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.

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.

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.

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.

Clinical utility of objective tests for dry eye disease: variability over time and implications for clinical trials and disease management.

PURPOSE: To evaluate the efficacy of commonly used biomarkers in dry eye disease management in a longitudinal observational case series study followed by an interventional study in a subset of subjects treated with cyclosporine A (0.05%). METHODS: Bilateral tear osmolarity, Schirmer, tear film breakup time (TBUT), staining, meibomian grading, and Ocular Surface Disease Index were measured for a period of 3 consecutive months in participants recruited from a clinic-based population at 2 study sites. Fifty-two subjects completed the study (n = 16 mild/moderate, n = 36 severe; age, 47.1 ± 16.1 years). After the 3-month observation period, severe dry eye patients were prescribed topical cyclosporine A and evaluated for an additional 3 months. RESULTS: Tear osmolarity (8.7 ± 6.3%) exhibited significantly less variability over a 3-month period than corneal staining (12.2 ± 8.8%, P = 0.040), conjunctival staining (14.8 ± 8.9%, P = 0.002), and meibomian grading (14.3 ± 8.8%, P < 0.0001) across the entire patient population. Osmolarity also demonstrated less variation than TBUT (11.7 ± 9.0%, P = 0.059), Schirmer tests (10.7 ± 9.2%, P = 0.67), and Ocular Surface Disease Index (9.3 ± 7.8%, P = 0.94), although the differences were not significant. Variation in osmolarity was less for mild dry eye patients (5.9 ± 3.1%) than severe dry eye patients (10.0 ± 6.9%, P = 0.038). After treatment, average osmolarity and variability were lowered from 341 ± 18 mOsm/L to 307 ± 8 mOsm/L (P < 0.0001, n = 10). A downward trend in symptoms followed changes in osmolarity, declining from 44 ± 17 mOsm/L to 38 ± 18 mOsm/L (P = 0.35). None of the other signs demonstrated a change after treatment. CONCLUSIONS: Over a 3-month period, tear film osmolarity was found to have the lowest variability among commonly used signs of dry eye disease. Reductions in osmolarity preceded changes in symptoms during therapy.

Distribution of aqueous-deficient and evaporative dry eye in a clinic-based patient cohort: a retrospective study.

PURPOSE: To evaluate in a general clinic-based cohort of patients with dry eye disease (DED) the distribution of patients with aqueous-deficient or evaporative subtype of DED. METHODS: Schirmer tests and meibomian gland dysfunction (MGD) (Foulks-Bron scoring) were evaluated in both eyes of 299 normal subjects and DED patients (218 women and 81 men) across 10 sites in the European Union and the United States. Using the more severe measurement of the 2 eyes, subjects were considered to have pure aqueous-deficient dry eye (ADDE) with Schirmer values of <7 mm and MGD grades of ≤5. Patients were classified as purely evaporative dry eye with MGD grades of >5 and Schirmer values of ≥7 mm. Subjects were placed into the mixed (hybrid) category if they exhibited both a low Schirmer value of <7 and evidence of MGD with a grade >5. RESULTS: Of the 224 subjects classified with DED using an objective, composite, disease severity scale, 159 were classified into 1 of 3 categories: 79 were classified with only MGD, whereas only 23 were classified as purely aqueous deficient, and 57 showed evidence of both MGD and aqueous deficiency. Overall, 86% of these qualified DED patients demonstrated signs of MGD. The remaining 65 patients showed evidence of DED through other clinical signs, without overt evidence of MGD or ADDE, possibly because of the inherent variability of these signs. CONCLUSIONS: The proportion of subjects exhibiting signs of evaporative dry eye resulting from MGD far outweighs that of subjects with pure ADDE in a general clinic-based patient cohort.

A new system, the LipiFlow, for the treatment of meibomian gland dysfunction.

