Ocular steroids for retinal disease

While steroids have a long and sometimes chequered history in the treatment of a wide spectrum of ocular diseases, the latest-generation drugs may still have a potentially groundbreaking role to play in combating retinal diseases such as diabetic retinopathy and chronic central serous chorioretinopathy (CSCR). This is according to Professor Francine Behar-Cohen MD, PhD, who delivered this year’s EURETINA Medal Lecture as part of the official opening ceremony at the 17th EURETINA Congress. “Glucocorticoids are a miracle drug in ophthalmology. Ocular implants have been specifically designed for the local controlled release of glucocorticoids and this has been a major advance in the delivery of steroids into the posterior segment of the eye,” she said. In a broad overview of current knowledge pertaining to the use of ocular steroids, Prof Behar-Cohen, Professor in Ophthalmology at Descartes University, Paris, and Lausanne University, Switzerland, said that current treatments tend to focus on the use of high doses of corticosteroids, particularly glucocorticoids, which are not well tolerated over the long term. She noted that the first reports of topical and systemic steroids for eye diseases date back to 1951, building on Nobel Prize-winning research by Edward Kendall, Tadeus Reichstein and Philip Hench into the hormones of the adrenal cortex, their structure and biological effects. In the human body, corticosteroids are involved in a wide range of physiological processes including immune response and control of inflammation and are divided into two main classes: glucocorticoids and mineralocorticoids. Mineralocorticoids (MC) are vital in the regulation of electrolyte balance, while glucocorticoids help in the regulation of carbohydrate, fat and protein metabolism, and possess important vasoconstrictive and anti-inflammatory properties. Both corticosteroids have different effects, which are mediated by their own class of receptors on the epithelial cell surface (glucocorticoid receptor (GR) and mineralocorticoid receptor (MR) respectively). Professor Behar-Cohen’s group has demonstrated that the retina and the choroid are mineral-sensitive tissues, and that overactivation of the receptor by its natural ligand aldosterone induced retinal swelling with most of the features of acute CSCR in a rat model. Importantly, MR overactivation in other organs has been implicated in endothelial dysfunction, vascular inflammation, metabolic syndrome and heart fibrotic remodelling after myocardial infarction. Based on this finding, her group hypothesised that CSCR and other related phenotypes could be the ocular phenotypic expression of MR vascular overactivation, and thus proposed oral mineralocorticoid receptor antagonists (MRA) as a treatment option. An initial pilot study in 2012 of 13 patients with CSCR and persistent subretinal fluid (SRF) treated with oral eplerenone showed promising results, with a significant reduction in central macular thickness, subretinal fluid level and an improvement in visual acuity. These positive outcomes were repeated in a prospective, randomised, controlled study of spironolactone in 16 patients, which showed that the drug significantly reduced both the SRF and the subfoveal choroidal thickness compared to placebo. Other groups have subsequently reported successful use of MRA for non-resolving CSCR. Further prospective randomised trials are now needed to better elucidate the precise role of MR antagonists in the management of the disease and determine optimal treatment strategies, concluded Prof Behar-Cohen. “We know that MR overactivation is pathogenic in the retina. MRA have potential in retinal diseases but no biomarker is yet available to help us identify which patients will benefit the most from this treatment. Discovering downstream corticoid molecular targets may help us to develop optimised drugs with fewer side-effects, as well as more specific drugs for eye diseases in the future,” she said.