Validation of a Modified National Eye Institute Grading Scale for Corneal Fluorescein Staining.

Purpose: Validation of the novel Lexitas modified NEI scale for use in assessment of corneal fluorescein staining. Patients and Methods: A series of 18 illustrations and 14 clinical photographs depicting varying severity levels of corneal fluorescein staining were assessed by 3 independent examiners. Regions of the cornea were graded for staining severity based on 3 different grading scales: the original NEI staining scale (density-based scoring; 0-3 scale), a structured version of the NEI scale (dot-count scoring; 0-3 scale), and the Lexitas modified NEI staining scale (0-4 scale with half-point increments). Kappa statistics (simple and weighted) were computed to determine intra-examiner image grading repeatability for each examiner over 2 separate assessments. Inter-examiner assessment reliability utilized the scores from the first read of each examiner, and pairs of examiners to compute kappa statistics. Results: Data was analyzed from the scores provided by the examiners from each gradable corneal region on 32 images (18 illustrations and 14 photographs) for a total of 154 corneal regions across the 3 grading scales for each validation run. The mean intra-examiner simple/weighted kappa values using the NEI density, NEI dot count, and the Lexitas modified NEI staining scales were 0.67/0.72, 0.91/0.94, 0.80/0.92 for the graded illustrations, and 0.83/0.88, 0.76/0.85, 0.77/0.88 for the graded photographs, respectively. The mean inter-examiner simple/weighted kappa values using the NEI density, NEI dot count, and the Lexitas modified NEI staining scales were 0.59/0.65, 0.86/0.90, and 0.78/0.91 for the graded illustrations, and 0.80/0.88, 0.84/0.89, 0.69/0.88 for the graded photographs, respectively. Conclusion: The expanded scale of the Lexitas modified NEI staining scale demonstrated a high degree of reliability and repeatability of grading assessments within and across individual examiners, comparing favorably with the original NEI staining scale. A future investigation into the in-office utility of the Lexitas modified NEI staining scale is warranted.

Safety of KPI-121 Ophthalmic Suspension 0.25% in Patients With Dry Eye Disease: A Pooled Analysis of 4 Multicenter, Randomized, Vehicle-Controlled Studies.

PURPOSE: The safety of KPI-121 0.25%, an ophthalmic nanoparticle suspension of loteprednol etabonate, was evaluated in subjects with dry eye disease (DED) in one phase 2 and three phase 3 randomized trials of similar design. METHODS: Adults with DED received KPI-121 0.25% or vehicle drops 4 times daily (QID) for ≥2 weeks; 1430 subjects received KPI-121 0.25% and 1438 subjects received vehicle drops. Main safety assessments were adverse events (AEs) and intraocular pressure (IOP). As a common side effect associated with the use of ocular corticosteroids is elevated IOP, subjects with a history of or current diagnosis of glaucoma were excluded. RESULTS: Instillation site pain was the most common AE, reported by 5.2% of subjects in the KPI-121 0.25% group and 4.4% of subjects in the vehicle group; other AEs were reported by ≤0.8% of subjects in the KPI-121 group. IOP elevations, a side effect associated with the use of ophthalmic corticosteroids, were observed with low incidence: 0.6% and 0.2% of subjects in the KPI-121 and vehicle groups, respectively. An IOP elevation was defined as an increase from baseline of >5 mm Hg that resulted in an IOP of ≥21 mm Hg in either eye during use of the study product. CONCLUSIONS: KPI-121 ophthalmic suspension 0.25% seemed to be safe and well tolerated when dosed QID for 2 to 4 weeks in those DED subjects included in the 4 trials.

Efficacy and safety of abatacept in active primary Sjögren's syndrome: results of a phase III, randomised, placebo-controlled trial.

