We appreciate the comments of Lee and Cho regarding short-term changes of aqueous inflammatory cytokines after intravitreal bevacizumab (IVB) for diabetic macular edema, and their remarks about possible acute alteration of associated cytokines after IVB are worth considering.
Although anti–vascular endothelial growth factor (VEGF) therapy acts only against VEGF, various cytokines interact so closely with each other that an influence on other intraocular cytokines is conceivable. A recent report of vitreous levels in eyes of patients with proliferative diabetic retinopathy (PDR) who received pretreatment with IVB has suggested that IVB influences intraocular mediators beyond VEGF. Thus, we theoretically agree with Lee and Cho. However, as stated in the discussion in our article, the Pan-American Collaborative Retina Study Group showed a dramatic decrease of diabetic macular edema 1 month after IVB treatment and a retinal penetration study suggested limited effect of bevacizumab on suppression of VEGF activation 4 weeks after IVB treatment. Therefore, we believe that 4 weeks after intravitreal injection is a meaningful detection time point, and a statistically significant result at 1 week after IVB in the study of Lee and Cho may not be clinically significant.
Another viewpoint contends that acute alterations in the intraocular cytokine profile after IVB may contribute to the complication (eg, tractional retinal detachment in PDR, pigment epithelial detachments, and tears of the retinal pigment epithelium in neovascular age-related macular degeneration) by promoting inflammation and fibrosis. Previous study has demonstrated that VEGF concentrations in the aqueous humor decreased, whereas the concentrations of interleukin-8 and transforming growth factor-β 2 increased 1 week after IVB treatment in PDR patients. Compensatory elevations of alternative angiogenic and inflammatory factors after VEGF inhibition are well described. The selective antagonism of one component of angiogenic process mediated by numerous growth factors and cytokines is likely to result in compensatory increases in other components, which may have deleterious effects.
It is difficult to obtain aqueous samples periodically for diagnostic or investigative purposes without performing surgery in each patient. As far as we know, a randomized interventional clinical trial to evaluate the acute changes in intraocular cytokines after IVB in PDR currently is recruiting participants. In this study, aqueous humor samples were obtained just before preoperative IVB treatment at 2 or 7 days before vitrectomy and at the time of surgery ( ClinicalTrials.gov identifier: NCT01439178 ). We are looking forward to a valuable report to enhance a better understanding of intraocular mediators and PDR.
Additionally, because of the relatively small sample size, there were some interindividual differences that could influence the overall results in our study. Even if the case report of Lee and Cho has value, further research with larger samples is required to clarify the effects of intravitreal bevacizumab on various cytokines in diabetic macular edema. We hope our report will add to the collective knowledge in this regard.