Possible Short-term Changes of Aqueous Inflammatory Cytokines After Intravitreal Bevacizumab for Diabetic Macular Edema

We read with great interest the article by Sohn and associates, “Changes in Aqueous Concentrations of Various Cytokines after Intravitreal Triamcinolone versus Bevacizumb for Diabetic Macular Edema.” They reported that only aqueous vascular endothelial growth factor (VEGF) was decreased significantly after intravitreal bevacizumab (IVB) treatment, but that aqueous levels of interleukin (IL)-6, IL-8, interferon-induced protein-10, monocyte chemotactic protein (MCP)-1, and platelet-derived growth factor-AA were not affected by IVB treatment. Previously, Funk and associates also reported that IVB resulted in a significant decrease of VEGF and that all other cytokines, including IL-8 and MCP-1, were not affected in patients with diabetic macular edema (DME).

We obtained aqueous humor samples of an 84-year-old man with DME just before IVB and at the beginning of cataract surgery 1 week after IVB treatment. At baseline, the levels of inflammatory and angiogenic cytokines in aqueous were elevated in accordance with the findings of Sohn and associates (IL-6, 58.13 pg/mL; IL-8, 23.18 pg/mL; MCP-1, 2971.96 pg/mL; VEFG, 57.52 pg/mL). However, in contrast to previous reports, aqueous levels of IL-6, IL-8, MCP-1, and VEFG were decreased at 1 week after IVB treatment (IL-6, 31.82 pg/mL; IL-8, 12.00 pg/mL; MCP-1, 2221.52 pg/mL; VEFG, <3.00 pg/mL). Previous reports evaluated aqueous samples at 4 weeks after IVB treatment, but we obtained the sample at 1 week after IVB treatment. Although it cannot be generalized because of single case, the results of this analysis definitely were different from those of previous reports. It could be presumed that inhibition of VEGF by IVB alters the associated cytokines acutely, but that associated cytokines are normalized by a complex feedback mechanism after some period. Because the aqueous levels of bevacizumab last for several weeks and because it can inhibit VEGF directly during this period, aqueous levels of VEGF remain decreased.

The underlying pathophysiology of DME is complicated and involves numerous interconnected pathways regulated by multifactorial feedback loops. Hyperglycemia causes the morphologic changes and mechanical disruption of blood vessels. This causes leakage of fluids into the surrounding tissues, and inflammatory responses are initiated with inflammatory mediators. This further facilitates the release of VEGF, and VEGF can induce leukostasis and can increase vascular permeability. Leukostasis directly can increase vascular permeability and can damage vascular endothelium by the release of numerous inflammatory cytokines. Therefore, an inflammation-induced breakdown of the blood-retinal barrier can be mediated by VEGF via binding to leukocytes and inducing their recruitment to the site of inflammation.

Associated cytokines other than VEGF also were decreased at 1 week after IVB treatment in our case, and so the assertion that IVB has no influence on other cytokines should be reconsidered. Inflammatory cytokines, including IL-6, IL-8, and MCP-1, may be affected acutely by IVB and may be normalized after some period. Future larger prospective studies are needed to determine the short-term effect of IVB on inflammatory cytokines and the timing when the cytokines were normalized after IVB in patients with DME.

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Jan 12, 2017 | Posted by in OPHTHALMOLOGY | Comments Off on Possible Short-term Changes of Aqueous Inflammatory Cytokines After Intravitreal Bevacizumab for Diabetic Macular Edema

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