Joshua D. Stein

Common Variants at 9p21 and 8q22 Are Associated with Increased Susceptibility to Optic Nerve Degeneration in Glaucoma

Optic nerve degeneration caused by glaucoma is a leading cause of blindness worldwide. Patients affected by the normal-pressure form of glaucoma are more likely to harbor risk alleles for glaucoma-related optic nerve disease. We have performed a meta-analysis of two independent genome-wide association studies for primary open angle glaucoma (POAG) followed by a normal-pressure glaucoma (NPG, defined by intraocular pressure (IOP) less than 22 mmHg) subgroup analysis. The single-nucleotide polymorphisms that showed the most significant associations were tested for association with a second form of glaucoma, exfoliation-syndrome glaucoma. The overall meta-analysis of the GLAUGEN and NEIGHBOR dataset results (3,146 cases and 3,487 controls) identified significant associations between two loci and POAG: the CDKN2BAS region on 9p21 (rs2157719 [G], OR = 0.69 [95%CI 0.63–0.75], p = 1.86×10−18), and the SIX1/SIX6 region on chromosome 14q23 (rs10483727 [A], OR = 1.32 [95%CI 1.21–1.43], p = 3.87×10−11). In sub-group analysis two loci were significantly associated with NPG: 9p21 containing the CDKN2BAS gene (rs2157719 [G], OR = 0.58 [95% CI 0.50–0.67], p = 1.17×10−12) and a probable regulatory region on 8q22 (rs284489 [G], OR = 0.62 [95% CI 0.53–0.72], p = 8.88×10−10). Both NPG loci were also nominally associated with a second type of glaucoma, exfoliation syndrome glaucoma (rs2157719 [G], OR = 0.59 [95% CI 0.41–0.87], p = 0.004 and rs284489 [G], OR = 0.76 [95% CI 0.54–1.06], p = 0.021), suggesting that these loci might contribute more generally to optic nerve degeneration in glaucoma. Because both loci influence transforming growth factor beta (TGF-beta) signaling, we performed a genomic pathway analysis that showed an association between the TGF-beta pathway and NPG (permuted p = 0.009). These results suggest that neuro-protective therapies targeting TGF-beta signaling could be effective for multiple forms of glaucoma.

The relationship between components of metabolic syndrome and open-angle glaucoma.

PURPOSE To determine whether an association exists between various components of metabolic syndrome (diabetes mellitus [DM], systemic arterial hypertension [HTN], hyperlipidemia, and obesity) and open-angle glaucoma (OAG) in a large, diverse group of individuals throughout the United States. DESIGN Longitudinal cohort study. PARTICIPANTS All beneficiaries aged ≥40 years continuously enrolled in a managed care network who had 1 or more visits to an eye care provider during 2001 to 2007 were identified. METHODS Billing codes were used to identify individuals with OAG and those with components of metabolic syndrome. Cox regression was used to determine the hazard of developing OAG in enrollees with individual components or combinations of components of metabolic syndrome, with adjustment for sociodemographic factors, systemic medical conditions, and other ocular diseases. MAIN OUTCOME MEASURES Hazard of developing OAG. RESULTS Of the 2 182 315 enrollees who met the inclusion criteria, 55090 (2.5%) had OAG. After adjustment for confounding factors, those with DM (hazard ratio [HR] = 1.35 [95% confidence interval [CI], 1.21-1.50]) or HTN (HR = 1.17 [95% CI, 1.13-1.22]) alone or in combination (HR = 1.48 [95% CI, 1.39-1.58]) had an increased hazard of developing OAG relative to persons with neither of these conditions. By contrast, persons with hyperlipidemia alone had a 5% decreased hazard of OAG (HR = 0.95 [95% CI, 0.91-0.98]). Comorbid hyperlipidemia attenuated the increased hazard between HTN (HR = 1.09 [95% CI, 1.05-1.12]) or DM (HR = 1.13 [95% CI, 1.05-1.21]) and OAG. CONCLUSIONS At a time when the prevalence of metabolic disorders in the United States, is increasing this study furthers our understanding of risk factors associated with OAG and helps identify persons who may be at increased risk for this condition.

Primary Open-Angle Glaucoma Preferred Practice Pattern® Guidelines

UNLABELLED PRIMARY OPEN-ANGLE GLAUCOMA PREFERRED PRACTICE PATTERN® GUIDELINES Evidence-based update of the Primary Open-Angle Glaucoma Preferred Practice Pattern® (PPP) guidelines, describing the diagnosis and management of patients with primary open-angle glaucoma with an algorithm for patient management and detailed recommendations for evaluation and treatment options.

