Effect of Omega-3 on HLA-DR Expression by Conjunctival Cells and Tear Cytokine Concentrations in the Dry Eye Assessment and Management Study.

OBJECTIVES: To determine effect of omega-3 supplementation on conjunctival cell HLA-DR expression and tear concentrations of interleukin (IL)-1ß, IL-6, IL-8, IL-10, IL-17A, interferon-γ, and tumor necrosis factor-α in dry eye disease patients in the Dry Eye Assessment and Management study. METHODS: Patients were randomized to receive a daily dose of eicosapentaenoic and docosahexaenoic acids (ω3) or refined olive oil (placebo) for 12 months. At baseline, 6 and 12 months, HLA-DR expression in conjunctival total, epithelial, and white blood cells and cytokine concentration in tears were determined. Differences in change from baseline between treatment groups were assessed using generalized estimating equations (HLA-DR) or Wilcoxon rank-sum test (cytokines). RESULTS: No differences were observed in HLA-DR expression in total, epithelial, or white blood cells between ω3 and placebo groups at 6 months (n=435) or 12 months (n=436). The median concentration percent change differed between ω3 and placebo groups at 6 months for IL-6 (-36.6 vs. 24.5%, P =0.02, n=75) and for IL-8 (3.7% vs. 72.6%, P =0.02, n=68); at 12 months, they did not differ ( P ≥0.18). No other differences between the treatment groups were detected. CONCLUSIONS: ω3 supplementation did not consistently affect ocular inflammatory status as measured by the frequency of HLA-DR expressing conjunctival cells or tear cytokines.

A Precise Method to Evaluate 360 Degree Measures of Optic Cup and Disc Morphology in an African American Cohort and Its Genetic Applications.

(1) Background: Vertical cup-to-disc ratio (CDR) is an important measure for evaluating damage to the optic nerve head (ONH) in glaucoma patients. However, this measure often does not fully capture the irregular cupping observed in glaucomatous nerves. We developed and evaluated a method to measure cup-to-disc ratio (CDR) at all 360 degrees of the ONH. (2) Methods: Non-physician graders from the Scheie Reading Center outlined the cup and disc on digital stereo color disc images from African American patients enrolled in the Primary Open-Angle African American Glaucoma Genetics (POAAGG) study. After converting the resultant coordinates into polar representation, the CDR at each 360-degree location of the ONH was obtained. We compared grader VCDR values with clinical VCDR values, using Spearman correlation analysis, and validated significant genetic associations with clinical VCDR, using grader VCDR values. (3) Results: Graders delineated outlines of the cup contour and disc boundaries twice in each of 1815 stereo disc images. For both cases and controls, the mean CDR was highest at the horizontal bisector, particularly in the temporal region, as compared to other degree locations. There was a good correlation between grader CDR at the vertical bisector and clinical VCDR (Spearman Correlation OD: r = 0.78 [95% CI: 0.76-0.79]). An SNP in the MPDZ gene, associated with clinical VCDR in a prior genome-wide association study, showed a significant association with grader VCDR (p = 0.01) and grader CDR area ratio (p = 0.02). (4) Conclusions: The CDR of both glaucomatous and non-glaucomatous eyes varies by degree location, with the highest measurements in the temporal region of the eye. This method can be useful for capturing innate eccentric ONH morphology, tracking disease progression, and identifying genetic associations.

Associations Between Systemic Omega-3 Fatty Acid Levels With Moderate-to-Severe Dry Eye Disease Signs and Symptoms at Baseline in the Dry Eye Assessment and Management Study.

