Purpose
To evaluate whether pseudoexfoliation glaucoma (PXG) is associated with an increased hazard of developing central serous chorioretinopathy (CSCR) compared with primary open-angle glaucoma (POAG).
Design
Retrospective cohort study using a multicenter, real-world electronic health record database.
Subjects
Adults aged ≥ 18 years diagnosed with PXG (study group) or POAG (control group).
Methods
We obtained deidentified patient data from the TriNetX U.S. Collaborative Network. Patients with a history of age-related macular degeneration (AMD) or prior anti-vascular endothelial growth factor (anti-VEGF) therapy were excluded. We performed multivariable Cox proportional hazards models to estimate adjusted hazard ratios (aHRs) with 95% confidence intervals (CIs), adjusting for baseline demographics; ocular and systemic comorbidities; psychiatric conditions; medication exposures (including corticosteroids); and prior ocular surgeries.
Main Outcome Measures
The primary outcome was the development of CSCR within 1- and 5-year follow-up periods following the glaucoma diagnoses.
Results
A total of 10,347 patients with PXG and 205,065 with POAG were included. In the Cox proportional hazards model, PXG was significantly associated with a higher hazard of developing CSCR compared with POAG. The aHR for CSCR was 1.807 (95% CI, 1.041-3.136; P =.036) at the 1-year follow-up and 1.631 (95% CI, 1.014-2.622; P =.044) at 5 years.
Conclusions
PXG is associated with an increased hazard of developing CSCR compared with POAG. These findings suggest that PXG may be associated with an increased susceptibility to posterior segment vascular pathology. Prospective studies incorporating longitudinal imaging are warranted to further elucidate shared choroidal mechanisms underlying this association.
INTRODUCTION
P seudoexfoliation syndrome (PXF) is an age -related systemic condition characterized by the accumulation of fibrillar extracellular material on ocular and extraocular tissues. This abnormal material classically causes predominantly ocular manifestations, including increased outflow resistance in the trabecular meshwork, resulting in the most common type of secondary open-angle glaucoma and zonular instability. ,,, Systemically, PXF is associated with widespread extracellular matrix alterations, with the presence of pseudoexfoliative material in the skin, heart, lungs, liver, kidneys, meninges, and vascular endothelium. PXF has been linked to increased cardiovascular and cerebrovascular morbidity, potentially mediated by fibrillopathy-induced endothelial dysfunction and aberrant extracellular matrix remodeling; however, these associations have not been consistently observed across studies.
This systemic vascular involvement of PXF has raised interest in whether similar alterations affect the choroidal circulation, given its uniquely high blood flow. A prior study showed an association between pseudoexfoliation glaucoma (PXG) and deep peripapillary choroidal vasculopathy. This supports the presence of broader ocular microvascular dysfunction, suggesting that choroidal vascular dysregulation may contribute to disease pathogenesis. Furthermore, altered nitric oxide signaling, oxidative stress, and elastin abnormalities within choroidal vessels have been proposed as potential mechanisms underlying these changes. , These vascular abnormalities may compromise choroidal autoregulation, providing a possible biological link between PXG and susceptibility to central serous chorioretinopathy (CSCR).
CSCR is a pachychoroid spectrum disorder characterized by dilated outer choroidal vessels (pachyvessels) and focal disruption of the retinal pigment epithelium (RPE), leading to serous detachment of the overlying neurosensory retina. Patients with CSCR exhibit impaired endothelium-dependent flow-mediated vasodilation, supporting the presence of peripheral endothelial dysfunction. CSCR has been classically associated with male sex (defined as a biological variable), corticosteroid exposure, and psychosocial stress. ,
Given these shared vascular and endothelial features, the purpose of this study is to assess the association between PXG and the development of CSCR, compared with that of primary open-angle glaucoma (POAG).
METHODS
Data Source
This retrospective cohort study used deidentified patient data from TriNetX. For this analysis, we accessed data from approximately 131 million patients across 70 United States (U.S.) health care organizations within the TriNetX U.S. Collaborative Network in October 2025. Because only deidentified data were used, the study was deemed exempt from Institutional Review Board (IRB) approval by the University of Arkansas for Medical Sciences. The research adhered to the ethical principles of the Declaration of Helsinki (2013 version) and followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines. Diagnoses were identified using International Classification of Diseases, Tenth Revision (ICD-10) codes. Diagnoses recorded before 2015 using the Ninth Revision (ICD-9) were internally mapped to ICD-10 equivalents to ensure consistency across health care organizations. Procedures were captured using Current Procedural Terminology (CPT) codes, and medications were identified using RxNorm, HCPCS (Healthcare Common Procedure Coding System), and Anatomical Therapeutic Chemical (ATC) classifications.