OBJECTIVES: To evaluate efficacy and safety of abatacept in adults with active primary Sjögren's syndrome (pSS) in a phase III, randomised, double-blind, placebo-controlled trial. METHODS: Eligible patients (moderate-to-severe pSS [2016 ACR/European League Against Rheumatism (EULAR) criteria], EULAR Sjögren's Syndrome Disease Activity Index [ESSDAI] ≥5, anti-SS-related antigen A/anti-Ro antibody positive) received weekly subcutaneous abatacept 125 mg or placebo for 169 days followed by an open-label extension to day 365. Primary endpoint was mean change from baseline in ESSDAI at day 169. Key secondary endpoints were mean change from baseline in EULAR Sjögren's Syndrome Patient Reported Index (ESSPRI) and stimulated whole salivary flow (SWSF) at day 169. Other secondary clinical endpoints included glandular functions and patient-reported outcomes. Selected biomarkers and immune cell phenotypes were examined. Safety was monitored. RESULTS: Of 187 patients randomised, 168 completed double-blind period and 165 continued into open-label period. Mean (SD) baseline ESSDAI and ESSPRI total scores were 9.4 (4.3) and 6.5 (2.0), respectively. Statistical significance was not reached for primary (ESSDAI -3.2 abatacept vs -3.7 placebo, p=0.442) or key secondary endpoints (ESSPRI, p=0.337; SWSF, p=0.584). No clinical benefit of abatacept over placebo at day 169 was seen with other clinical and PRO endpoints. Relative to baseline, abatacept was associated with significant differences vs placebo in some disease-relevant biomarkers (including IgG, IgA, IgM-rheumatoid factor) and pathogenic cell subpopulations (post hoc analyses). No new safety signals were identified. CONCLUSIONS: Abatacept treatment did not result in significant clinical efficacy compared with placebo in patients with moderate-to-severe pSS, despite evidence of biological activity.

Perspective on Systematic Medical Literature Reviews and Meta-Analyses.

PURPOSE: This study sought to identify factors contributing to the inadequacies of systematic reviews and meta-analyses (SRMAs) published in the ophthalmology literature. DESIGN: Perspective. METHODS: Review and synthesis of selective literature, with interpretation and perspective. RESULTS: Although recommendations for the design, conduct, assessment of quality, and risk of bias of systematic reviews have been widely available, some recent publications illustrate a serious potential failing in this domain: inclusion of refuted science, lack of citation of post-publication correspondence and failure to use ≥1 alternative search strategy. CONCLUSIONS: Examples of inadequacies of peer review in medical literature and perpetuation of erroneous science by unfiltered inclusion in subsequent systematic reviews have been identified, and the problem can be traced to authors, peer reviewers, and editors of journals. This perspective identifies and analyzes several possible causes of the problem and recommends some specific corrective actions to improve the quality and accuracy of such reviews.

Human Meibum Cholesteryl and Wax Ester Variability With Age, Sex, and Meibomian Gland Dysfunction.

Purpose: Relationships between tear film lipid (TFL) layer composition, structure, and function could provide insight into the etiology of dry eye. The molar ratio of cholesteryl ester (CE)/wax ester (WE) was measured in meibum from normal donors (Mn) and compared with meibum from donors with meibomian gland dysfunction (MMGD). Methods: CE/WE was measured using nuclear magnetic resonance spectroscopy. Results: CE/WE was distributed into two populations with 81% distributed near 0.55 and 19% near 0.3. CE/WE were higher in donors 13 to 19 years old compared with donors 1 to 12 years old and 20 to 88 years old. CE/WE for MMGD was 30% lower, 0.34 ± 0.04, compared with Mn, 0.49 ± 0.04. There were no sex differences in CE/WE. There were no significant racial differences between the CE/WE ratios for Asians and Caucasians. The CE/WE ratio was higher for blacks and lower for Hispanics compared to Caucasians. Due to the small number sampled, confirmation of the later racial results is needed. The packing of CE and WE in the TFL layer was proposed. Conclusions: Although MMGD contains much less CE than Mn, factors other than the CE content, such as the levels of saturation and/or proteins, may be responsible for the higher order of MMGD. In addition to saturation, CE could contribute to the increase in order of Mn between 0 and 20 years of age. Observed changes in the meibum content of CE alone is not likely to influence tear film stability.

TFOS DEWS II Clinical Trial Design Report.

The development of novel therapies for Dry Eye Disease (DED) is formidable, and relatively few treatments evaluated have been approved for marketing. In this report, the Subcommittee reviewed challenges in designing and conducting quality trials, with special reference to issues in trials in patients with DED and present the regulatory perspective on DED therapies. The Subcommittee reviewed the literature and while there are some observations about the possible reasons why so many trials have failed, there is no obvious single reason other than the lack of correlation between signs and symptoms in DED. Therefore the report advocates for conducting good quality studies, as described, going forward. A key recommendation for future studies is conduct consistent with Good Clinical Practice (GCP), including use of Good Manufacturing Practice (GMP) quality clinical trial material. The report also recommends that the design, treatments, and sample size be consistent with the investigational treatment, the objectives of the study, and the phase of development. Other recommendations for pivotal studies are a priori selection of the outcome measure, and an appropriate sample size.

A randomized, double-masked, parallel-group, comparative study to evaluate the clinical efficacy and safety of 1% azithromycin-0.1% dexamethasone combination compared to 1% azithromycin alone, 0.1% dexamethasone alone, and vehicle in the treatment of subjects with blepharitis.

