Abstract
Glucocorticoids are widely used as an ophthalmic medication. A common, sight-threatening adverse event of glucocorticoid usage is ocular hypertension, caused by dysfunction of the conventional outflow pathway. We report that netarsudil, a rho-kinase inhibitor, decreased glucocorticoid-induced ocular hypertension in patients whose intraocular pressures were poorly controlled by standard medications. Mechanistic studies in our established mouse model of glucocorticoid-induced ocular hypertension show that netarsudil both prevented and reduced intraocular pressure elevation. Further, netarsudil attenuated characteristic steroid-induced pathologies as assessed by quantification of outflow function and tissue stiffness, and morphological and immunohistochemical indicators of tissue fibrosis. Thus, rho-kinase inhibitors act directly on conventional outflow cells to prevent or attenuate fibrotic disease processes in glucocorticoid-induced ocular hypertension in an immune-privileged environment. Moreover, these data motivate the need for a randomized prospective clinical study to determine whether netarsudil is indeed superior to first-line anti-glaucoma drugs in lowering steroid-induced ocular hypertension.
Highlights
Topical glucocorticoids (GCs) are routinely used after ocular surgery and to treat common ocular disorders such as uveitis and macular edema (Noble and Goa, 1998; Haeck et al, 2011)
intraocular pressure (IOP) was reduced to an average of 16.4 ± 4.9 mmHg, which is within the normal range
It is important to note that none of the patients were ‘tapered’ from their steroid during the first month of treatment, and the observed IOP lowering cannot be due to a removal of steroid
Summary
Topical glucocorticoids (GCs) are routinely used after ocular surgery and to treat common ocular disorders such as uveitis and macular edema (Noble and Goa, 1998; Haeck et al, 2011). 90% of people with primary open-angle glaucoma (POAG), the most common type of glaucoma, develop OHT after GC treatment (Becker, 1965) This is more than double the rate of the general population, likely because GCs increase extracellular matrix (ECM) material, cell contractility, and stiffness in an already dysfunctional conventional outflow pathway (Johnson et al, 1997; Zhou et al, 1998), as is found in POAG (Ronkkoet al., 2007; Tamm and Fuchshofer, 2007). ROCKi are the only available glaucoma drug class that directly targets and improves conventional outflow function (Schehlein and Robin, 2019) Their use is currently limited to patients whose IOPs are inadequately controlled by medications that target other ocular sites. We help define NT’s mechanism of restorative, anti-fibrotic action in treating steroid-induced OHT using our established mouse model (Li et al, 2019)
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