PURPOSE: Omega-3 (n-3) fatty acid supplementation is used to treat systemic inflammatory diseases, but the role of n-3 in the pathophysiology and therapy of dry eye disease (DED) is not definitive. We evaluated the relationship of systemic n-3 levels with signs and symptoms at baseline in the Dry Eye Assessment and Management (DREAM) Study. METHODS: Blood samples from participants at baseline were analyzed for n-3 and n-6, measured as relative percentage by weight among all fatty acids in erythrocytes. Symptoms were evaluated using the Ocular Surface Disease Index. Signs including conjunctival staining, corneal staining, tear breakup time (TBUT), and Schirmer's test with anesthesia were also evaluated. RESULTS: There was no correlation between the systemic n-3 levels and DED symptoms. When the associations with signs of DED were assessed, lower DHA levels were associated with higher conjunctival staining, with mean scores of 3.31, 2.96, and 2.82 for low, medium, and high levels of DHA, respectively (linear trend P=0.007). None of the other signs were associated with DHA or the other measures of n-3. CONCLUSION: Previous studies have found varying results on the role of n-3 supplementation with the signs and symptoms of DED. Among patients with DED enrolled in the DREAM Study, lower systemic n-3 levels were not associated with worse symptoms and most signs of DED.

Ocular Discomfort and Quality of Life Among Patients in the Dry Eye Assessment and Management Study.

PURPOSE: To assess the association of severity of ocular discomfort with measures of quality of life among patients with moderate to severe dry eye disease (DED). METHODS: This is a prospective, observational, cohort study within a randomized clinical trial. Patients (N = 535) in the Dry Eye Assessment and Management study with moderate to severe DED completed the Ocular Surface Disease Index on DED symptoms, the SF-36 on quality of life, and the Brief Ocular Discomfort Inventory questionnaire and had a comprehensive ophthalmic assessment by a study-certified clinician. The ocular discomfort on average over the past week was scored on an 11-point scale (0 for no discomfort and 10 for discomfort as bad as you can imagine). RESULTS: The average ocular discomfort scores for patients ranged from 0 to 10, with a mean of 4.28. Discomfort scores did not vary with demographic characteristics, signs of DED, self-reported depression, or self-reported nonocular pain conditions. Ocular discomfort scores did correlate moderately to strongly with total Ocular Surface Disease Index scores (Spearman correlation coefficient, rs, 0.47-0.67) and with measures of interference with activities of daily living [general activity level, mood, walking ability, ability for normal work, relations with other people, sleep, and enjoyment of life (rs = 0.39-0.65)]. CONCLUSIONS: Among patients in the Dry Eye Assessment and Management study, worse ocular discomfort was associated with worse overall DED symptoms and interfered to a greater degree with activities of daily living. Ocular discomfort is an important part of the assessment of patients with DED.

The Dry Eye Assessment and Management (DREAM) extension study - A randomized clinical trial of withdrawal of supplementation with omega-3 fatty acid in patients with dry eye disease.

PURPOSE: To determine effects of continued or discontinued use of omega-3 (ω3) fatty acid supplements through a randomized withdrawal trial among patients assigned to ω3 supplements in the first year of the DREAM study. METHODS: Patients who were initially assigned to ω3 (3000 mg) for 12 months in the primary trial were randomized 1:1 to ω3 active supplements or placebos (refined olive oil) for 12 more months. The primary outcome was change in the Ocular Surface Disease Index (OSDI) score. Secondary outcomes included change in conjunctival staining, corneal staining, tear break-up time, Schirmer test, and adverse events. RESULTS: Among 22 patients assigned to ω3 and 21 to placebo supplements, the mean change in OSDI score between month 12 and 24 was similar between treatment groups (mean difference in change -0.6 points, 95% confidence interval [CI], (-10.7, 9.5), p = 0.91). There were no significant differences between groups in mean change in conjunctival staining (difference in mean change -0.5 points; 95% CI (-1.2, 0.3)), corneal staining (-0.3 points; 95% CI (-1.2, 0.3)), tear break-up time (-0.8 s; 95% CI (-2.6, 0.9)) and Schirmer test (0.6 mm, 95% CI (-2.0, 3.2)). Rates of adverse events were similar in both groups. CONCLUSION: Among patients who received ω3 supplements for 12 months in the primary trial, those discontinuing use of ω3 for an additional 12 months did not have significantly worse outcomes compared to those who continued use of ω3. ClinicalTrials.gov number NCT02128763.

