Regular Examinations for Toxic Maculopathy in Long-term Chloroquine or Hydroxychloroquine Users

Importance  According to evidence-based, expert recommendations, long-term users of chloroquine or hydroxychloroquine sulfate should undergo regular visits to eye care providers and diagnostic testing to check for maculopathy.

Objective  To determine whether patients with rheumatoid arthritis (RA) or systemic lupus erythematosus (SLE) taking chloroquine or hydroxychloroquine are regularly visiting eye care providers and being screened for maculopathy.

Design, Setting, and Participants  Patients with RA or SLE who were continuously enrolled in a particular managed care network for at least 5 years between January 1, 2001, and December 31, 2011, were studied. Patients’ amount of chloroquine or hydroxychloroquine use in the 5 years since the initial RA or SLE diagnosis was calculated, along with their number of eye care visits and diagnostic tests for maculopathy. Those at high risk for maculopathy were identified. Logistic regression was performed to assess potential factors associated with regular eye care visits (annual visits in ≥3 of 5 years) among chloroquine or hydroxychloroquine users, including those at highest risk for maculopathy.

Main Outcomes and Measures  Among chloroquine or hydroxychloroquine users and those at high risk for toxic maculopathy, the proportions with regular eye care visits and diagnostic testing, as well as the likelihood of regular eye care visits.

Results  Among 18 051 beneficiaries with RA or SLE, 6339 (35.1%) had at least 1 record of chloroquine or hydroxychloroquine use, and 1409 (7.8%) had used chloroquine or hydroxychloroquine for at least 4 years. Among those at high risk for maculopathy, 27.9% lacked regular eye care visits, 6.1% had no visits to eye care providers, and 34.5% had no diagnostic testing for maculopathy during the 5-year period. Among high-risk patients, each additional month of chloroquine or hydroxychloroquine use was associated with a 2.0% increased likelihood of regular eye care (adjusted odds ratio, 1.02; 95% CI, 1.01-1.03). High-risk patients whose SLE or RA was managed by rheumatologists had a 77.4% increased likelihood of regular eye care (adjusted odds ratio, 1.77; 95% CI, 1.27-2.47) relative to other patients.

Conclusions and Relevance  In this insured population, many patients at high risk for maculopathy associated with the use of chloroquine or hydroxychloroquine are not undergoing routine monitoring for this serious adverse effect. Future studies should explore factors contributing to suboptimal adherence to expert guidelines and the potential effect on patients’ vision-related outcomes.

Chloroquine and hydroxychloroquine sulfate are commonly used medications for rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and other connective tissue disorders.^1-5 More than 1.5 million persons have these conditions,⁶ and many of them receive hydroxychloroquine as the initial treatment.^7-10 Although hydroxychloroquine is safer than chloroquine, both medications can cause irreversible retinal toxic effects. Early in the course of these toxic effects, patients are often asymptomatic but exhibit abnormalities on fundus examination or diagnostic testing. Because no effective treatment exists for chloroquine-induced or hydroxychloroquine-induced retinopathy, early identification of this adverse effect and prompt discontinuation of therapy are essential.^11-13 Therefore, periodic monitoring with ocular examinations and diagnostic testing is crucial.

Although no gold standard test can identify retinopathy associated with the use of chloroquine or hydroxychloroquine, guidelines published by the American Academy of Ophthalmology¹⁴ (AAO) in 2002 recommend that all patients using these agents should have a baseline ocular examination within 1 year after chloroquine or hydroxychloroquine therapy commences. In addition, annual retinopathy screening is recommended for anyone with more than 5 years of exposure to chloroquine or hydroxychloroquine use or those at high risk for toxic maculopathy (including persons who are ≥60 years, those who take >3.0 mg/kg daily of chloroquine, those who take >6.5 mg/kg daily of hydroxychloroquine, or those who have obesity, renal or hepatic disease, or concomitant retinal disease). Retinal toxic effect screening involves a dilated eye examination, Amsler grid or Humphrey 10-2 visual field testing (Carl Zeiss Meditec), and optional color vision testing, fundus photography, fluorescein angiography, or multifocal electroretinography.