PURPOSE: To evaluate the safety and effectiveness of the LipiFlow System compared to the iHeat Warm Compress (WC) for adults with meibomian gland dysfunction (MGD). METHODS: This was a non-significant risk, prospective, open-label, randomized, crossover multicenter clinical trial. One hundred thirty-nine subjects were randomized between LipiFlow (n=69) and WC control (n=70). Subjects in the LipiFlow group received a 12-minute LipiFlow treatment and were reexamined at 1 day, 2 weeks and 4 weeks. Control subjects received a 5-minute iHeat treatment with instructions to perform the same treatment daily for 2 weeks. At 2 weeks, they crossed over (LipiFlow Crossover) and received the LipiFlow treatment. Effectiveness parameters: meibomian gland (MG) assessment, tear break-up time (TBUT) and dry eye symptoms. Safety parameters: adverse events, ocular health exam, ocular surface staining, intraocular pressure, visual acuity and discomfort. RESULTS: LipiFlow resulted in significant improvement (P < 0.05) in MG secretion at 2 and 4 weeks (mean ± standard deviation at baseline = 6.3 ± 3.5; 2 weeks = 14.3 ± 8.7; 4 weeks = 16.7 ± 8.7); and TBUT at 2 and 4 weeks: (at baseline = 5.5 ± 2.9; 2 weeks = 6.9 ± 5.0; 4 weeks = 7.4 ± 5.5). There was no significant change in MG secretion or TBUT in the control group. LipiFlow resulted in a greater significant reduction in dry eye symptoms than the iHeat WC. The crossover group demonstrated similar significant improvement 2 weeks post-treatment with the LipiFlow. There was no significant difference between groups in the incidence of non-serious, device-related adverse events. CONCLUSION: The LipiFlow System was significantly more effective than iHeat WC. These results support its safety and effectiveness in the treatment of MGD and dry eye symptoms.

Preservative use in topical glaucoma medications.

Benzalkonium chloride (BAK) is the principal preservative employed in topical ocular hypotensive medications, although alternative compounds recently have begun to be employed or examined. Individual clinical trials have shown that exposure to BAK concentrations contained in ophthalmic solutions does not produce adverse sequelae in the majority of glaucoma patients, but concerns continue with regard to its long-term use. These concerns have resulted from an extensive research effort, including preclinical studies with in vitro and in vivo models, as well as recent clinical investigations dedicated specifically to this issue. The aim of this systematic literature review of both preclinical and clinical data was to determine the relevance of these findings to clinical practice. Most preclinical studies reported negative effects of BAK exposure, but with few exceptions, BAK concentrations and exposure times greatly exceeded those likely to be experienced by patients, given the normal physiological dilution by the tear film. In addition, consistent evidence of BAK-related toxicity did not emerge from our review of dedicated clinical investigations. Thus, taken together, current evidence supports the safety of BAK for most glaucoma patients, although subpopulations with abnormal tearing may benefit from alternative preservative compounds or preservative-free formulations. Further studies to identify these populations are needed.

Tear osmolarity in the diagnosis and management of dry eye disease.

PURPOSE: To evaluate the use of tear osmolarity in the diagnosis of dry eye disease. DESIGN: A prospective, observational case series to determine the clinical usefulness of tear osmolarity and commonly used objective tests to diagnose dry eye disease. METHODS: A multicenter, 10-site study consisting of 314 consecutive subjects between 18 and 82 years of age. Bilateral tear osmolarity, tear film break-up time (TBUT), corneal staining, conjunctival staining, Schirmer test, and meibomian gland grading were performed. Diagnostic performance was measured against a composite index of objective measurements that classified subjects as having normal, mild or moderate, or severe dry eye. The main outcome measures were sensitivity, specificity, area under the receiver operating characteristic curve, and intereye variability. RESULTS: Of the 6 tests, tear osmolarity was found to have superior diagnostic performance. The most sensitive threshold between normal and mild or moderate subjects was found to be 308 mOsms/L, whereas the most specific was found at 315 mOsms/L. At a cutoff of 312 mOsms/L, tear hyperosmolarity exhibited 73% sensitivity and 92% specificity. By contrast, the other common tests exhibited either poor sensitivity (corneal staining, 54%; conjunctival staining, 60%; meibomian gland grading, 61%) or poor specificity (tear film break-up time, 45%; Schirmer test, 51%). Tear osmolarity also had the highest area under the receiver operating characteristic curve (0.89). Intereye differences in osmolarity were found to correlate with increasing disease severity (r(2) = 0.32). CONCLUSIONS: Tear osmolarity is the best single metric both to diagnose and classify dry eye disease. Intereye variability is a characteristic of dry eye not seen in normal subjects.

An objective approach to dry eye disease severity.

