In the present study, we have confirmed our previous findings2
in an independent group of 52 patients with diabetes that CTGF (CCN2) levels are strongly correlated with the degree of vitreoretinal fibrosis in PDR. In addition, we confirmed that the CTGF/VEGF ratio is the strongest predictor of fibrosis in PDR patients, including those treated with intravitreal anti-VEGF antibodies.
Retrospectively, five out of seven patients who received bevacizumab and were operated at least 4 weeks later (the bevacizumab 2 group), showed an increased degree of fibrosis after bevacizumab, ie, developed retinal fibrosis or progressed to TRD and therefore needed vitreoretinal surgery. In the 17 patients in the bevacizumab 1 group who were operated within 1 week after injection, progression of fibrosis was not observed, which may be due to the short time interval between bevacizumab injection and vitrectomy. This suggests that the chance that fibrosis develops or progresses increases with time, possibly due to prolonged high CTGF/VEGF ratios, which only gradually decline after anti-VEGF treatment.
The post-bevacizumab fibrotic phenomenon has been observed previously in PDR as well as in age-related macular degeneration.20
In a series of 211 patients with PDR, Arevalo et al19
found progression or development of TRD after bevacizumab injection in 11 (5.2%) patients. In this prospective study, bevacizumab was administered as an adjunct for vitrectomy and TRD was noted after a mean of 13 days after bevacizumab. Patients who did not develop TRD had their vitrectomies earlier. The authors could not discern whether TRD happened by natural history or by rapid neovascular involution with accelerated fibrosis as a response to decreased VEGF levels. Based on our present findings, it can be stated that decreased VEGF levels combined with elevated CTGF levels may well have accelerated the fibrotic response in these patients.
Is it possible that high CTGF levels combined with low VEGF levels after anti-VEGF treatment also increase the risk of fibrotic complications after vitrectomy? During surgery, fibrovascular membranes are peeled and the vitreous, and thereby the pool of growth factors, is removed. However, in the time interval between bevacizumab and vitrectomy VEGF but not CTGF is inactivated, and thus CTGF may well induce fibrotic responses in the retina or the vitreoretinal surface. As an example, two patients in the bevacizumab 1 group developed TRD after vitrectomy. These cases had the two highest CTGF levels and CTGF/VEGF ratios that we encountered. In comparison, a PDR patient with comparable CTGF levels and degree of fibrosis, but without anti-VEGF treatment and therefore a lower CTGF/VEGF ratio, did not develop fibrotic complications postoperatively. This suggests that a high CTGF level in combination with low levels of VEGF after bevacizumab, even for a short period of time, is a risk factor for the development of (late) postoperative fibrotic complications.
Anti-VEGF therapy is directed at the angiogenic stimulus for retinal neovascularisation and its introduction has made a significant advance in the management of PDR. However, retinal fibrosis can develop or progress as a consequence. Therefore, the development of adjuvant therapy targeted against pathways other than the angiogenic pathway may be required in combination with anti-VEGF therapy. Our present study and other studies in various organs and conditions4
have identified CTGF and in particular the CTGF/VEGF ratio in vitreous as markers of fibroproliferative disease. Targeting of the fibrotic pathway with anti-CTGF therapy may be an attractive option in combination with anti-VEGF treatment to prevent the angiofibrotic switch in PDR patients and other diseases with ocular angiogenesis.
In conclusion, we confirmed that CTGF levels and in particular the CTGF/VEGF ratio in vitreous are associated with vitreoretinal fibrosis in PDR. These findings support our working model that the balance of VEGF and CTGF in the vitreous in PDR drives the course of the disease, in particular the angiofibrotic switch. As predicted by this model, anti-VEGF therapy shifts the CTGF/VEGF ratio causing the angiofibrotic switch, which may lead to harmful accelerated fibrosis in PDR.