In addition, revised recommendations issued in 2011 defined high-risk patients as anyone with cumulative dosing exceeding 600 g of chloroquine or exceeding 1000 g of hydroxychloroquine sulfate.¹⁵ The updated guidelines no longer recommend Amsler grid testing, fundus photography, color vision testing, or fluorescein angiography for screening; instead, the use of spectral-domain optical coherence tomography (SD-OCT), multifocal electroretinography, or fundus autofluorescence is encouraged. Still recommended is annual screening of high-risk patients.

Retinal toxic effect rates from chloroquine or hydroxychloroquine use have been documented.^13,16-19 However, no prior study to date has investigated adherence to the AAO guidelines¹⁴ on ophthalmologic care for chloroquine or hydroxychloroquine users. We assessed whether patients with RA or SLE taking chloroquine or hydroxychloroquine had regular eye care visits and testing to check for maculopathy as the guidelines recommend.

This study was exempt from the requirement of University of Michigan Institutional Review Board approval. The database used (Clinformatics; OptumInsight) contains deidentified records of all beneficiaries in a nationwide managed care network. For January 1, 2001, to December 31, 2011, we accessed data on all eye care recipients, including patients with at least 1 International Classification of Diseases, Ninth Revision, Clinical Modification²⁰ code for any eye-related diagnosis (codes 360-379.9) or at least 1 Current Procedural Terminology (revision 4)²¹ code for any eye-related visit or diagnostic or therapeutic procedure (codes 65091-68899 and 92002-92499). The database includes claims for all ocular and nonocular medical conditions, records of all outpatient medications prescribed, and sociodemographic information (age, sex, race/ethnicity, education, and personal income) for the enrollees.^22-24

All persons with continuous plan enrollment for at least 5 years after their initial RA or SLE diagnosis were identified based on International Classification of Diseases, Ninth Revision, Clinical Modification billing codes (code 710.0 for SLE and code 714.0 for RA). To help address concerns about miscoding, we also required at least 1 confirmatory RA or SLE diagnosis made on a different date. Noncontinuously enrolled beneficiaries were excluded, as were enrollees with less than 5 years of postdiagnosis follow-up data.

We reviewed outpatient pharmacy records to identify chloroquine or hydroxychloroquine users on the basis of American Hospital Formulary Service drug class codes for Aralen hydrochloride, Aralen phosphate, chloroquine phosphate, hydroxychloroquine sulfate, and Plaquenil sulfate. We calculated the number of days for which hydroxychloroquine was prescribed in the 5-year period after patients’ first-documented RA or SLE diagnosis. Patients’ drug exposure in the 5-year period was categorized as none, less than 12 months, 12 to 23 months, 24 to 47 months, or 48 months or longer.

We determined the proportion of patients with RA or SLE who visited an eye care provider (ophthalmologist or optometrist) in each of the 5 years after the initial diagnosis. Visits were identified using Current Procedural Terminology (revision 4) codes (eTable 1 in the Supplement). Regular eye care was defined as annual visits in at least 3 of 5 years.

We used Current Procedural Terminology (revision 4) billing codes to assess the use of perimetry (codes 92081-92083), multifocal electroretinography (code 92275), fluorescein angiography (code 92235), and fundus photography (code 92250). We also assessed SD-OCT use (codes 92134 and 92135), which was not specifically recommended in the 2002 guidelines¹⁴ but became widely used in evaluating macular disease during the past decade and was included in the 2011 guidelines.¹⁵

On the basis of the 2002 guidelines,¹⁴ high risk for maculopathy associated with the use of chloroquine or hydroxychloroquine was identified in the database as patients 60 years or older or patients who used chloroquine or hydroxychloroquine for at least 1 of the first 5 years after the initial diagnosis of RA or SLE and had renal or hepatic disease or concomitant retinal disease (nonneovascular or neovascular age-related macular degeneration). Further details are listed in eTable 1 in the Supplement.

We also assessed eye services use for patients with the greatest chloroquine or hydroxychloroquine exposure. Identified were patients who had been prescribed these medications for at least 4 of 5 years examined.

In another analysis, we identified patients with RA or SLE who had no recorded chloroquine or hydroxychloroquine use during their first 3 years in the plan who subsequently began using one of these drugs. Among these new users, the proportion undergoing a baseline ocular examination in the first year of therapy was calculated.

