Glucocorticoid-induced ocular hypertension: origins and new approaches to minimize

ABSTRACT

Introduction

Glucocorticoids (GCs) have unique actions in their combined anti-inflammatory and immunosuppressive activities and are among the most commonly prescribed drugs, particularly for inflammatory conditions. They are often used clinically to treat inflammatory eye diseases like uveitis, optic neuritis, conjunctivitis, keratitis, and others, but are often accompanied by side effects, like ocular hypertension that can be vision threatening.

Areas covered

The review will focus on the complex molecular mechanism of action of GCs that involve both transactivation and transrepression and their use therapeutically that can cause significant systemic side effects, particularly ocular hypertension that can lead to glaucoma.

Expert Opinion

While we are still unclear as to all the mechanisms responsible for GC-induced ocular hypertension, however, there are potential novel therapies that are in development that can separate some of the anti-inflammatory therapeutic efficacy from their ocular hypertension side effect. This review provides some insight into these approaches.

KEYWORDS:

• Glucocorticoids
• ocular hypertension
• glaucoma
• glucocorticoid molecular mechanisms
• SEGRAs

Article Highlights

• It has been over fifty years since the first report of steroid-induced ocular hypertension resulting from chronic glucocorticoid (GC) administration, particularly from their use in ocular inflammation.

• Glucocorticoid ocular hypertension responsiveness varies within the normal population with 5% of individuals having a high IOP following GC administration and 33% with a moderate response.

• Primary open-angle glaucoma patients almost all respond with an elevation in intraocular pressure following the ocular delivery of GCs.

• Present genome-wide association studies (GWAS data) on GC responsiveness have not identified specific genes responsible for this difference in responsiveness. However, research efforts have identified the subtype of the glucocorticoid receptor, GRβ, may play a role in GC responsiveness. GC OH is dependent on GC potency, route of administration, duration of therapy, and individual susceptibility.

• Novel approaches to separate the anti-inflammatory action from its effects on intraocular pressure resulted in a new class of Selective Glucocorticoid Receptor Agonists (SEGRAs) that differentiate the transactivation from transrepression effects of GCs.

Declaration of interest

Thomas Yorio and Abbott F. Clark have received previous funding from the National Institutes of Health (NIH) for this study. Guarang C. Patel is also an employee of Regeneron. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer Disclosures

A reviewer on this manuscript has disclosed that they received honoraria for consultation and lecture fees from Allergan and Alimera. Peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.

Correction Statement

This article has been republished with minor changes. These changes do not impact the academic content of the article.

Additional information

Funding

Manuscript has been funded in part by the National Institutes of Health (grant 2 R01 EY016242).