PURPOSE: To evaluate the clinical efficacy and safety of a 1% azithromycin-0.1% dexamethasone combination in DuraSite ("combination") compared to 0.1% dexamethasone in DuraSite, 1% azithromycin in DuraSite, and vehicle in the treatment of subjects with blepharitis. MATERIALS AND METHODS: This was a Phase III, double-masked, vehicle-controlled, four-arm study in which 907 subjects with blepharitis were randomized to combination (n=305), 0.1% dexamethasone (n=298), 1% azithromycin (n=155), or vehicle (n=149). Ten study visits were scheduled: screening visit, days 1 and 4 (dosing phase) and 15, and months 1-6 (follow-up phase). On day 1, subjects applied one drop of the study drug to the eyelid of the inflamed eye(s) twice daily, and continued with twice-daily dosing for 14 days. After completing 14 days of dosing, subjects were followed for 6 months for efficacy and safety. RESULTS: A total of 57 subjects (6.3%) had complete clinical resolution at day 15: 25 (8.2%), 17 (5.7%), 8 (5.2%), and 7 (4.7%) subjects in the combination-, 0.1% dexamethasone-, 1% azithromycin-, and vehicle-treatment groups, respectively. The combination was superior to 1% azithromycin and vehicle alone, but not to 0.1% dexamethasone alone. Mean composite (total) clinical sign and symptom scores improved in all four treatment groups during the post-treatment evaluation phase for the intent-to-treat population, but outcomes were superior when a drop containing 0.1% dexamethasone was utilized. Clinical response was noted as early as day 4, and persisted as long as 6 months. Most adverse events were considered mild in severity and not related to the study drug. CONCLUSION: A higher percentage of subjects in the combination group achieved complete clinical resolution of the signs and symptoms of blepharitis at day 15 than with 1% azithromycin and vehicle, but outcomes were similar to treatment with 0.1% dexamethasone alone. The combination was well tolerated.

New Treatment Guidelines for Sjögren's Disease.

Sjögren's disease is associated with a high burden of illness, diminished quality of life, and increased health care costs. The Sjögren's Syndrome Foundation developed the first US clinical practice guidelines for management of the oral, ocular, and rheumatologic or systemic manifestations. Guideline recommendations were reviewed by a consensus expert panel using a modified Delphi process. This initiative should improve the quality and consistency of care for Sjögren's disease in the United States, guide insurance reimbursement, and define areas for future study. Guidelines will be periodically reviewed and revised as new information becomes available.

Clinical guidelines for management of dry eye associated with Sjögren disease.

PURPOSE: To provide a consensus clinical guideline for management of dry eye disease associated with Sjögren disease by evaluating published treatments and recommending management options. DESIGN: Consensus panel evaluation of reported treatments for dry eye disease. METHODS: Using the 2007 Report of the International Workshop on Dry Eye (DEWS) as a starting point, a panel of eye care providers and consultants evaluated peer-reviewed publications and developed recommendations for evaluation and management of dry eye disease associated with Sjögren disease. Publications were graded according to the American Academy of Ophthalmology Preferred Practice Pattern guidelines for level of evidence. Strength of recommendation was according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE) guidelines. RESULTS: The recommendations of the panel are briefly summarized herein. Evaluation should include symptoms of both discomfort and visual disturbance as well as determination of the relative contribution of aqueous production deficiency and evaporative loss of tear volume. Objective parameters of tear film stability, tear osmolarity, degree of lid margin disease, and ocular surface damage should be used to stage severity of dry eye disease to assist in selecting appropriate treatment options. Patient education with regard to the nature of the problem, aggravating factors, and goals of treatment is critical to successful management. Tear supplementation and stabilization, control of inflammation of the lacrimal glands and ocular surface, and possible stimulation of tear production are treatment options that are used according to the character and severity of dry eye disease. SUMMARY: Management guidelines for dry eye associated with Sjögren's disease are presented.

Rethinking dry eye disease: a perspective on clinical implications.

