More than half of DME patients respond well to anti-VEGF therapies; however, inflammation in a significant proportion of cases does not subside with such therapeutic approaches alone (2). Both VEGF-dependent and -independent pathways are suggested to be involved in DME; in rDME, the latter has more pronounced effects than the former (7). VEGF overexpression in rDME triggers downstream pathways involving Rho/ROCK signaling, capable of independently promoting a retinal inflammatory milieu and disrupting the blood-retinal barrier integrity. The delay between VEGF overexpression and Rho/ROCK pathway upregulation may explain the failure of anti-VEGF therapies in controlling rDME (7). Moreover, Rho/ROCK pathway upregulation promotes inflammation and leukocyte adhesion to the endothelial surface (8) and exerts vasoconstrictive and apoptotic effects on endothelial cells via inhibiting endothelial nitric oxide synthesis (9).
We have previously reported the favorable outcome of combined fasudil and bevacizumab intravitreal administration in rDME compared to bevacizumab monotherapy (4), but data on ROCK-inhibitors monotherapy in rDME was lacking. An in-vivo study on Kimba mice has shown that ripasudil (a selective ROCK-inhibitor) could suppress the expression of some inflammatory cytokines present in rDME, namely, tumor necrosis factor-α (TNF-α), MCP-1, and KC (the murine homolog of interleukin-8), whereas bevacizumab suppressed TNF-α and interleukin-6. Ripasudil alone could bring about a significant reduction in retinal thickness; bevacizumab co-administration could synergistically enhance this reduction (7).
The present preliminary study shows a clinically modest effect of fasudil monotherapy in rDME cases resistant to prior standard treatments with bevacizumab; visual improvements with or without anatomical changes were achieved in 50% of the eyes; however, the changes did not reach statistical significance. In some cases, the functional and anatomical improvements did not necessarily ensue in parallel, i.e., visual improvements were achieved in three eyes with no significant CMT reductions. Such discordances between visual improvements and CMT changes have been described by some previous studies as well (10). For instance, plasma kallikrein inhibition in rDME eyes has shown acceptable visual improvements without significant changes in DME anatomical parameters (11); plasma kallikrein is a serine protease elevated in DME eyes vitreous, capable of increasing vascular permeability and contributing to retinal edema in a VEGF-independent fashion (12). This incongruity may stem from variable edema and ischemia durations with different patterns of influencing CMT and visual acuity; disorganization of the inner retinal layers, in lieu of CMT changes, is suggested to better correspond with visual acuity modifications (10, 13).
It is noteworthy that cases without significant CMT change had morphologic improvement of retinal microstructure to some extent (Case No. 4). None of the eyes with baseline BCVA of 20/400 (1.30 LogMAR) or worse (n=3) benefited from Fasudil monotherapy in terms of visual function.
We injected 0.025mg/0.05mL fasudil intravitreally and detected no adverse events a day and a week after each injection, in line with previous animal studies (14) and our prior experiences (4–6).
To summarize, intravitreal fasudil monotherapy in rDME eyes unresponsive to previous conventional treatments is safe and has a moderate beneficial effect in improving visual function, not necessarily accompanied by significant anatomical improvement. However, no substantial therapeutic gain may be achieved in patients with severe baseline visual impairments (BCVA<20/400).