Glaucoma associated with Boston type i keratoprosthesis

Purpose: To evaluate outcomes of the Boston type I keratoprosthesis (KPro) and associated incidence of glaucoma. Design: Retrospective cohort study. Participants: All patients who underwent KPro surgery at 1 institution from 2003 to 2009 with at least 3 months of follow-up. Methods: Preoperative visual acuity, diagnosis, history of glaucoma, and intraoperative and postoperative parameters were recorded. Statistical analysis was performed to identify factors that may influence increase in intraocular pressure (IOP) and glaucoma development or progression after surgery. Main Outcome Measures: Best-corrected visual acuity (BCVA), IOP, postoperative medical and surgical treatments for glaucoma, and KPro retention and complications. Results: Thirty-six KPro procedures were performed in 30 eyes of 29 patients with a mean (±SD) follow-up of 17 ± 19 months (range, 3–67 months). The main indication for KPro implantation was corneal graft failure (77%). Primary KPro procedures were performed in 23% of eyes for limbal stem cell deficiency secondary to chemical burns and aniridia and for herpetic disease. Median preoperative BCVA was hand motions with an overall improvement to 20/330 (range, 20/20 to hand motions) at 9 months postoperatively; mean BCVA was 20/600 (range, 20/40 to NLP) at the last follow-up. Twenty eyes (67%) had a preoperative history of glaucoma, with 8 of those eyes (40%) having undergone previous glaucoma surgery. Twenty-one eyes (70%) underwent concomitant glaucoma surgery. Postoperative increased IOP (22 mm Hg or higher) was noted in 15 eyes (50%), although definite glaucoma development or progression was noted in 7 of those 15 eyes (23% of total eyes). Mean BCVA at the last follow-up in eyes with glaucoma development or progression was 3/200 compared with 20/563 in the remaining 23 eyes. Six patients (20%) required repeat KPro implantation, and retroprosthetic membranes developed in 23 eyes (77%). No patient had vitritis or infectious endophthalmitis develop. Conclusions: The Boston type I KPro is an effective option for management of eyes with poor prognosis for primary or repeat penetrating keratoplasty. Visual potential is limited by preoperative comorbidities; however, glaucoma development or progression of preexisting glaucoma is a significant cause of postoperative visual loss. Rigorous perioperative management of elevated IOP is essential for long-term success of KPro surgery.

Short term use of oral corticosteroids and related harms among adults in the United States: population based cohort study

Objective To determine the frequency of prescriptions for short term use of oral corticosteroids, and adverse events (sepsis, venous thromboembolism, fractures) associated with their use. Design Retrospective cohort study and self controlled case series. Setting Nationwide dataset of private insurance claims. Participants Adults aged 18 to 64 years who were continuously enrolled from 2012 to 2014. Main outcome measures Rates of short term use of oral corticosteroids defined as less than 30 days duration. Incidence rates of adverse events in corticosteroid users and non-users. Incidence rate ratios for adverse events within 30 day and 31-90 day risk periods after drug initiation. Results Of 1 548 945 adults, 327 452 (21.1%) received at least one outpatient prescription for short term use of oral corticosteroids over the three year period. Use was more frequent among older patients, women, and white adults, with significant regional variation (all P<0.001). The most common indications for use were upper respiratory tract infections, spinal conditions, and allergies. Prescriptions were provided by a diverse range of specialties. Within 30 days of drug initiation, there was an increase in rates of sepsis (incidence rate ratio 5.30, 95% confidence interval 3.80 to 7.41), venous thromboembolism (3.33, 2.78 to 3.99), and fracture (1.87, 1.69 to 2.07), which diminished over the subsequent 31-90 days. The increased risk persisted at prednisone equivalent doses of less than 20 mg/day (incidence rate ratio 4.02 for sepsis, 3.61 for venous thromboembolism, and 1.83 for fracture; all P<0.001). Conclusion One in five American adults in a commercially insured plan were given prescriptions for short term use of oral corticosteroids during a three year period, with an associated increased risk of adverse events.

The Association Between Glaucomatous and Other Causes of Optic Neuropathy and Sleep Apnea

PURPOSE To determine whether an association exists between sleep apnea and open-angle glaucoma, normal-tension glaucoma, nonarteritic ischemic optic neuropathy (NAION), papilledema, or idiopathic intracranial hypertension (IIH) and whether treatment with continuous positive airway pressure affects the development of these conditions. DESIGN Retrospective, longitudinal cohort study. METHODS Billing records for beneficiaries 40 years of age and older enrolled in a large United States managed care network from 2001 through 2007 were reviewed. Incidence of open-angle glaucoma, normal-tension glaucoma, NAION, papilledema, and IIH were determined for the beneficiaries and were stratified by sleep apnea status. Cox regression analyses determined the hazard of each of these conditions developing among individuals with and without sleep apnea, with adjustment for sociodemographic, ocular, and medical conditions. RESULTS Among the 2 259 061 individuals in the study, 156 336 (6.9%) had 1 or more sleep apnea diagnoses. The hazard of open-angle glaucoma was no different among persons with sleep apnea either treated (adjusted hazard ratio [HR], 0.99; 95% confidence interval [CI], 0.82 to 1.18) or untreated with continuous positive airway pressure (HR, 1.01; 95% CI, 0.98 to 1.05) and individuals without sleep apnea. Similar findings were observed when assessing the hazard of normal-tension glaucoma developing (P > .05 for both comparisons). A significantly increased hazard of NAION developing (HR, 1.16; 95% CI, 1.01 to 1.33) and IIH (HR, 2.03; 95% CI, 1.65 to 2.49) was observed among individuals with sleep apnea who were not receiving continuous positive airway pressure therapy as compared with individuals without sleep apnea, although similar increased risks could not be demonstrated among continuous positive airway pressure-treated sleep apnea patients for these conditions (P > .05 for both comparisons). CONCLUSIONS Patients with untreated sleep apnea are at increased risk for IIH and NAION. Clinicians should consider appropriate screening for these conditions in sleep apnea patients.