According to the AAO guidelines,¹⁴ all patients with at least 5 years of chloroquine or hydroxychloroquine use should receive annual examinations for toxic maculopathy irrespective of other risk factors present. Therefore, we also analyzed (separately) patients with continuous chloroquine or hydroxychloroquine use for at least 5 years to assess eye visits and diagnostic testing in years 6 and 7.

Statistical analysis was performed with commercial software (SAS 9.3; SAS Institute). Visits, diagnostic testing, and chloroquine or hydroxychloroquine use were summarized using the means (SDs) for continuous variables and the frequencies and percentages for categorical variables.

We compared the frequency of eye visits and maculopathy-related diagnostic testing between patients with RA or SLE who did and did not have the greatest chloroquine or hydroxychloroquine exposure and between those with and without high maculopathy risk. χ² Test, Fisher exact test, and 2-sample t test were used for these comparisons.

In the first 3 of 4 logistic regression models, we evaluated (1) the potential effect of each additional month’s chloroquine or hydroxychloroquine use on the likelihood of receiving regular eye care among all patients with RA or SLE, (2) the odds of regular eye care among the patients at high risk for maculopathy associated with the use of chloroquine or hydroxychloroquine, and (3) potential factors associated with regular eye care among the highest chloroquine or hydroxychloroquine users. The fourth model calculated the odds of regular eye care among an aggregated sample of the users with the greatest chloroquine or hydroxychloroquine exposure and those with high maculopathy risk. Covariates for all models included age, sex, education, race/ethnicity, and personal income, as well as depression, hypertension with and without complications, long-term (≥3 months) oral corticosteroid use, diabetes mellitus with and without complications, and care by a rheumatologist (≥2 visits during the study). Complicated disease was defined as concomitant hypertension-related or diabetes mellitus–related end organ damage (eg, nephropathy) (eTable 1 in the Supplement). Regression analyses generated odds ratios (ORs) with 95% CIs. For all analyses, P < .05 was considered statistically significant.

In total, 18 051 enrollees met the inclusion criteria (eFigure 1 in the Supplement), 13 102 patients (72.6%) had RA, 3385 (18.8%) had SLE, and 1564 (8.7%) had at least 2 records of both conditions. The mean (SD) age of participants at enrollment was 51.6 (12.1) years. Among the participants, 78.2% (n = 14 114) were female; 83.5% (n = 13 850) were of white race/ethnicity, 5.3% (n = 883) were black, and 8.1% (n = 1342) were Latino (Table 1). Seventy-two percent (n = 12 964) of participants received care from a rheumatologist.

In total, 6339 patients (35.1%) had at least 1 record of chloroquine or hydroxychloroquine use in the first 5 years after the initial RA or SLE diagnosis. Thirty-six beneficiaries (0.6%) received chloroquine prescriptions only, 6248 (98.6%) received hydroxychloroquine prescriptions only, and 55 (0.9%) received at least 1 prescription of both medications. The mean (SD) duration of participants’ drug exposure was 824.1 (610.2) days. Overall, 11 712 patients (64.9%) took neither medication in the 5-year study period; 4930 patients (27.3%) received prescriptions for less than 4 years. A total of 1409 patients (7.8%) had used chloroquine or hydroxychloroquine for at least 4 years; these patients were considered the users with the greatest medication exposure.

Among the participants, 4214 (23.3%) saw no eye care provider in the 5-year period (Table 2). Each year, 67.6% to 72.5% of participants visited an eye care provider. Among 11 712 participants who were consistent nonusers of chloroquine or hydroxychloroquine, the proportions with eye care visits in 0, 1, 2, 3, and at least 4 of 5 years were 28.2%, 24.0%, 15.1%, 12.8%, and 19.9%, respectively, whereas the proportions among 6339 participants who had any chloroquine or hydroxychloroquine use were 14.3%, 17.9%, 16.4%, 14.3%, and 37.1%, respectively (Table 2).

Of the enrollees at high risk for maculopathy, 6.1% had no eye care visits in the 5-year period (Table 3). Overall, 66.3% to 71.9% of patients each year received specialty eye care. The proportions with visits in 1, 2, 3, and at least 4 of 5 years were 9.2%, 12.6%, 15.0%, and 57.0%, respectively. Among this group of high-risk patients, 72.1% had regular eye visits.

