subset of adenoviral conjunctivitis that has been associated with large outbreaks at military installations and at medical facilities. It is accompanied by severe conjunctival inflammation, watery discharge, and light sensitivity, and can lead to chronic complications such as corneal and conjunctival scarring with discomfort and poor quality of vision. Due to a lack of consensus on the efficacy of any pharmacotherapy to alter the clinical course of EKC, no standard of care exists, therefore many clinicians offer only supportive care. OBJECTIVES: To assess the efficacy and safety of topical pharmacological therapies versus placebo, an active control, or no treatment for adults with EKC. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL, which contains the Cochrane Eyes and Vision Trials Register; 2021, Issue 4); Ovid MEDLINE; Ovid Embase; Latin American and Caribbean Health Sciences database (LILACS); ClinicalTrials.gov; and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP), with no restrictions on language or year of publication. The date of the last search was 27 April 2021. SELECTION CRITERIA: We included randomized controlled trials in which antiseptic agents, virustatic agents, or topical immune-modulating therapy was compared with placebo, an active control, or no treatment. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methodology. MAIN RESULTS: We identified 10 studies conducted in Asia, Europe, the Middle East, and North Africa with a total of 892 participants who were treated for 7 days to 6 months and followed for 7 days up to 1.5 years. Study characteristics and risk of bias In most studies participants were predominantly men (range: 44% to 90%), with an age range from 9 to 82 years. Three studies reported information on trial registration, but we found no published study protocol. The majority of trials had small sample sizes, ranging from 18 to 90 participants enrolled per study; the only exception was a trial that enrolled 350 participants. We judged most studies to be at high or unclear risk of bias across risk of bias domains. Findings We included 10 studies of 892 EKC participants and estimated combined intervention effects in analyses stratified by steroid-containing control treatment or artificial tears. Six trials contributed to the comparisons of topical interventions (povidone-iodine [PVP-I], trifluridine, ganciclovir, dexamethasone plus neomycin) with artificial tears (or saline). Very low certainty evidence from two trials comparing trifluridine or ganciclovir with artificial tears showed inconsistent effects on shortening the mean duration of cardinal symptoms or signs of EKC. Low certainty evidence based on two studies (409 participants) indicated that participants treated with PVP-I alone more often experienced resolution of symptoms (risk ratio (RR) 1.15, 95% confidence interval (CI) 1.07 to 1.24) and signs (RR 3.19, 95% CI 2.29 to 4.45) during the first week of treatment compared with those treated with artificial tears. Very low certainty evidence from two studies (77 participants) suggested that PVP-I or ganciclovir prevented the development of subepithelial infiltrates (SEI) when compared with artificial tears within 30 days of treatment (RR 0.24, 95% CI 0.10 to 0.56). Four studies compared topical interventions (tacrolimus, cyclosporin A [CsA], trifluridine, PVP-I + dexamethasone) with topical steroids, and one trial compared fluorometholone (FML) plus polyvinyl alcohol iodine (PVA-I) with FML plus levofloxacin. Evidence from one trial showed that more eyes receiving PVP-I 1.0% plus dexamethasone 0.1% had symptoms resolved by day seven compared with those receiving dexamethasone alone (RR 9.00, 95% CI 1.23 to 66.05; 52 eyes). In two trials, fewer eyes treated with PVP-I or PVA-I plus steroid developed SEI within 15 days of treatment compared with steroid alone or steroid plus levofloxacin (RR 0.08, 95% CI 0.01 to 0.55; 69 eyes). One study found that CsA was no more effective than steroid for resolving SEI within four weeks of treatment (RR 0.84, 95% CI 0.67 to 1.06; N = 88). The evidence from trials comparing topical interventions with steroids was overall of very low level certainty. Adverse effects Antiviral or antimicrobial agents plus steroid did not differ from artificial tears in terms of ocular discomfort upon instillation (RR 9.23, 95% CI 0.61 to 140.67; N = 19). CsA and tacrolimus eye drops were associated with more cases of severe ocular discomfort, and sometimes intolerance, when compared with steroids (RR 4.64, 95% CI 1.15 to 18.71; 2 studies; N = 141). Compared with steroids, tacrolimus did not increase the risk of elevated intraocular pressure (RR 0.07, 95% CI 0 to 1.13; 1 study; N = 80), while trifluridine conferred no additional risk compared to tear substitute (RR 5.50, 95% CI 0.31 to 96.49; 1 study; N = 97). Overall, bacterial superinfection was rare (one in 23 CsA users) and not associated with use of the intervention steroid (RR 3.63, 95% CI 0.15 to 84.98; N = 51). The evidence for all estimates was of low or very low certainty. AUTHORS' CONCLUSIONS: The evidence for the seven specified outcomes was of low or very low certainty due to imprecision and high risk of bias. The evidence that antiviral agents shorten the duration of symptoms or signs when compared with artificial tears was inconclusive. Low certainty evidence suggests that PVP-I alone resolves signs and symptoms by seven days relative to artificial tears. PVP-I or PVA-I, alone or with steroid, is associated with lower risks of SEI development than artificial tears or steroid (very low certainty evidence). The currently available evidence is insufficient to determine whether any of the evaluated interventions confers an advantage over steroids or artificial tears with respect to virus eradication or its spread to initially uninvolved fellow eyes. Future updates of this review should provide evidence of high-level certainty from trials with larger sample sizes, enrollment of participants with similar durations of signs and symptoms, and validated methods to assess short- and long-term outcomes.

