Getting to the Core of Netarsudil- Associated Honeycombing

Cases of reticular corneal epithelial oedema (RCEE) are on the rise. What’s behind this increase in ‘honeycombing’?

RCEE occurring after treatment with the Rho-associated protein kinase inhibitor (ROCK) netarsudil (Rhopressa, Alcon) is a growing problem. Approved for glaucoma treatment in the US and EU, the drug’s most common side effects include conjunctival hyperaemia, haemorrhage, and cornea verticillata.

RCEE, a rarer side effect, is usually encountered in patients treated with netarsudil who also have pre-existing corneal disease, such as corneal oedema. However, cases of RCEE, characterized by its honeycomb-like pattern of superficial epithelial bullae on the cornea, are increasing, reports Ursula Schlötzer-Schrehardt PhD.

To find out more, Professor Schlötzer-Schrehardt examined a 32-year-old patient with secondary open-angle glaucoma who developed RCEE following netarsudil administration. She wanted to determine whether ripasudil (Glanatec, Kowa Pharmaceuticals), another ROCK inhibitor currently approved for use in Japan, could be an effective treatment for the patient without the risk of developing or exacerbating RCEE.

Prof Schlötzer-Schrehardt considered two hypotheses to explain bullae development associated with honeycombing. The first suggested that improved corneal endothelial pump function from a shift from stromal oedema to the corneal epithelium was the cause. The second explored whether fluid entry from the stroma into the corneal epithelium due to impaired epithelial barrier function served as the culprit.

Both hypotheses were tested in vitro using primary human corneal endothelial cells (pHCEnC) and primary human corneal epithelial cells (pHCEpC). These were incubated with netarsudil and ripasudil at subclinical concentrations which would not induce cellular toxicity.

The first hypothesis resolved swiftly. Prof Schlötzer-Schrehardt reported that both netarsudil and ripasudil “improved endothelial pump function but showed no relevant difference in effects and supported the use of both drugs in clinical use for corneal endothelial dysfunction and restoration.”

The second hypothesis yielded more answers. Prof Schlötzer-Schrehardt pointed out that, as Rho-kinase activities can negatively affect cell barriers, causing epithelial bullae formation, ROCK inhibitors should stabilize proper cell function while also improving barrier function.

“Ripasudil would continuously upregulate all the molecules relevant [to the] cell matrix adhesion structure. On the other hand, netarsudil had no effect on these structural components—or even actively downregulated them,” Prof Schlötzer-Schrehardt said.

“Ripasudil appears to be superior to netarsudil in upregulating epithelial tight and adherens junctions, improving epithelial barrier function. It thereby enhances resistance to fluid entry into the epithelial layer from the stroma, preventing bullae formation.”

Prof Schlötzer-Schrehardt added that while RCEE-associated honeycombing caused by netarsudil use is serious, it is also reversible, as discontinuation of the drug results in the normalization of the cells after six days. She emphasized ROCK inhibitor drugs such as netarsudil do improve corneal endothelial function, but clinicians should be aware of their potential side effects on the corneal epithelium as well.

Prof Schlötzer-Schrehardt presented at the 2025 EuCornea congress in Prague.

Ursula Schlötzer-Schrehardt PhD is a scientist at the Friedrich-Alexander University of Erlangen-Nuremberg, Germany. ursula.schloetzer-schrehardt@uk-erlangen.de