ASSOCIATION BETWEEN ORAL IRON SUPPLEMENTATION AND RETINAL OR SUBRETINAL HEMORRHAGE IN THE COMPARISON OF AGE-RELATED MACULAR DEGENERATION TREATMENT TRIALS.

PURPOSE: Because patients often take iron supplements without medical indication, and iron can accumulate in vascular endothelial cells, the authors evaluated the association of oral iron supplementation with retinal/subretinal hemorrhage in patients with neovascular age-related macular degeneration. METHODS: A post hoc secondary data analysis of comparison of age-related macular degeneration treatments trials was performed. Participants were interviewed for use of oral iron supplements. Trained readers evaluated retinal/subretinal hemorrhage in baseline fundus photographs. Adjusted odds ratios from multivariate logistic regression models assessed the association between iron use and baseline hemorrhage adjusted by age, sex, smoking, hypertension, anemia, and use of antiplatelet/anticoagulant drugs. RESULTS: Among 1,165 participants, baseline retinal/subretinal hemorrhage was present in the study eye in 71% of 181 iron users and in 61% of 984 participants without iron use (adjusted odds ratio = 1.47, P = 0.04), and the association was dose dependent (adjusted linear trend P = 0.048). Iron use was associated with hemorrhage in participants with hypertension (adjusted odds ratio = 1.87, P = 0.006) but not without hypertension. The association of iron use with hemorrhage remained significant among hypertensive participants without anemia (adjusted odds ratio = 1.85, P = 0.02). CONCLUSION: Among participants of comparison of age-related macular degeneration treatments trials, the use of oral iron supplements was associated with retinal/subretinal hemorrhage in a dose-response manner. Unindicated iron supplementation may be detrimental in patients with wet age-related macular degeneration.

Dry Eye Assessment and Management (DREAM©) Study: Study design and baseline characteristics.

PURPOSE: Describe trial design and baseline characteristics of participants in the DRy Eye Assessment and Management (DREAM©) Study. DESIGN: Prospective, multi-center, randomized, double-masked "real-world" clinical trial assessing efficacy and safety of oral omega-3 (ω3) supplementation for the treatment of dry eye disease (DED). METHODS: RESULTS: Mean age of participants was 58.0 ±â€¯13.2 years. Mean OSDI score at baseline was 44.4 ±â€¯14.2. Mean conjunctival staining score (scale 0-6) was 3.0 ±â€¯1.4, corneal staining score (scale 0-15) was 3.9 ±â€¯2.7, tear break-up time was 3.1 ±â€¯1.5 s, and Schirmer test was 9.6 ±â€¯6.5 mm/5 min. CONCLUSIONS: DREAM© participants mirror real world patients who seek intervention for their DED-related symptoms despite their current treatments. Results regarding the efficacy of omega-3 supplementation will be helpful to clinicians and patients with moderate to severe DED who are considering omega-3 as a treatment. This trial design may be a model for future RCT's on nutritional supplements and DED treatments seeking to provide useful information for clinical practice. TRIAL REGISTRATION: ClinicalTrials.gov number NCT02128763.

n-3 Fatty Acid Supplementation for the Treatment of Dry Eye Disease.