Among the highest chloroquine or hydroxychloroquine users, 7.5% saw no eye care provider in the 5-year period (Table 2). The proportion receiving eye care in a given year was 67.6% to 72.5%. The proportions with visits in 1, 2, 3, and at least 4 of the years were 8.7%, 10.6%, 14.3%, and 58.8%, respectively. The proportion of highest users with regular eye visits was 73.2%.

Among 959 patients taking chloroquine or hydroxychloroquine continuously for more than 5 years, an optometrist or ophthalmologist was seen by 753 (78.5%) in year 6 or 7, while the remaining 206 (21.5%) did not visit an eye care provider in year 6 or 7. Further details are listed in eTable 2 in the Supplement.

Overall, 1110 participants were new chloroquine or hydroxychloroquine users. Among them, 497 (44.8%) had a baseline eye care visit in the first 12 months after initiating therapy with chloroquine or hydroxychloroquine.

Approximately 75% of participants underwent no diagnostic tests for maculopathy in 5 years. Approximately 10% to 13% of patients underwent testing in any given year.

Of the participants with consistent nonuse of chloroquine or hydroxychloroquine, the proportions undergoing diagnostic testing in 0, 1, 2, 3, and at least 4 of 5 years were 84.4%, 8.4%, 3.2%, 1.8%, and 2.2%, respectively (Table 2). In comparison, these values were 51.2%, 18.8%, 11.6%, 7.8%, and 10.6% among patients with any chloroquine or hydroxychloroquine exposure.

Of patients at high risk for maculopathy, 65.5% received at least 1 form of diagnostic testing in 5 years; 63.2% had visual field testing and 16.1% underwent SD-OCT (Table 3). Among patients with the highest chloroquine or hydroxychloroquine use, 36.1% underwent no diagnostic testing for maculopathy in 5 years (Table 2). The proportions undergoing any diagnostic testing in 1, 2, 3, and at least 4 of 5 years were 18.0%, 13.7%, 11.6%, and 20.6%, respectively.

Among the patients with more than 5 years of chloroquine or hydroxychloroquine use, 47.8% had at least 1 visual field test, and 9.5% had SD-OCT in year 6 or 7. Further details are listed in eTable 2 in the Supplement.

After adjustment for potential confounders, chloroquine or hydroxychloroquine users had a 3.5% increased odds of receiving regular eye care for each additional month of use (adjusted OR, 1.04; 95% CI, 1.03-1.04) compared with nonusers. Other factors associated with increased odds of regular eye care include female sex (adjusted OR, 1.48; 95% CI, 1.36-1.62), older age (adjusted OR, 1.05; 95% CI, 1.04-1.05), higher education level (2 of 4 levels above the less than high school reference level were significant), and comorbid diabetes mellitus with complications (adjusted OR, 1.97; 95% CI, 1.75-2.23) or hypertension with complications (adjusted OR, 1.21; 95% CI, 1.08-1.36) (P < .004 for all comparisons). Black patients had an 18.6% decreased odds of regular eye care (adjusted OR, 0.81; 95% CI, 0.69-0.96) relative to patients of white race/ethnicity. Patients receiving care by rheumatologists had a 28.9% increased odds of regular eye care (adjusted OR, 1.29; 95% CI, 1.19-1.40) (Figure 1).

For patients at high risk for maculopathy, each additional month of chloroquine or hydroxychloroquine use was associated with a 2.0% increased likelihood of regular eye care (adjusted OR, 1.02; 95% CI, 1.01-1.03). Among the high-risk patients, older age (adjusted OR, 1.02; 95% CI, 1.01-1.04) and care by a rheumatologist (adjusted OR, 1.77; 95% CI, 1.27-2.47) were associated with increased likelihood of regular eye care visits (Figure 2).

Among the users with the greatest chloroquine or hydroxychloroquine exposure, female sex and older age were associated with elevated odds of regular eye care (P < .05 for both). The likelihood of regular eye care visits was increased by 58.4% among patients with care by a rheumatologist (adjusted OR, 1.58; 95% CI, 1.12-2.25) but was decreased by 56.4% among black patients (adjusted OR, 0.44; 95% CI, 0.21-0.88) (eFigure 2 in the Supplement).

The findings of an additional regression model assessing factors associated with receipt of regular eye care among the highest chloroquine or hydroxychloroquine users or the patients at high risk for toxic retinopathy are similar to those of the other models. Further details are listed in eTable 3 in the Supplement.