Effect of Autologous Serum Eye Drops on Corneal Haze after Corneal Cross-linking.

SIGNIFICANCE: Corneal haze remains a frequent post-operative finding in patients undergoing corneal cross-linking. It has been shown that autologous serum tears promote epithelial healing and reduce post-operative pain; however, the role in the prevention of corneal haze has not been reported. PURPOSE: This study aimed to compare the effect of autologous serum tears versus preservative-free artificial tears on the prevention and resolution of post-cross-linking corneal haze. METHODS: A retrospective cohort study was conducted in a sample population from one surgeon at a tertiary eye center from 2016 to 2019. Seventy-six eyes of consecutive patients who underwent cross-linking were included. Records were reviewed for corneal Scheimpflug densitometry values and maximum keratometry, epithelial healing time, and the use of either autologous serum tears or preservative-free artificial tears. Corneal densitometry values, expressed in standardized grayscale units (GSU), were recorded for the anterior 150-µm corneal stroma and in the 0.0 to 2.0 mm and 2.0 to 6.0 mm zones. RESULTS: Forty-four eyes received autologous serum tears, whereas 32 eyes received preservative-free artificial tears. The baseline GSU of the anterior stromal 0 to 2 mm annulus and the 2 to 6 mm annulus did not significantly differ between groups (P = .50 and P = .40, respectively). There was a statistically significant increase in mean GSU for both anterior 0 to 2 mm and 2 to 6 mm zones between baseline and 1 month (P < .001) and 3 months (P < .001). When comparing the two groups, no statistically significant difference was found post-operatively between the mean GSU at 1 month for the anterior 0 to 2 mm (P = .38) nor the 2 to 6 mm zone (P = .12), or for the third month (P = .60 and P = .44, respectively). CONCLUSIONS: Using Scheimpflug densitometry, we did not find a significant difference in the post-cross-linking corneal haze at 1 and 3 post-operative months between patients who use autologous serum tears and those who use preservative-free artificial tears.

Artificial Tears: Biological Role of Their Ingredients 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.

Porcine Corneas Incubated at Low Humidity Present Characteristic Features Found in Dry Eye Disease.

Dry eye is a multifactorial disease that affects the ocular surface and tear fluid. Current treatment options include lubricant eye drop application several times a day. However, these eye drops often cause local side effects like ocular allergies or blurred vision after the application. To test new treatment options, a robust dry eye model is needed. Here, a porcine ex vivo model was established by means of incubation of porcine corneas in low humidity (LH) and characterized by histological damage evaluation, epithelial thickness and by relevant dry eye markers, such as interleukin 1 beta (IL-1ß), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), occludin and galectin-3. In the dry eye model proposed, an increased secretion of IL-1ß was observed, as well as an upregulation of NF-κB, occludin and galectin-3 mRNA expression. Moreover, the model presented a higher rate of cell death in comparison to the controls. These effects could be reversed with successful treatment of dexamethasone (dexa) and partially reversed with hyaluronic acid (HA) containing eye drops. Furthermore, medium-molecular-weight HA stimulated an increase in IL-1ß in the model proposed. In conclusion, this dry eye model mimics the in vivo condition and hence allows for animal-free testing of novel dry eye treatments.

EULAR recommendations for the management of Sjögren's syndrome with topical and systemic therapies.