BACKGROUND: Dry eye disease is a common chronic condition that is characterized by ocular discomfort and visual disturbances that decrease quality of life. Many clinicians recommend the use of supplements of n-3 fatty acids (often called omega-3 fatty acids) to relieve symptoms. METHODS: In a multicenter, double-blind clinical trial, we randomly assigned patients with moderate-to-severe dry eye disease to receive a daily oral dose of 3000 mg of fish-derived n-3 eicosapentaenoic and docosahexaenoic acids (active supplement group) or an olive oil placebo (placebo group). The primary outcome was the mean change from baseline in the score on the Ocular Surface Disease Index (OSDI; scores range from 0 to 100, with higher scores indicating greater symptom severity), which was based on the mean of scores obtained at 6 and 12 months. Secondary outcomes included mean changes per eye in the conjunctival staining score (ranging from 0 to 6) and the corneal staining score (ranging from 0 to 15), with higher scores indicating more severe damage to the ocular surface, as well as mean changes in the tear break-up time (seconds between a blink and gaps in the tear film) and the result on Schirmer's test (length of wetting of paper strips placed on the lower eyelid), with lower values indicating more severe signs. RESULTS: A total of 349 patients were assigned to the active supplement group and 186 to the placebo group; the primary analysis included 329 and 170 patients, respectively. The mean change in the OSDI score was not significantly different between the active supplement group and the placebo group (-13.9 points and -12.5 points, respectively; mean difference in change after imputation of missing data, -1.9 points; 95% confidence interval [CI], -5.0 to 1.1; P=0.21). This result was consistent across prespecified subgroups. There were no significant differences between the active supplement group and the placebo group in mean changes from baseline in the conjunctival staining score (mean difference in change, 0.0 points; 95% CI, -0.2 to 0.1), corneal staining score (0.1 point; 95% CI, -0.2 to 0.4), tear break-up time (0.2 seconds; 95% CI, -0.1 to 0.5), and result on Schirmer's test (0.0 mm; 95% CI, -0.8 to 0.9). At 12 months, the rate of adherence to treatment in the active supplement group was 85.2%, according to the level of n-3 fatty acids in red cells. Rates of adverse events were similar in the two trial groups. CONCLUSIONS: Among patients with dry eye disease, those who were randomly assigned to receive supplements containing 3000 mg of n-3 fatty acids for 12 months did not have significantly better outcomes than those who were assigned to receive placebo. (Funded by the National Eye Institute, National Institutes of Health; DREAM ClinicalTrials.gov number, NCT02128763 .).

Red blood cell fatty acid analysis for determining compliance with omega3 supplements in dry eye disease trials.

PURPOSE: To evaluate pill counts and red blood cell (RBC) membrane fatty acid profiles as measures of compliance with oral omega3 polyunsaturated fatty acids (ω3 PUFAs) and to compare the two techniques. METHODS: Sixteen dry eye disease subjects were given oral ω3 PUFA or placebo for 3 months. Compliance was measured by pill counts and blood tests at baseline and 3 months. The Wilcoxon signed-rank tests and rank-sum tests were used to compare changes from baseline and the difference between the two groups; Spearman correlation coefficients were used to assess the relationship of pill counts to changes in blood FAs. RESULTS: Pill counts for the ω3 (n=7) and placebo (n=9) groups showed a mean consumption of 4.39 and 4.76 pills per day, respectively. In the ω3 group, the median change from baseline was +1.46% for eicosapentaenoic acid (EPA) (P=0.03), +1.49% for docosahexaenoic acid (DHA) (P=0.08), and -1.91% for arachidonic acids (AA) (P=0.02). In the placebo group, median changes in all measured FAs were small and not statistically significant. The difference in change in FA levels between the two groups was significantly greater for EPA (P=0.01) and AA (P=0.04). The correlations between pill counts and changes in EPA (r=0.36, P=0.43) and DHA (r=0.17, P=0.70) were not strong. CONCLUSIONS: RBC FA analysis can be used to measure compliance in the active group and also monitor the placebo group for nonstudy ω3 intake. Low correlation of pill counts with blood levels suggests that pill counts alone may be inaccurate and should be replaced or supplemented with objective measures.

Characteristics of incident geographic atrophy in the complications of age-related macular degeneration prevention trial.