Publication of the DEWS report in 2007 established the state of the science of dry eye disease (DED). Since that time, new evidence suggests that a rethinking of traditional concepts of dry eye disease is in order. Specifically, new evidence on the epidemiology of the disease, as well as strategies for diagnosis, have changed the understanding of DED, which is a heterogeneous disease associated with considerable variability in presentation. These advances, along with implications for clinical care, are summarized herein. The most widely used signs of DED are poorly correlated with each other and with symptoms. While symptoms are thought to be characteristic of DED, recent studies have shown that less than 60% of subjects with other objective evidence of DED are symptomatic. Thus the use of symptoms alone in diagnosis will likely result in missing a significant percentage of DED patients, particularly with early/mild disease. This could have considerable impact in patients undergoing cataract or refractive surgery as patients with DED have less than optimal visual results. The most widely used objective signs for diagnosing DED all show greater variability between eyes and in the same eye over time compared with normal subjects. This variability is thought to be a manifestation of tear film instability which results in rapid breakup of the tearfilm between blinks and is an identifier of patients with DED. This feature emphasizes the bilateral nature of the disease in most subjects not suffering from unilateral lid or other unilateral destabilizing surface disorders. Instability of the composition of the tears also occurs in dry eye disease and shows the same variance between eyes. Finally, elevated tear osmolarity has been reported to be a global marker (present in both subtypes of the disease- aqueous-deficient dry eye and evaporative dry eye). Clinically, osmolarity has been shown to be the best single metric for diagnosis of DED and is directly related to increasing severity of disease. Clinical examination and other assessments differentiate which subtype of disease is present. With effective treatment, the tear osmolarity returns to normal, and its variability between eyes and with time disappears. Other promising markers include objective measures of visual deficits, proinflammatory molecular markers and other molecular markers, specific to each disease subtype, and panels of tear proteins. As yet, however, no single protein or panel of markers has been shown to discriminate between the major forms of DED. With the advent of new tests and technology, improved endpoints for clinical trials may be established, which in turn may allow new therapeutic agents to emerge in the foreseeable future. Accurate recognition of disease is now possible and successful management of DED appears to be within our grasp, for a majority of our patients.

New testing options for diagnosing and grading dry eye disease.

PURPOSE: To describe new options for diagnosis and severity grading of dry eye disease. DESIGN: Perspective on technological advancements to identify tear dysfunction and their value in diagnosing and grading dry eye disease. METHODS: Evidence is presented on new and evolving technologies to measure tear stability, composition, and meniscus height and their role in dry eye diagnosis and therapeutic efficacy grading is assessed. RESULTS: Evolving concepts regarding pathogenesis and new technologies to evaluate the tears and ocular surface have improved the ability to diagnose, classify, and grade the severity of dry eye disease. New technologies include noninvasive imaging of tear stability and tear meniscus height as a measure of tear volume and tear composition (osmolarity, lacrimal factors, inflammatory mediators, growth and differentiation factors). Approved tests, such as tear osmolarity and tear imaging, are being integrated into clinical practice and may eventually supplant certain traditional tests that have greater variability and less sensitivity. Other tests, such as molecular assays of tears and conjunctival cells, are currently being used in studies investigating pathogenesis and therapeutic mechanism of action. They may eventually translate to routine clinical practice. CONCLUSIONS: New technologies have emerged that can noninvasively evaluate the tears and measure disease-associated compositional changes. These tests are being integrated into clinical practice and therapeutic trials for diagnosis, classification, and severity grading of dry eye disease.

Correlations between commonly used objective signs and symptoms for the diagnosis of dry eye disease: clinical implications.

PURPOSE: To evaluate the relationship between signs and symptoms of dry eye disease (DED) in a clinic-based population. METHODS: In a retrospective analysis, clinical signs and symptoms were evaluated for 344 subjects (n = 82, normal; n = 263, dry eye), across 11 sites from the EU and United States. Pearson correlations between signs and symptoms (r(2) ) and an independent components analysis (ICA) mixing matrix were derived from the data set. Similar analysis was performed on an independent data set from 200 subjects in a previous study in Munich, Germany. RESULTS: No correlations above r(2) = 0.17 were found between any signs and symptoms, except for corneal and conjunctival staining, which reported an r(2) = 0.36. In the multisite study, the average r(2) for osmolarity (0.07), tear breakup time (0.12), Schirmer test (0.09), corneal (0.16) and conjunctival staining (0.17), meibomian grading (0.11) and Ocular Surface Disease Index(®) (0.11) were consistently low. Among patients who showed evidence of DED by consensus of clinical signs, only 57% reported symptoms consistent with a diagnosis of DED. Similar results were observed in the Munich-based study data set. Each component of the ICA mixing matrix exhibited minimal residual information. CONCLUSIONS: No consistent relationship was found between common signs and symptoms of DED. Each type of measurement provides distinct information about the condition of the ocular surface. These results also demonstrate that symptoms alone are insufficient for the diagnosis and management of DED and argue for a consensus of clinical signs that better reflect all aspects of the disease.