The therapeutic management of Sjögren syndrome (SjS) has not changed substantially in recent decades: treatment decisions remain challenging in clinical practice, without a specific therapeutic target beyond the relief of symptoms as the most important goal. In view of this scenario, the European League Against Rheumatism (EULAR) promoted and supported an international collaborative study (EULAR SS Task Force) aimed at developing the first EULAR evidence and consensus-based recommendations for the management of patients with SjS with topical and systemic medications. The aim was to develop a rational therapeutic approach to SjS patients useful for healthcare professionals, physicians undergoing specialist training, medical students, the pharmaceutical industry and drug regulatory organisations following the 2014 EULAR standardised operating procedures. The Task Force (TF) included specialists in rheumatology, internal medicine, oral health, ophthalmology, gynaecology, dermatology and epidemiology, statisticians, general practitioners, nurses and patient representatives from 30 countries of the 5 continents. Evidence was collected from studies including primary SjS patients fulfilling the 2002/2016 criteria; when no evidence was available, evidence from studies including associated SjS or patients fulfilling previous sets of criteria was considered and extrapolated. The TF endorsed the presentation of general principles for the management of patients with SjS as three overarching, general consensus-based recommendations and 12 specific recommendations that form a logical sequence, starting with the management of the central triplet of symptoms (dryness, fatigue and pain) followed by the management of systemic disease. The recommendations address the use of topical oral (saliva substitutes) and ocular (artificial tear drops, topical non-steroidal anti-inflammatory drugs, topical corticosteroids, topical CyA, serum tear drops) therapies, oral muscarinic agonists (pilocarpine, cevimeline), hydroxychloroquine, oral glucocorticoids, synthetic immunosuppressive agents (cyclophosphamide, azathioprine, methotrexate, leflunomide and mycophenolate), and biological therapies (rituximab, abatacept and belimumab). For each recommendation, levels of evidence (mostly modest) and TF agreement (mostly very high) are provided. The 2019 EULAR recommendations are based on the evidence collected in the last 16 years in the management of primary 2002 SjS patients and on discussions between a large and broadly international TF. The recommendations synthesise current thinking on SjS treatment in a set of overarching principles and recommendations. We hope that the current recommendations will be broadly applied in clinical practice and/or serve as a template for national societies to develop local recommendations.

Diagnosing and managing allergic conjunctivitis in childhood: The allergist's perspective.

Allergic conjunctivitis in childhood often poses problems of diagnosis and management for the allergist. We present the salient points concerning the diagnosis and treatment of ocular allergy emerging from a large cohort survey conducted jointly in the departments of ophthalmology and paediatric allergy in a French teaching hospital. Seasonal acute conjunctivitis is a common disorder and not overly difficult to diagnose and treat when associated with rhinitis leading to allergic rhinoconjunctivitis. An ophthalmologist should be consulted when conjunctivitis occurs alone and if another form of conjunctivitis is suspected, such as perennial allergic conjunctivitis, vernal keratoconjunctivitis or atopic keratoconjunctivitis. When IgE-mediated hypersensitivity assessment does not establish aetiological diagnosis, a conjunctival allergen provocation test can be performed. The principal non-IgE-mediated allergy is chronic blepharoconjunctivitis. The main problem for differential diagnosis is the presence of signs suggestive of dry eye. Management includes non-pharmacological treatments, such as lacrimal substitutes, avoidance measures and protection of the ocular surface. Second-line treatment consists of eye drops, preferably single dose or without additives and with dual local action, mast cell stabilizer action and antihistaminic action. Third-line treatment is reserved for severe forms. Short-lasting local steroid therapy can control flare-ups of allergic keratoconjunctivitis, which should have specialized follow-up. Cyclosporine is a disease-modifying treatment, which is both effective and well tolerated.

Topical cyclosporine A therapy for dry eye syndrome.

