Mean Visual Acuity Changes Following Five Injections of Aflibercept and the Relationship Between Ocular and Serum Cytokine Levels and Mean Visual Acuity Gains in DME Patients

Diabetic macular edema (DME) is a common and serious complication of diabetic retinopathy and is one of the leading causes of vision loss in the developed world. Traditionally, DME was treated with focal grid laser which was not very efficacious. More recently, over the last decade, the development of intravitreal steroids such as Triamcinolone acetonide and anti- vascular endothelial growth factor antibodies such as Bevacizumab (off label usage), Ranibizumab and Aflibercept have proven to be promising. In fact, Aflibercept, being the latest anti-VEGF entering the market, was found superior to traditional treatment in DA VINCI, VIVID DME and VISTA DME studies and there are more trials ongoing. Also, several trials have shown steroids to be superior to laser treatments. The steroids continue to have a role in management of patient refractory to other treatments. This is thought to be due to the inflammatory nature of diabetic macular edema.

Much of the recent success in treatment of DME is owed to the recent developments in our understanding of the inflammatory cascade in a diabetic eye specially the discovery and therapeutic targeting of VEGF. The pathophysiology of DME is thought to be complex and is yet to be fully elucidated; however, a review of literature reveals that there is consensus amongst researchers and clinicians with regards to the importance of disruption of blood retinal barrier involving numerous inflammatory mediators and cytokines in this process. It has been shown that the interruption in BRB is not merely a direct consequence of hyperglycemia but the outcome of inflammatory cascade initiated by chronic hyperglycemia. Chronic hyperglycemia leads to increased production of pro-inflammatory molecules such as advanced glycation end products (AGEs) which are molecules that promote formation of abnormal cross-links in between proteins. These compounds in turn lead to disruptions of the functioning BRB through the up regulation of several inflammatory pathways. Currently the best method to battle AGEs is to prevent their formation through tight glycemic control and the development of therapies has been focused on targeting downstream inflammatory and angiogenic mediators such as VEGFs. It has been shown that VEGFs( VEGF A, B, C, D, E and PLGF) play a major role in neovascularization, formation of new highly friable blood vessels, increased permeability and disruption of BRB with VEGF-A being the most potent promoter of neovascularization. Other factors involved include pigment epithelial derived factor (PEDF), Interleukin-6 and 8( IL-6 and 8), monocyte chemotactic protein-1 (MCP-1), Interferon gamma protein 10(IP-10) etc. It is theorized that some factors play a protective role against the pathogenesis of DME, including PEDF, FLT3L, GM-CSF, IP-10, IFN alpha. It is therefore the lack of balance of these factors that is thought to play a major role in diabetic eye disease.

Since, not all patients respond to anti-VEGF therapies injections; researchers have been pursuing other cytokines and inflammatory mediators as the culprit in the non-responsive group. Up-to-date there have been numerous studies investigating the levels of cytokines in the eyes of diabetic patients and based on our extensive review of the literature this/these mystery molecules can be any of the following cytokines: IL-1, IL-6, IL-7, IL-8, IL-10, IL-12, MCP-1, MCP-3, IP-10,VEGF, PLGF, PEDF, ICAM-1, VCAM-1, GM-CSF, GRO(CXCL-1), TNF-alpha, TGF- beta, Eotaxin, FGF-2, FLT3L,IFN alpha, MDC, MIG(CXCL 9), PKC, and MMP-9. These cytokines may also present a novel path to monitor disease activity.

Until now, there has not been a study attempting to determine whether basal cytokine levels are an indication to response to treatment or lack thereof. It is therefore, in our opinion, essential to carry out such a study as a significant relationship between (an) elevated/ suppressed cytokine and letters gained on best corrected visual acuity or a relationship between an elevated cytokine and not responding to our VEGF treatments could present a path for deciding whether a patient is suited for the anti-VEGF treatment at hand. In addition, it could pave the way for development of a new medication that could act complementary to our current treatments. Above all, we hope to assist eye surgeons and physicians to help their patients with the treatment that fits them the best.