PURPOSE: A prospective, multisite clinical study (10 sites in the European Union and the United States) evaluated the clinical utility of commonly used tests and tear osmolarity for assessing dry eye disease severity. METHODS: Three hundred fourteen consecutive subjects between the ages of 18 and 82 years were recruited from the general patient population, 299 of which qualified with complete datasets. Osmolarity testing, Schirmer test without anesthesia, tear film breakup time (TBUT), corneal staining, meibomian dysfunction assessment, and conjunctival staining were performed bilaterally. A symptom questionnaire, the Ocular Surface Disease Index (OSDI), was also administered to each patient. Distributions of clinical signs and symptoms against a continuous composite severity index were evaluated. RESULTS: Osmolarity was found to have the highest correlation coefficient to disease severity (r(2) = 0.55), followed by conjunctival staining (r(2) = 0.47), corneal staining (r(2) = 0.43), OSDI (r(2) = 0.41), meibomian score (r(2) = 0.37), TBUT (r(2) = 0.30), and Schirmer result (r(2) = 0.17). A comparison of standard threshold-based classification with the composite severity index revealed significant overlap between the disease severities of prospectively defined normal and dry eye groups. Fully 63% of the subjects were found to be poorly classified by combinations of clinical thresholds. CONCLUSIONS: Tear film osmolarity was found to be the single best marker of disease severity across normal, mild/moderate, and severe categories. Other tests were found to be informative in the more severe forms of disease; thus, clinical judgment remains an important element in the clinical assessment of dry eye severity. The results also indicate that the initiation and progression of dry eye is multifactorial and supports the rationale for redefining severity on the basis of a continuum of clinical signs. (ClinicalTrials.gov number, NCT00848198.).

The relationship between dry eye symptoms and lipid layer thickness.

PURPOSE: (1) To investigate the relationship between dry eye symptoms and lipid layer thickness (LLT) in patients presenting for routine eye examination and (2) to consider the practicality of interferometry in a clinical practice. METHODS: Patients presenting consecutively for routine eye examinations were recruited (n = 137, age range = 18-60 years, mean = 41.7 +/- 15.5 years, 102 females and 35 males). Patients were required to complete the Standard Patient Evaluation of Eye Dryness (SPEED) questionnaire after which their LLT was evaluated using a new interferometer (Ocular Surface Interferometer). Patients were assigned to 1 of 3 symptom categories: no symptoms (SPEED = 0), mild to moderate symptoms (SPEED = 1-9), and severe symptoms (SPEED > or = 10). Categorical analysis (contingency table) and linear regression were performed on the data. RESULTS: For patients with severe dry eye symptoms, 74% had an LLT < or =60 nm. Conversely, 72% of patients with no dry eye symptoms had an LLT of > or =75 nm (contingency table, chi = 12.63, df = 2, p = 0.0018). Furthermore, a linear regression of LLT and SPEED score reveal a significant linear relationship (as LLT increases, SPEED score decreases; p = 0.0014). CONCLUSIONS: (1) The data indicate that approximately 3 of 4 patients reporting severe symptoms have relatively thin lipid layers of 60 nm or less, whereas approximately 3 of 4 patients without symptoms have relatively thick lipid layers of 75 nm or more. Thus, the presence of dry eye symptoms significantly increases the likelihood of a relatively thin lipid layer. LLT seems to correlate better to symptoms, especially severe symptoms, than other reported correlations with objective clinical tests for dry eye disease. (2) Interferometry has the potential to be a practical and useful addition to clinical practice.

Blepharitis in the United States 2009: a survey-based perspective on prevalence and treatment.

ABSTRACT Like dry eye disease 15 years ago, blepharitis today is a poorly defined condition about which there is considerable misunderstanding. For a variety of reasons, there is little good data on either the prevalence of blepharitis or how eyecare practitioners currently treat it. The work reported herein consists of two recent studies: a telephone survey of a representative sample of the adult US population (n = 5,000) whose purpose was to discover the frequency of common ocular surface symptoms associated with blepharitis; and a study that queried a selected group of ophthalmologists (n = 120) and a similarly selected group of optometrists (n = 84) about the frequency of blepharitis in their practices, the existence comorbid conditions, and their management strategies. This data suggests that blepharitis symptoms are very common in the US population, with younger individuals reporting more, and more frequent, symptoms than older people, contrary to clinical dogma. Ophthalmologists and optometrists report that blepharitis is commonly seen in clinical practice in 37% and 47% of their patients, respectively, and it is widely agreed that meibomian gland dysfunction (MGD) is the most common cause of evaporative dry eye disease. In addition, management paradigms are shifting away from more traditional management with antibiotic ointment and warm compress therapy to prescription therapy for anterior and posterior blepharitis.