Inclusion/Exclusion Criteria and Study Groups
The study compared adults (≥18 years) diagnosed with PXG (ICD-10 code H40.14) and those with POAG (ICD-10 code H40.11). We excluded individuals with overlapping diagnoses, prior diagnoses of nonexudative (H35.31) or exudative (H35.32) age-related macular degeneration (AMD), or previous exposure to anti-vascular endothelial growth factor (anti-VEGF) therapies such as ranibizumab (RxNorm: 595 060; HCPCS: J2778), aflibercept (RxNorm:1 232 150; HCPCS: J0178), brolucizumab (RxNorm:2 204 915; HCPCS: J0179), faricimab (RxNorm:2 591 519; HCPCS: J2777), pegaptanib (RxNorm:498 509; HCPCS: J2503), and bevacizumab (RxNorm:253 337; HCPCS: J9035, HCPCS: C9257). Additionally, any patients with established diagnoses of CSCR prior to the index were excluded in order to assess for the development of the diagnosis during the observation period.
To ensure active ophthalmologic follow-up, patients in both cohorts were required to have at least 3 documented ophthalmology visits during the study period. The index event was defined as the first qualifying diagnosis of PXG or POAG with all inclusion and exclusion criteria being met, and outcomes were assessed over a 1- and 5-year follow-up period, spanning from October 1, 2004, to October 1, 2024. Patients who entered the cohort closer to 2024 and did not have sufficient follow-up to complete the 5-year time point were excluded from the 5-year analysis ( Figure 1 ).
Flowchart illustrating the inclusion and exclusion criteria of the studied populations.
Clinical Endpoints
The clinical outcome assessed was the development of CSCR (ICD-10: H35.71) among patients with PXG compared to those with POAG.
Statistical Analysis
We performed a Cox proportional hazards model to estimate adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs) for the development of the outcome of interest. Statistical significance was defined as a 2-sided p -value <.05. In the model, we adjusted for a comprehensive set of demographics, systemic, ophthalmic, procedural, pharmacologic (including systemic and topical steroids), laboratory, and socioeconomic variables to minimize potential confounding. A comprehensive list can be found in E-supplement 1 . We included ophthalmic procedures in the adjustment to account for differences in surveillance intensity between groups and to reduce potential misclassification of CSCR, particularly in the context of postoperative macular edema, given the absence of detailed imaging confirmation.
Baseline characteristics were summarized using descriptive statistics, presenting continuous variables as means with standard deviation (SD) and categorical variables as percentages. All analyses were performed on the TriNetX analytics platform, with a 2-sided P value of <.05 considered statistically significant.
RESULTS
Baseline Characteristics
The analysis included 10,347 patients with PXG and 205,065 with POAG. At baseline, patients with PXG were older (73.9 ± 10.1 vs 67.9 ± 12.9 years) and more frequently female (62.9% vs 53.2%). The PXG cohort had a higher proportion of White patients (79.5% vs 52.8%) and a lower proportion of African American (5.5% vs 32.1%) and Hispanic (4.9% vs 6.9%) patients compared with POAG ( Table 1 ).
Table 1
Baseline Demographic Characteristics of Patients with Pseudoexfoliation Glaucoma (PXG) vs Those with Primary Open-Angle Glaucoma (POAG).