OBJECTIVE: To characterize the size, location, conformation, and features of incident geographic atrophy (GA) as detected by annual stereoscopic color photographs and fluorescein angiograms (FAs). DESIGN: Retrospective cohort study within a larger clinical trial. PARTICIPANTS: Patients with bilateral large drusen in whom GA developed during the course of the Complications of Age-related Macular Degeneration Prevention Trial (CAPT). METHODS: Annual stereoscopic color photographs and FAs were reviewed from 114 CAPT patients in whom GA developed in the untreated eye during 5 to 6 years of follow-up. Geographic atrophy was defined according to the Revised GA Criteria for identifying early GA.(23) Color-optimized fundus photographs were viewed concurrently with the FAs during grading. MAIN OUTCOME MEASURES: Size and distance from the fovea of individual GA lesions, number of areas of atrophy, and change in visual acuity (VA) when GA first developed in an eye. RESULTS: At presentation, the median total GA area was 0.26 mm(2) (0.1 disc area). Geographic atrophy presented as a single lesion in 89 (78%) eyes. The median distance from the fovea was 395 µm. Twenty percent of incident GA lesions were subfoveal and an additional 18% were within 250 µm of the foveal center. Development of GA was associated with a mean decrease of 7 letters from the baseline VA level compared with 1 letter among matched early age-related macular degeneration eyes without GA. Geographic atrophy that formed in areas previously occupied by drusenoid pigment epithelial detachments on average were larger (0.53 vs. 0.20 mm(2); P = 0.0001), were more central (50 vs. 500 µm from the center of the fovea; P<0.0001), and were associated with significantly worse visual outcome (20/50 vs. 20/25; P = 0.0003) than GA with other drusen types as precursors. CONCLUSIONS: Incident GA most often appears on color fundus photographs and FAs as a small, singular, parafoveal lesion, although a large minority of lesions are subfoveal or multifocal at initial detection. The characteristics of incident GA vary with precursor drusen types. These data can facilitate design of future clinical trials of therapies for GA. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Safety and efficacy of gene transfer for Leber's congenital amaurosis.

Leber's congenital amaurosis (LCA) is a group of inherited blinding diseases with onset during childhood. One form of the disease, LCA2, is caused by mutations in the retinal pigment epithelium-specific 65-kDa protein gene (RPE65). We investigated the safety of subretinal delivery of a recombinant adeno-associated virus (AAV) carrying RPE65 complementary DNA (cDNA) (ClinicalTrials.gov number, NCT00516477 [ClinicalTrials.gov]). Three patients with LCA2 had an acceptable local and systemic adverse-event profile after delivery of AAV2.hRPE65v2. Each patient had a modest improvement in measures of retinal function on subjective tests of visual acuity. In one patient, an asymptomatic macular hole developed, and although the occurrence was considered to be an adverse event, the patient had some return of retinal function. Although the follow-up was very short and normal vision was not achieved, this study provides the basis for further gene therapy studies in patients with LCA.

Macular pigment and lutein supplementation in choroideremia.

Choroideremia is an incurable X-linked retinal degeneration caused by mutations in the gene encoding Rab escort protein-1. A group of clinically defined and genotyped patients were studied to determine: (1) the degree of rod and cone dysfunction and structural abnormality in the central retina and the level of macular pigment; and (2) the response of macular pigment and foveal vision to a 6 month trial of supplementation with oral lutein (at 20 mg per day). Rod and cone-mediated function was measured with dark-adapted static perimetry; in vivo retinal structure was determined with optical coherence tomography; and macular pigment optical density was measured with heterochromatic flicker photometry. In this cohort of patients (ages 15-65 years), both rod- and cone-mediated central function declined with age as did central retinal thickness. Macular pigment levels did not differ between patients and male control subjects. Supplementation of oral lutein in a subset of patients led to an increase in serum lutein and macular pigment levels; absolute foveal sensitivity did not change. It is concluded that macular pigment density can be augmented by oral intake of lutein in patients with choroideremia. There was no short-term change in the central vision of the patients on the supplement, but long-term influences of lutein supplementation on disease natural history warrant further study.