THE EFFECTIVENESS OF RHO KINASE (ROCK) INHIBITORS IN FUCHS' ENDOTHELIAL CORNEAL DYSTROPHY: A SYSTEMATIC REVIEW

Fuchs’ Endothelial Corneal Dystrophy (FECD) is a prevalent age-related condition causing visual dysfunction, affecting over 4.5% of individuals over 50. It is progressive, leading to corneal endothelial cell loss and oedema, reducing visual acuity. In advanced stages, corneal transplantation is required, making it the leading indication for keratoplasty in the developed world. Rho kinase inhibitors (ROCKi) have recently emerged as a potential medical treatment to promote endothelial regeneration and delay or avoid surgery. However, current evidence regarding indications, safety, efficacy, and long-term outcomes of ROCKi in FECD remains limited. This systematic review aims to synthesise the current evidence base to guide clinical practice and identify research gaps.

Systematic review of available clinical studies for the indications, effectiveness and safety of ROCKi in FECD (PROSPERO ID: CRD420251087464).

A systematic search of MEDLINE, PubMed, Embase, CENTRAL and Web of Science was conducted from inception using terms for FECD and ROCKi. Eligible studies included clinical investigations in FECD assessing ROCKi as monotherapy, combined with Descemet Stripping Only (DSO) or cell-based therapy. Pre-clinical studies, case reports, editorials and studies involving gene-based modification of ROCK activity were excluded. Two reviewers independently screened studies and extracted data. The risk of bias was assessed using the RoB 2 and ROBINS-I tools.

10 studies met inclusion criteria (4 randomised and 6 non-randomised studies). ROCKi were evaluated across various stages of FECD, as monotherapy (2 studies; n= 29-40), combined with DSO (6 studies; n=12-50), and for endothelial preservation in cataract surgery (2 studies; n=41-48). ROCKi monotherapy significantly reduced central corneal thickness (CCT) and improved best-corrected visual acuity (BCVA) in symptomatic FECD compared to placebo. A study assessing 2 dosing regimens of Netarsudil demonstrated complete resolution of corneal oedema in 12.5% (n=40). Across 6 studies combining ROCKi with DSO (± phacoemulsification) corneal clearance was achieved in 67-100% of eyes (n=109/111). Combined treatment generally accelerated recovery (4-7 weeks vs 6.5-18 weeks with DSO alone), improved BCVA and reduced CCT. In cataract surgery, a study showed that ROCKi reduced endothelial cell loss, while another study demonstrated preserved CCT and improved BCVA compared to control. The most common side effects were conjunctival hyperaemia and mild irritation. Overall risk of bias was mostly low in randomised trials and low to serious in non-randomised studies, based on the RoB 2 and ROBINS-I tools respectively.

ROCKi show clear benefit when combined with DSO in FECD. Evidence for their use as monotherapy or for endothelial preservation in cataract surgery is promising but limited. Larger studies are required to fully establish their clinical effectiveness and safety profile in these indications.