The Quality of Life of Patients With Hypertension

The authors evaluated the self‐reported quality of life in patients with systemic arterial hypertension and assessed whether clinicians and normotensive respondents from the general public appreciate the impact that hypertension has on health‐related quality of life. A quality‐of‐life questionnaire was completed by 385 individuals: persons with hypertension (n=188), normotensive persons (n=148), and clinicians (n=49). A utility score, which represents ones self‐perceived health‐related quality of life, was generated for each group by using standardized time tradeoff questionnaires. Quality of life with hypertension was judged to be significantly higher according to affected individuals (mean utility score, 0.980), compared with normotensive persons (mean utility score, 0.948) and clinicians (mean utility score, 0.942), who were asked to assume that they had hypertension (p<0.0005). Clinicians and normotensive individuals tend to overemphasize the impact that hypertension has on quality of life, as compared to affected patients. The relatively low impact that hypertensive individuals indicate high blood pressure has on their quality of life May contribute to their lack of compliance with treatment regimens

A Longitudinal Analysis of Risk Factors Associated with Central Retinal Vein Occlusion

PURPOSE To identify risk factors associated with central retinal vein occlusion (CRVO) among a diverse group of patients throughout the United States. DESIGN Longitudinal cohort study. PARTICIPANTS All beneficiaries aged ≥ 55 years who were continuously enrolled in a managed care network for at least 2 years and who had ≥ 2 visits to an eye care provider from 2001 to 2009. METHODS Insurance billing codes were used to identify individuals with a newly diagnosed CRVO. Multivariable Cox regression was performed to determine the factors associated with CRVO development. MAIN OUTCOME MEASURES Adjusted hazard ratios (HRs) with 95% confidence intervals (CIs) of being diagnosed with CRVO. RESULTS Of the 494 165 enrollees who met the study inclusion criteria, 1302 (0.26%) were diagnosed with CRVO over 5.4 (± 1.8) years. After adjustment for known confounders, blacks had a 58% increased risk of CRVO compared with whites (HR, 1.58; 95% CI, 1.25-1.99), and women had a 25% decreased risk of CRVO compared with men (HR, 0.75; 95% CI, 0.66-0.85). A diagnosis of stroke increased the hazard of CRVO by 44% (HR, 1.44; 95% CI, 1.23-1.68), and hypercoagulable state was associated with a 145% increased CRVO risk (HR, 2.45; 95% CI, 1.40-4.28). Individuals with end-organ damage from hypertension (HTN) or diabetes mellitus (DM) had a 92% (HR, 1.92; 95% CI, 1.52-2.42) and 53% (HR, 1.53; 95% CI, 1.28-1.84) increased risk of CRVO, respectively, relative to those without these conditions. CONCLUSIONS This study confirms that HTN and vascular diseases are important risk factors for CRVO. We also identify black race as being associated with CRVO, which was not well appreciated previously. Furthermore, we show that compared with patients without DM, individuals with end-organ damage from DM have a heightened risk of CRVO, whereas those with uncomplicated DM are not at increased risk of CRVO. This finding may provide a potential explanation for the conflicting reports in the literature on the association between CRVO and DM. Information from analyses such as this can be used to create a risk calculator to identify possible individuals at greatest risk for CRVO.

Cost-effectiveness of Medications Compared With Laser Trabeculoplasty in Patients With Newly Diagnosed Open-Angle Glaucoma

OBJECTIVE To determine the most cost-effective treatment option for patients with newly diagnosed mild open-angle glaucoma: observation only, treatment with generic topical prostaglandin analogs (PGAs), or treatment with laser trabeculoplasty (LTP). METHODS Using a Markov model with a 25-year horizon, we compared the incremental cost-effectiveness of treating newly diagnosed mild open-angle glaucoma with PGAs, LTP, or observation only. RESULTS The incremental cost-effectiveness of LTP over no treatment is

Cost-Effectiveness of Bevacizumab and Ranibizumab for Newly Diagnosed Neovascular Macular Degeneration

16,824 per quality-adjusted life year. By comparison, the incremental cost-effectiveness of PGAs over no treatment is