BACKGROUND: Topical cyclosporine A (also known as ciclosporin A) (CsA) is an anti-inflammatory that has been widely used to treat inflammatory ocular surface diseases. Two CsA eyedrops have been approved by US Food and Drug Administration for managing dry eye: Restasis (CsA 0.05%, Allergan Inc, Irvine, CA, USA), approved in 2002, and Cequa (CsA 0.09%, Sun Pharma, Cranbury, NJ, USA), approved in 2018. Numerous clinical trials have been performed to assess the effectiveness and safety of CsA for dry eye; however, there is no universal consensus with regard to its effect. OBJECTIVES: To assess the effectiveness and safety of topical CsA in the treatment of dry eye. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (which contains the Cochrane Eyes and Vision Trials Register) (2018, Issue 2); Ovid MEDLINE; Embase.com; PubMed; Latin American and Caribbean Health Sciences Literature Database (LILACS); ClinicalTrials.gov; and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP). We did not use any date or language restrictions in the electronic search for trials. We last searched the electronic databases on 16 February 2018. SELECTION CRITERIA: We included randomized controlled trials (RCTs) of people with dry eye regardless of age, sex, severity, etiology, or classification of dry eye. We included RCTs in which different concentrations of topical CsA were compared with one another or with artificial tears, placebo, or vehicle. We also included RCTs in which CsA in combination with artificial tears was compared to artificial tears alone. DATA COLLECTION AND ANALYSIS: We followed the standard Cochrane methodology and assessed the certainty of the evidence using GRADE. MAIN RESULTS: We included 30 RCTs (4009 participants) with follow-up periods ranging from 6 weeks to 12 months. We studied dry eye of various severity and underlying causes. The interventions investigated also varied across RCTs: CsA versus artificial tears; CsA with artificial tears versus artificial tears alone; and in some studies, more than one concentration of CsA. Artificial tears were used as adjunctive to study medication in all but five trials. Almost all trials had deficiencies in the reporting of results (e.g. reporting P values or direction only), precluding the calculation of between-group estimates of effect or meta-analysis.Eighteen trials compared topical CsA 0.05% plus artificial tears versus vehicle plus artificial tears or artificial tears alone. One trial reported subjective symptoms of dry eye at 6 months and the results were in favor of CsA (mean difference (MD) -4.80, 95% confidence interval (CI) -6.41 to -3.19; low-certainty evidence). Two trials reported MD in ocular surface dye staining at 6 months, but the results were inconsistent in these two trials (MD -0.35, 95% CI -0.69 to -0.01 in one and MD 0.58, 95% CI 0.06 to 1.10 in the other; low-certainty evidence). Four trials reported MD in Schirmer test scores at 6 months and the estimates ranged from -4.05 (95% CI -6.67 to -1.73) to 3.26 (95% CI -1.52 to 5.00) (low-certainty evidence). Three trials reported risk ratio (RR) of improved Schirmer test scores at 6 months; estimates ranged from 0.98 (95% CI 0.83 to 1.17) to 3.50 (95% CI 2.09 to 5.85) (low-certainty evidence). Four trials reported MD in tear film stability measured by tear break-up time at 6 months and the estimates ranged from -1.98 (95% CI -3.59 to -0.37) to 1.90 (95% CI 1.44 to 2.36) (low-certainty evidence). Three trials reported RR of improved tear break-up time at 6 months and the estimates ranged from 0.90 (95% CI 0.77 to 1.04) to 4.00 (95% CI 2.25 to 7.12) (low-certainty evidence). Three trials reported frequency of artificial tear usage at 6 months without providing any estimates of effect; the direction of effect seem to be in favor of CsA (low-certainty evidence). Because of incomplete reporting of the results data or considerable statistical heterogeneity, we were only able to perform a meta-analysis on mean conjunctival goblet cell density. Mean conjunctival goblet cell density in the CsA treated group may be greater than that in the control group at the end of follow-up at four and 12 months (MD 22.5 cells per unit, 95% CI 16.3 to 28.8; low-certainty evidence). All but two trials reported adverse events that included burning and stinging. Participants treated with CsA may be more likely to have treatment-related adverse events than those who treated with vehicle (RR 1.33, 95% CI 1.00 to 1.78; low-certainty evidence).Other comparisons evaluated were CsA 0.05% plus artificial tears versus higher concentrations of CsA plus artificial tears (4 trials); CsA 0.05% versus placebo or vehicle (4 trials); CsA 0.1% plus artificial tears versus placebo or vehicle plus artificial tears (2 trials);CsA 0.1% cationic emulsion plus artificial tears versus vehicle plus artificial tears (2 trials); CsA 1% plus artificial tears versus placebo plus artificial tears (3 trials); and CsA 2% plus artificial tears versus placebo plus artificial tears (3 trials). Almost all of these trials reported P value or direction of effect only (mostly in favor of CsA), precluding calculation of between-group effect estimates or meta-analyses. AUTHORS' CONCLUSIONS: Despite the widespread use of topical CsA to treat dry eye, we found that evidence on the effect of CsA on ocular discomfort and ocular surface and tear film parameters such as corneal fluorescein staining, Schirmer's test, and TBUT is inconsistent and sometimes may not be different from vehicle or artificial tears for the time periods reported in the trials. There may be an increase in non-serious, treatment-related adverse effects (particularly burning) in the CsA group. Topical CsA may increase the number of conjunctival goblet cells. However, current evidence does not support that improvements in conjunctival mucus production (through increased conjunctival goblet cells) translate to improved symptoms or ocular surface and tear film parameters. All published trials were short term and did not assess whether CsA has longer-term disease-modifying effects. Well-planned, long-term, large clinical trials are needed to better assess CsA on long-term dry eye-modifying effects. A core outcome set, which ideally includes both biomarkers and patient-reported outcomes in the field of dry eye, is needed.