Among 6339 patients with RA or SLE who took chloroquine or hydroxychloroquine, more than half had regular eye care visits, and almost one-fifth underwent diagnostic testing annually for maculopathy as AAO guidelines recommend.¹⁴ However, among patients at highest risk for toxic maculopathy, more than one-quarter (27.9%) received no regular eye care; moreover, among the high-risk patients, 6.1% had no eye care visits, and 34.5% had no diagnostic testing for maculopathy during the 5-year period examined.

Although all enrollees had health insurance and theoretically had access to services, we identified many long-term chloroquine or hydroxychloroquine users and those at high risk for toxic maculopathy who were not routinely examined by eye care providers or given diagnostic tests to detect maculopathy. Likewise, among new chloroquine or hydroxychloroquine users, less than half had an ocular examination in their first year of therapy. Possible explanations for these findings are that chloroquine-prescribing or hydroxychloroquine-prescribing health care providers may be unfamiliar with the ocular adverse effects of long-term use or with the patient characteristics associated with high risk for macular toxic effects, or they may not appreciate the usefulness of preemptive screening before vision is lost. Alternatively, patients may be nonadherent to health care providers’ recommendations to seek eye care or may not understand the importance of maculopathy screening. Furthermore, communication between the prescribing clinicians and eye care providers may be poor, and some eye care providers may lack access to the appropriate diagnostic equipment.

Patients receiving care by a rheumatologist had increased odds of eye care visits. Rheumatologists may have more experience prescribing chloroquine or hydroxychloroquine and may be more familiar with the drugs’ adverse effects and the need for eye care provider referral. In addition, uveitis is common in patients with autoimmune conditions.^25,26 These patients often require long-term treatment for the ocular diseases associated with these conditions, leading to close rheumatologist-ophthalmologist collaboration. Another possibility is that patients of rheumatologists may have more severe disease, requiring higher chloroquine or hydroxychloroquine dosages for longer durations. In 2001, Fraenkel and Felson²⁷ reported that most surveyed rheumatologists valued routine retinopathy screening of chloroquine or hydroxychloroquine users. Our findings support these practice patterns.

Other factors associated with eye care visits in this setting include female sex, older age, higher education level, and complicated diabetes mellitus or hypertension. Visual impairment is known to worsen with increasing age, making older persons more inclined to seek eye care. According to published data, 1 in 6 US adults 70 years or older is visually impaired.²⁸ Women have higher risks for most major eye diseases, rendering them more likely to use eye care services.^29-32 We also found that better-educated patients had higher odds of eye care use, consistent with previous studies.^32-36 Similar to other studies,^32-34,37,38 black patients had decreased odds of eye care visits relative to patients of white race/ethnicity, although blacks often have more visual impairment.^28,39,40 Such disparities are particularly disconcerting because black patients herein had substantially reduced odds of eye care visits among the users with the greatest chloroquine or hydroxychloroquine exposure.

Mavrikakis and coworkers¹³ first reported toxic retinopathy after nonoverdose hydroxychloroquine therapy, raising concerns about long-term use. Among 1207 hydroxychloroquine users, Levy and colleagues¹⁷ described 1 patient with definite toxic effects and 5 patients with probable toxic effects. In the largest published series to date, by Wolfe and Marmor,¹⁸ involving 3995 patients, the toxic effect rate exceeded 1% among patients with 5 to 7 years of chloroquine or hydroxychloroquine use. In another study¹⁹ among 67 patients with cumulative doses exceeding 1250 g of hydroxychloroquine, 50% developed abnormalities detected on multifocal electroretinography associated with toxic maculopathy. As the toxic effect risk increases, screening becomes more important.

We used the 2002 AAO guidelines¹⁴ on screening for retinopathy associated with chloroquine and hydroxychloroquine use in our analysis because they were in place for much of the study period (2001-2011). The updated 2011 guidelines¹⁵ reflected the development of more sensitive diagnostic tests and recognized that the toxic effect risk is higher than previously realized.