| Demographics | PXG n, (%) n = 10,347 | POAG n, (%) n = 205,065 | Standard Difference | P -value |
|---|---|---|---|---|
| Age at Index (mean ± SD) | 73.9 ± 10.1 | 67.9 ± 12.9 | 0.521 | <.001 |
| Sex | ||||
| Male | 3045 (37.0%) | 77,859 (46.8%) | 0.198 | <.001 |
| Female | 5173 (62.9%) | 88,573 (53.2%) | 0.198 | <.001 |
| Ethnicity | ||||
| Hispanic or Latino | 399 (4.9%) | 11,516 (6.9%) | 0.088 | <.001 |
| Not Hispanic or Latino | 6405 (77.9%) | 121,542 (73.0%) | 0.114 | <.001 |
| Unknown Ethnicity | 1413 (13.8%) | 33,842 (16.7%) | 0.0727 | <.001 |
| Race | ||||
| White | 6531 (79.5%) | 87,926 (52.8%) | 0.586 | <.001 |
| Black or African American | 451 (5.5%) | 53,390 (32.1%) | 0.724 | <.001 |
| American Indian or Alaska Native | 26 (0.3%) | 587 (0.4%) | 0.006 | .586 |
| Asian | 227 (2.8%) | 7223 (4.3%) | 0.085 | <.001 |
| Native Hawaiian or Other Pacific Islander | 10 (0.1%) | 268 (0.2%) | 0.01 | .382 |
| Unknown Race | 558 (6.8%) | 11,277 (6.8%) | 0.001 | .964 |
| Other Race | 421 (5.1%) | 5771 (3.5%) | 0.082 | <.001 |
Systemic comorbidities were generally similar across groups, although diabetes mellitus and obesity were more prevalent in POAG, whereas thyroid disorders were more common in PXG. Cataract and vitreous degeneration were more common in PXG ( Table 2 ).
Table 2
Baseline Systemic and Ocular Comorbidities Characteristics as Well as, Medication Usage of Patients With Pseudoexfoliation Glaucoma (PXG) vs Those with Primary Open-Angle Glaucoma (POAG).
| Diagnoses | PXG n, (%) n = 10,347 | POAG n, (%) n = 205,065 | Standard Difference | P -value |
|---|---|---|---|---|
| Systemic Comorbidities | ||||
| Hypertensive diseases | 4792 (46.9) | 97,949 (48.2) | 0.025 | .027 |
| Ischemic heart diseases | 1502 (14.7) | 27,594 (13.6) | 0.031 | .006 |
| Diabetes mellitus | 2064 (20.2) | 56,609 (27.9) | 0.182 | <.001 |
| Chronic kidney disease | 807 (7.9) | 19,673 (9.7) | 0.065 | <.001 |
| Chronic lower respiratory diseases | 1533 (15.0) | 30,232 (14.9) | 0.002 | .894 |
| Sleep disorders | 1502 (14.7) | 31,247 (15.4) | 0.018 | .12 |
| Disorders of lipoprotein metabolism | 4281 (41.9) | 81,789 (40.3) | 0.032 | .005 |
| Overweight and obesity | 1001 (9.8) | 30,029 (14.8) | 0.152 | <.001 |
| Disorders of thyroid gland | 1778 (17.4) | 28,609 (14.1) | 0.092 | <.001 |
| Cushing’s syndrome | 10 (0.1) | 203 (0.1) | 0.013 | .213 |
| Hyperaldosteronism | 10 (0.1) | 203 (0.1) | 0.003 | .786 |
| Benign neoplasm of adrenal gland | 41 (0.4) | 812 (0.4) | 0.007 | .548 |
| Malignant neoplasm of adrenal gland | 10 (0.1) | 81 (0.0) | 0.042 | <.001 |
| Enteropathic arthropathies | 0 (0.0) | 0 (0.0) | 0.018 | .24 |
| Psoriasis | 143 (1.4) | 2638 (1.3) | 0.006 | .579 |
| Systemic lupus erythematosus | 31 (0.3) | 1217 (0.6) | 0.038 | .003 |
| Rheumatoid arthritis with rheumatoid factor | 31 (0.3) | 1015 (0.5) | 0.041 | .001 |
| Other rheumatoid arthritis | 204 (2.0) | 4464 (2.2) | 0.015 | .19 |
| Other systemic involvement of connective tissue | 286 (2.8) | 4261 (2.1) | 0.05 | <.001 |
| Other specified immune mechanism disorders | 20 (0.2) | 406 (0.2) | 0.006 | .632 |
| Ocular Comorbidities | ||||
