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Purpose: To evaluate the effect of chewing versus smoking tobacco on corneal endothelial health. Methods: This was a cross-sectional, observational study analyzing 1797 eyes of 1797 patients. The study cohorts comprised tobacco smokers (N=605); tobacco chewers (N=595), and non-tobacco users (N=597). All the subjects underwent corneal endothelial evaluation by non-contact specular microscopy (EM 4000 Tomey Nishi-Ku, Nagoya, Aichi, Japan). Endothelial cell density (ECD; cells/mm2), coefficient of variation in cell size (CV; %), hexagonality (Hex; %), and central corneal thickness (CCT; µm) were recorded and compared among the 3 groups. Results: ECD (p<0.001) was significantly lower in chewers when compared to smokers, and was significantly highest in non-tobacco users, whereas CV (p<0.001) and CCT (p=0.009) were found to be significantly higher in chewers when compared to smokers and non-tobacco users. Hex (p<0.001) was significantly lower in chewers when compared with non-tobacco users and smokers. Multivariate linear regression analysis showed that increasing age was a significantly important factor in both the smokers and chewers in all the study parameters (negatively for ECD, Hex, and CCT; and positively for CV), except for CCT in chewers. Frequency and duration of smoking were significantly associated with higher CCT in smokers as well as chewers, whereas the duration of tobacco chewing negatively impacted ECD and Hex in chewers additionally. Conclusions: Chewing tobacco, especially long-term, appears to be detrimental to the corneal endothelial structure when compared to smoking.

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Purpose Chronic local inflammation underlies the pathogenesis of age-related macular degeneration (AMD) causing damage to the neurosensory retina. However, there is minimal research on systemic cell-mediated inflammation in AMD. Interleukin-4 (IL-4) is an immunoregulatory cytokine with an important role in modulating inflammation in chronic immune mediated disease. The purpose of this study was to: (1) investigate the role of systemic IL-4 in patients with intermediate AMD (iAMD) and in geographic atrophy (GA), an advanced form of AMD, compared to controls without AMD, and (2) determine if IL-4 levels are moderated by sex. Methods We examined plasma levels of IL-4 in patients with iAMD, GA, and controls without AMD included in the University of Colorado AMD registry (August 2014 to June 2021). Cases and controls were defined by multimodal imaging. IL-4 was measured by multiplex immunoassay. Data were analyzed using a nonparametric rank based linear regression model fit to IL-4. Results There were 199 patients with iAMD, 97 patients with GA, and 139 controls, with a percentage of female patients 61%, 55%, and 66%, respectively. We demonstrated significantly higher median IL-4 levels in GA (35.3; interquartile range [IQR] = 22.8–50.5) compared to iAMD (6.1; IQR = 2.2–11.3, P < 0.01) and controls (10.7; IQR = 5.0–16.8, P < 0.01). There were no significant differences in levels of IL-4 for cases and controls when stratified by sex. Conclusions These findings demonstrate a systemic immunological difference between iAMD and GA, indicating IL-4 may be a systemic biomarker for GA development. Translational Relevance The plasma biomarker IL-4 is significantly elevated in patients with GA.