Screening for toxic maculopathy could be improved by developing automated alert systems and incorporating them in electronic health records to identify high-risk patients. In addition, tool sets calculating patients’ cumulative chloroquine or hydroxychloroquine dose taken per ideal body weight may be developed and used in primary care settings, reminding health care providers to refer high-risk patients for eye care screening. Implementing pay-for-performance programs to incentivize physicians to improve screening rates may also help. Moreover, a practice improvement module on chloroquine and hydroxychloroquine screening could be offered to improve ophthalmologists’ rates of diagnostic testing. Educating non–eye care providers about the ocular adverse effects of chloroquine and hydroxychloroquine and better identifying patients at high risk for toxic maculopathy are also important. Programs to assist non–eye care providers at the point of care may also be helpful. Furthermore, pharmacists may have a role in educating chloroquine and hydroxychloroquine users.

Comanagement is an integral part of our health care system, which increasingly relies on specialization, but it comes with its own set of challenges. Improved communication among hydroxychloroquine-prescribing and chloroquine-prescribing clinicians, patients, and eye care providers could reduce the nonscreening of high-risk patients. Telemedicine may offer additional opportunities to enhance screening efforts. Retinal photography, increasingly available, offers improved access to subspecialty care.⁴¹ The SD-OCT images and nonmydriatic fundus photographs acquired by nonophthalmologists can be sent to eye care providers to determine which patients require referral for further evaluation.

This study has several strengths. Because all of the patients in our study had health insurance, they should have all (at least theoretically) had access to eye care services. Patients in the sample resided in communities throughout the country and received care from various types of health care providers in myriad practice settings. Unlike in cross-sectional studies, the patients were followed up for at least 5 years. Finally, claims data enabled accurate estimation of the duration and amount of chloroquine or hydroxychloroquine exposure, without reliance on patient self-report, which is of uncertain reliability.⁴²

Our study has several limitations. The database lacked information on height and weight (to calculate the milligrams per kilogram of chloroquine or hydroxychloroquine exposure), best-corrected visual acuity, and the presence of symptoms of metamorphopsias, which could influence eye care use. Likewise, diagnostic tests such as Amsler grid or color vision testing lack Current Procedural Terminology codes and were not studied. We also cannot deduce from the claims data whether each visit to and test conducted at eye care providers’ offices were done specifically to screen for chloroquine or hydroxychloroquine toxic effects, and we lacked information on chloroquine or hydroxychloroquine use before patients’ enrollment in the plan. Therefore, only cumulative exposure in the 5-year study period (not overall cumulative drug exposure) could be calculated. Also, SD-OCT imaging tests were recommended by the AAO¹¹ starting only in 2011, which may account for the substantial nonuse of this diagnostic test for much of the study period. Finally, our findings may be nongeneralizable to uninsured or underinsured patients, who likely have lower visit and testing rates.

We find that many chloroquine or hydroxychloroquine users, including patients at high risk for retinal toxic effects and long-term users for multiple years, are not undergoing regular visits to eye care providers and receiving diagnostic testing to check for maculopathy, as recommended by the AAO.^14,15 Future studies should identify reasons for nonadherence to the recommendations and ways of improving adherence.

Submitted for Publication: November 3, 2013; final revision received March 15, 2014; accepted March 22, 2014.

Corresponding Author: Joshua D. Stein, MD, MS, W. K. Kellogg Eye Center, Department of Ophthalmology and Visual Sciences, University of Michigan, 1000 Wall St, Ann Arbor, MI 48105 (jdstein@med.umich.edu).

Published Online: June 26, 2014. doi:10.1001/jamaophthalmol.2014.1720.

Author Contributions: Dr Stein had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Nika, Edwards, Lee, Stein.

Acquisition, analysis, or interpretation of data: Blachley, Edwards, Stein.

Drafting of the manuscript: Nika, Blachley, Stein.

Critical revision of the manuscript for important intellectual content: Blachley, Edwards, Lee.

Statistical analysis: Nika, Blachley.

Obtained funding: Lee.

Administrative, technical, or material support: Nika, Stein.

Study supervision: Edwards.

Conflict of Interest Disclosures: None reported.

Funding/Support: This study was supported by K23 Mentored Clinician Scientist Award 1K23EY019511 from the National Eye Institute (Dr Stein), by the Blue Cross Blue Shield of Michigan Foundation (Dr Stein), and by a Physician Scientist Award from Research to Prevent Blindness (Dr Stein).

Role of the Sponsor: The funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Previous Presentation: This study was presented in part at the Association for Research in Vision and Ophthalmology Annual Meeting; May 8, 2013; Seattle, Washington.