CORNEAL GRAFT SURVIVAL

A growing body of research suggests that targeting existing blood and lymph vessels and the growth factors that promote them could improve survival rates for corneal grafts, Claus Cursiefen MD, of the University of Cologne, Germany, told the second annual EuCornea Congress. However, large-scale translational studies are needed to confirm the efficacy and safety of several drugs and procedures that show great promise in early human and animal trials.

For corneas with immature blood and lymph vessels, anti-VEGF compounds, such as bevacizumab and VEGF trap, as well as a novel Insulin Receptor Substrate-1 inhibitor, which blocks both blood and lymph vessel formation, have been shown to regress neovascularisation in humans and animals, and reduce graft rejection rates in animals.

For established blood vessels that are less sensitive to anti-VEGF compounds, a combination of fine-needle cautery to physically occlude blood vessels before transplantation combined with topical and subconjunctival bevacizumab before and after surgery can regress blood vessels and improve visual acuity after corneal transplants (Koenig Y & Cursiefen C., Cornea; in press).

However, this combined approach has not been shown to improve graft survival, Prof Cursiefen pointed out. Questions also remain about the efficacy of primary prevention of corneal neovascularisation in promoting corneal graft survival, the impact of different hemangiogenic and lymphangiogenic inhibitors on corneal disease in genetically diverse subjects, and the risk of side effects.

Basic science

“We all know that numerous studies show that blood vessels in the cornea increase the rejection of corneal grafts,†Prof Cursiefen said. He pointed to a meta-analysis of studies involving more than 24,000 patients that shows the risk of graft rejection increases with the number of cornea quadrants affected (Bachmann, Taylor, Cursiefen, Ophthalmology 2010; 117:1300-5). Neovascularisation is a risk factor for rejection whether it occurs before or after the transplant (Vinh et al, Am J Ophthalmol 2006; 141:260-266).

Several studies also suggest that lymph vessels play a major role in graft rejection. One mouse study found that “high-risk†cornea beds that had visible blood vessels but were alymphatic had a similar graft survival rate to avascular corneas. But corneas with both blood and lymph vessels failed at a much higher rate (Dietrich et al. J Immunol 2010; 184:535-9). Pre-existing lymph vessels are also important for induction of the immune response that leads to failure, (Cursiefen et al. Invest Ophthalmol Vis Sci 2004; 45:2666-73).

“There is abundant evidence of the role of lymphangiogenesis in graft rejection. So how can we make our patients benefit?†Prof Cursiefen asked.

Recommendations

An expert roundtable including Prof Cursiefen published a consensus statement on the use of anti-angiogenic therapy in the management of corneal diseases associated with neovascularisation (BJO Online First June 28, 2011; 10.1136/bjo.2011.204701). He presented several options. “The best thing is to prevent angiogenesis in the first place, for example in infectious keratitis,†said Prof Cursiefen, calling this strategy primary prevention.

Because blood and lymph vessels in this scenario are very immature, they are sensitive to steroids, anti-VEGF and anti-IRS-1 medications. These compounds are also effective in blocking neovascularisation after transplantation (Regenfuss et al. Lymphat Res Biol 2008; 6:191-201).

Steroids are anti-inflammatory and can also inhibit lymphatic vessels, but their effectiveness varies widely from agent to agent, with prednisolone a top choice after transplant, Prof Cursiefen said.

Among anti-VEGF compounds, bevacizumab regresses post-keratoplasty neovascularisation and can block progressive neovascularisation (Koenig et al. Graefes Arch Clin Exp Ophthalmol 2009; 247:1375-82), but carries a risk of side effects, such as neurotrophic keratopathy and ulceration. Transient topical bevacizumab for tertiary prevention after transplantation is in trials, and controlled phase I/II trials are needed for other applications, he said.

A new compound, GS-101 (Aganirsen), an antisense oligonucleotide that blocks IRS-1, inhibiting both VEGF and IL1 production, regressed corneal neovascularisation in a phase II trial (Cursiefen et al. Ophthalmology 2009; 116:1630-7). A phase III trial is under way and Prof Cursiefen hopes to have results this year. Targeting IRS-1 also inhibits inflammatory lymphangiogenesis in vivo (Hos D & Cursiefen C. Invest Ophthalmol Vis Sci, in press).

In vivo studies also suggest GS-101 may be more reliable than steroids in suppressing lymphangiogenesis, which can be difficult to detect (Hos D & Cursiefen C. Invest Ophthalmol Vis Sci in press). However, another study has found that mice with different genetic types have very different responses to the same anti-lymphangiogenic treatment (Regenfuss B et al. Am J Pathol 2010; 177:501-10). The same could be true in humans, and trials will be needed to determine it, Prof Cursiefen said.

Prof Cursiefen noted that lymph vessels can be visualised by staining, but they may not be detected with current clinical procedures and equipment. In-vivo confocal microscopy can help “but it is not fail-proof in the clinic.â€

Often, though, corneal blood vessels are well established by the time keratoplasty is indicated. Regressing them improves outcomes, but mature vessels that are surrounded by pericytes are less sensitive to anti-VEGF compounds.

Prof Cursiefen recommends fine needle cautery to occlude them followed by subconjunctival and topically as eye drops bevacizumab to dampen the inflammatory response caused by the cautery and prevent recurrence. This is known as secondary prevention. He has had good results with this approach, but cautions against high concentrations or too-frequent applications of bevacizumab to avoid complications.