Comparison of 0.05% cyclosporine and 3% diquafosol solution for dry eye patients: a randomized, blinded, multicenter clinical trial.

BACKGROUND: This study is aim to compare the clinical effectiveness between the two most prominent dry eye disease (DED)-specific eye drops, 0.05% cyclosporine (CN) and 3% diquafosol (DQ). METHODS: This is a multi-centered, randomized, masked, prospective clinical study. A total of 153 DED patients were randomly allocated to use CN twice per day or DQ six times daily. Cornea and conjunctival staining scores (NEI scale), tear break-up time (TBUT), Schirmer test scores, and ocular surface disease index (OSDI) score were measured at baseline, 4 and 12 weeks after treatment. RESULTS: At 12 weeks after treatment, NEI scaled scores were significantly reduced from the baseline by - 6.60 for CN and - 6.63 for DQ group (all P < 0.0001, P = 0.9739 between groups). TBUT and Schirmer values for CN were significantly improved from the baseline at 4 and 12 weeks (P = 0.0034, P < 0.0001 for TBUT, P = 0.0418, P = 0.0031 for Schirmer test). However, for DQ, TBUT showed significant improvement at 12 weeks only (P = 0.0281). Mean OSDI score differences from the baseline to 12 weeks were improved by - 13.03 ± 19.63 for CN and - 16.11 ± 20.87 for DQ, respectively (all P < 0.0001, P = 0.854 between groups). Regarding drug compliance, the mean instillation frequency of CN was less than that of DQ (P < 0.001). There were no statistically significant intergroup differences in safety evaluation. CONCLUSIONS: The level of improvement regarding NEI, TBUT, and OSDI scores were not significantly different between the two treatment groups. However, with regards to the early improvement of TBUT and patient compliance, patients using CN improved faster and with greater adherence to drug usage than did those treated with DQ. TRIAL REGISTRATION: KCT0002180 , retrospectively registered on 23 December 2016.

Effects of 5% sodium chloride ophthalmic ointment on thickness and morphology of the normal canine cornea.

OBJECTIVE: To determine the effect of 5% sodium chloride ophthalmic ointment (5% NaCl) on thickness and morphology of the normal canine cornea using ultrasonic pachymetry (USP), in vivo confocal microscopy (IVCM), and Fourier-domain optical coherence tomography (FD-OCT). METHODS: Five healthy laboratory Beagles received ophthalmic examinations including USP, IVCM, and FD-OCT prior to and at fixed intervals following treatment. The right and left eyes were treated with 5% NaCl and artificial tears ophthalmic ointment (AT), respectively, every 2 hours for 4 treatments/d (days 2-9), and then hourly for 7 treatments/d (day 10). Treatment groups were statistically compared using mixed-effects linear regression. RESULTS: Treatment with 5% NaCl resulted in a 12 µm decrease in corneal thickness from baseline (P < .001), while there was no significant difference in corneal thickness between values obtained at baseline and following treatment with AT (P = .82). Epithelial cell density significantly increased from baseline (530 ± 52 cells/mm2 ) to 577 ± 43 and 567 ± 15 cells/mm2 with 5% NaCl and AT, respectively (P = .003 and .005, respectively). However, keratocyte cell density in the anterior and posterior stroma and endothelial cell density did not significantly differ following treatment with 5% NaCl or AT ointment (P > .05). CONCLUSIONS: Short-term topical treatment with 5% NaCl decreased corneal thickness in normal dogs with no observable changes in corneal morphology or signs of ocular toxicity.

The Use of Junfeng BFS Water (JBW) in Dry Eye Syndrome.

