BLOG: Does anti-VEGF work for the cornea?

In the retina field, it seems like there is nothing for which anti-VEGF injections cannot be used. Originally designed to limit the vasculature supply of tumors in cases of systemic cancer, anti-VEGF medications have for years been injected into the vitreous chamber for a variety of maladies such as: exudative macular degeneration, diabetic retinopathy, cystoid macular edema and retinal vein occlusion.

However, ischemia can occur in the cornea as well, and one wonders if these drugs could play a role in the treatment of ocular surface neovascularization.

When neovascularization of the cornea occurs, it decreases the immune privilege of the cornea, increasing the likelihood of past or future corneal graft rejection. Neovascularization also causes lipid deposition and decreased vision if it progresses centrally enough. Right now, chronic corneal neovascularization is difficult to treat, with specialists using long-term steroids, amniotic membranes or sometimes laser treatment directly to the new vessels. Let’s explore the literature to see if there could be a better way.

If you search for this treatment, you’ll find a lot of articles, mostly studies with small sample sizes, which is probably to be expected. But the information can still be useful. The applications are primarily subconjunctival injection, with some trying topical drops and some using a stromal injection technique.

Nearly all the studies use Avastin (bevacizumab, Genentech), although they admit that Lucentis (ranibizumab, Genentech) is a smaller molecule and might have better penetration. The differences between these two drugs has been extensively discussed elsewhere. If taken topically as a drop, the drug is weakened (by five times) from its injection concentration and dosed four times daily. As an injection (for systemic or intravitreal), bevacizumab is administered as 25 mg/mL; as a topical solution, bevacizumab is given as 5 mg/mL.

Failed corneal grafts, chemical-induced limbal stem cell injury and herpetic eye disease are the major etiologies of neovascularization treated with anti-VEGF in the literature. Based on meta-analyses of the literature, anti-VEGF treatment was overall successful in treating neovascularization, but results varied among several studies. The overall reduction in surface area of neovascularization was only slightly reduced; however, the caliber of the vessels was significantly reduced, and the lipid exudation was slowed.

The takeaway from most of the studies was that anti-VEGF treatment could play a role in prevention of graft rejection and in mild limbal stem cell injuries, but that solo treatment in severe cases would have less of an effect.

Interestingly, there have been just as many studies looking into anti-VEGF treatment for pterygia, and the literature was much more in agreement: There is not much benefit in using these drugs for pterygia or pterygia recurrence. The thought is that a pterygium has well-established vasculature, and anti-VEGF molecules respond best to recent-onset neovascularization. Just as bevacizumab doesn’t play much of a role in eliminating the fibrovascular disciform scar in an old choroidal neovascular membrane, it also doesn’t work well in regressing the fibrous tissue in a pterygium.

Perhaps anti-VEGF drugs for the cornea are not the home run they are for the retina, but there are still uses where they could and should be considered. Especially interesting is the thought of dosing them topically as a drop. There is also work being done using drugs with smaller molecules and in conjunction with amniotic membranes. Remember that most of these patients where treatment would be considered have very advanced disease. So, improvement will be slow and hard to quantify, and studies will have small numbers. But, perhaps more importantly, is the reminder that a lot of breakthroughs in medicine happen from people who aren’t afraid to come up with new solutions to old problems. So, get out there and push the envelope.

References:

Amadio M, et al. Pharmacol Res. 2016;doi:10.1016/j.phrs.2015.11.027.

Dastjerdi MH, et al. Arch Ophthalmol. 2009;doi:10.1001/archophthalmol.2009.18.

Kim LE, et al. Am J Pathol. 2012;doi:10.1016/j.ajpath.2012.06.006.

Kim SW, et al. Ophthalmology. 2008;doi:10.1016/j.ophtha.2008.02.013.

Mak RK, et al. Acta Ophthalmol. 2017;doi:10.1111/aos.13178.