| Age-related cataract | 7735 (75.7) | 94,186 (46.4) | 0.63 | <.001 |
| Other cataract | 4485 (43.9) | 38,957 (19.2) | 0.552 | <.001 |
| Myopia | 1011 (9.9) | 24,147 (11.9) | 0.065 | <.001 |
| Presbyopia | 1778 (17.4) | 31,247 (15.4) | 0.053 | <.001 |
| Hypermetropia | 899 (8.8) | 12,783 (6.3) | 0.096 | <.001 |
| Background retinopathy & vascular changes | 204 (2.0) | 5885 (2.9) | 0.055 | <.001 |
| Retinal detachments and breaks | 347 (3.4) | 8522 (4.2) | 0.041 | .001 |
| Retinal vascular occlusions | 235 (2.3) | 4870 (2.4) | 0.011 | .327 |
| Disorders of globe | 215 (2.1) | 6087 (3.0) | 0.054 | <.001 |
| Vitreous hemorrhage | 133 (1.3) | 2435 (1.2) | 0.011 | .326 |
| Vitreous degeneration | 1369 (13.4) | 17,855 (8.8) | 0.146 | <.001 |
| Vitreomacular adhesion | 61 (0.6) | 812 (0.4) | 0.033 | .001 |
| Other disorders of vitreous body | 10 (0.1) | 609 (0.3) | 0.036 | .006 |
| Unspecified disorder of vitreous body | 0 (0.0) | 0 (0.0) | 0.03 | .051 |
| Behavioral Comorbidities | ||||
| Depressive episode | 1185 (11.6) | 23,533 (11.6) | <0.001 | .987 |
| Major depressive disorder, recurrent | 276 (2.7) | 6493 (3.2) | 0.03 | .011 |
| Phobic anxiety disorders | 51 (0.5) | 1217 (0.6) | 0.006 | .58 |
| Other anxiety disorders | 1165 (11.4) | 21,710 (10.7) | 0.023 | .043 |
| Reaction to severe stress & adjustment disorders | 409 (4.0) | 9131 (4.5) | 0.026 | .027 |
| Specific personality disorders | 20 (0.2) | 609 (0.3) | 0.02 | .104 |
| Nicotine dependence | 501 (4.9) | 15,421 (7.6) | 0.109 | <.001 |
| Alcohol-related disorders | 215 (2.1) | 5885 (2.9) | 0.048 | <.001 |
| Cocaine-related disorders | 20 (0.2) | 1623 (0.8) | 0.084 | <.001 |
| Medications | ||||
| Corticosteroids | 4568 (44.7) | 83,585 (41.2) | 0.069 | <.001 |
| HMG CoA reductase (Statin) | 3976 (38.9) | 77,737 (38.3) | 0.012 | .287 |
| Beta Blockers/ Related | 4148 (40.6) | 97,392 (48.0) | 0.15 | <.001 |
| Diuretics | 3115 (30.5) | 64,523 (31.8) | 0.029 | .011 |
| ACE inhibitors | 2238 (21.9) | 47,955 (23.5) | 0.039 | .001 |
| Calcium channel blockers | 2043 (20.0) | 47,876 (23.6) | 0.088 | <.001 |
| Angiotensin II inhibitor | 1533 (15.0) | 31,045 (15.3) | 0.008 | .486 |
| Alpha blockers | 909 (8.9) | 18,666 (9.2) | 0.011 | .319 |
| Insulin | 869 (8.5) | 24,959 (12.3) | 0.126 | <.001 |
| Hypoglycemic agents, Other | 123 (1.2) | 4870 (2.4) | 0.09 | <.001 |
| Oral hypoglycemic agents | 1195 (11.7) | 35,725 (17.6) | 0.166 | <.001 |
| Sildenafil | 286 (2.8) | 7915 (3.9) | 0.064 | <.001 |
| Nitroprusside | 22 (0.3) | 406 (0.2) | 0.01 | .369 |
| Nitroglycerin | 747 (7.3) | 13,594 (6.7) | 0.023 | .04 |
| Isosorbide | 194 (1.9) | 3877 (1.9) | <0.001 | .976 |
| Isosorbide dinitrate | 61 (0.6) | 1623 (0.8) | 0.02 | .094 |
| Antidepressants | 2206 (21.6) | 41,187 (20.4) | 0.028 | .011 |
| Antipsychotics | 494 (4.8) | 11,160 (5.5) | 0.032 | .006 |
| Antiglaucoma medications | 3463 (33.9) | 131,885 (65.0) | 0.656 | <.001 |
| Miotics, topical ophthalmic | 378 (3.7) | 7509 (3.7) | <0.001 | .988 |
| Sympathomimetics (Adrenergics) | 2248 (22.0) | 41,569 (20.5) | 0.036 | .001 |
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