BACKGROUND AND PURPOSE: Junfeng BFS Water (JBW) is normal drinking water treated by an extremely low frequency electromagnetic field with certain electromagnetic oscillations. This leads to a change in physical water properties, such as an increase in permittivity and an increase in dissolved oxygen. Animal studies show that JBW has certain biological effects, such as improvement in microcirculation, cell hydration, and blood rheology. In a clinical study, we were able to show an improvement in ocular blood flow after drinking JBW. Since people drinking JBW reported an improvement in dry eye symptoms, we wanted to examine tear film stability by determining the break-up time (BUT) through patient interviews. METHODS: Sixty patients (120 eyes) were age matched and randomized in a double-blind study using the JBW device, or an identical looking nonworking device, without influence on drinking water (control group). All participants had to drink 2 liters of water per day over a period of 2 months. All study subjects underwent a complete ophthalmological examination, including measurement of BUT at day 0, 1 month, and 2 months. At the same time, the patients were interviewed about their eyes, their subjective feelings, and their vision. Statistical analysis was performed using the IBM SSPS program. Bivariate statistics were performed using the ANOVA test. The level of significance was a = 0.05 RESULTS: The increase in BUT was significantly higher in both eyes (a< = 0.01) of the population drinking JBW after 1 and 2 months compared to the control group using untreated water. This result was confirmed in patient interviews. Therefore, patients drinking JBW judged the question "do you have tired eyes?" significantly better (a = 0.04) than the control group after 1 month. Eighty percent of the JBW group continued to drink JBW 6 months after the end of the study, and more than 50% were able to reduce treatment with artificial tears or stop it completely. CONCLUSIONS: Apart from an improvement in microcirculation, drinking JBW seems to have a positive effect on dry eye syndrome. Mechanisms are still unknown, and improvement in microcirculation of the lacrimal gland should be discussed. If our results can be confirmed in a larger study, and with more sophisticated methods, we see a potential for JBW's use as an additive to conventional dry eye therapy.

In vivo and ex vivo evaluation of cell-cell interactions, adhesion and migration in ocular surface of patients undergone excimer laser refractive surgery after topical therapy with different lubricant eyedrops.

PURPOSE: To investigate, in vivo by means of in vivo confocal microscopy (IVCM) and ex vivo by impression cytology, epithelial cellular damage after excimer laser refractive surgery in patients under different topical lubricant therapies. METHODS: Two hundred eyes of 100 patients, undergone bilateral excimer laser refractive surgery for medium myopic error correction [spherical equivalent refraction from -1.75 to -3.50 dioptres (D) with refractive astigmatism under -0.75 D], have been recruited. All patients received, in addition to standard therapy for refractive surgery, high weight hyaluronic acid 0.2% eyedrops in one randomly selected eye and carboxymethylcellulose 1% eyedrop in the comparator eye (control eye) 4 times daily for 90 days. Follow-up included a baseline visit and further examination 7-, 30- and 90-day intervals [clinical evaluation with Schirmer test and tear break-up time (TBUT), IVCM and impression cytology]. RESULTS: No significant difference in Schirmer test and TBUT was observed during the follow-up period in eyes under different therapies. IVCM showed an improvement of conjunctival and corneal epithelial cells quality in eye in treatment with high weight hyaluronic acid 0.2% when compared to carboxymethylcellulose. Conjunctival impression cytology demonstrated an evident positivity for CD44 in eyes treated with both treatments in all follow-up controls. ICAM1 expression showed an increasing positivity starting at 30 days that became statistically significant after 90 days of high weight hyaluronic acid 0.2% therapy (p = 0.0167). CONCLUSIONS: In vivo and in vitro results showed the effectiveness of high weight hyaluronic acid 0.2% in facilitating cell-cell interaction, migration, cell proliferation, stabilizing epithelial barrier of the ocular surface. Moreover, use of high weight hyaluronic acid in treatment of corneal tissue damage after refractive surgery, in concordance with standard topical corticosteroids and antibiotics therapy, could be effective in promoting corneal epithelial wound healing with consequent good results in clinical outcome and patients' satisfaction.

Sjogren's syndrome from the perspective of ophthalmology.

Sjogren's syndrome (SS) is an autoimmune disease affecting the lacrimal glands resulting in dry eye disease (DED). Ophthalmologists may be the first line of detection of Sjogren's syndrome given the frequency of DED in SS and that dry eye is often the presenting symptom. Numerous symptom questionnaires and tests have been developed to help diagnose DED, but as of yet, there is no "gold standard." Minimally invasive objective metrics are needed for a reliable diagnosis of DED. Currently there is no single test to diagnose SS-associated DED. Although there are several approaches to treatment, none are specific for DED in SS, and, generally, several methods need to be tried to find what works best for a specific patient. Treatment for DED continues to be an unmet medical need, especially given that DED in SS is typically on the severe end of the spectrum.