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Prospective multicenter cohort study shows association between cytokine biomarkers and anti-VEGF treatment of DME

Canadian research with DME (diabetic macular edema) patients has shown a statistically significant association between aqueous humour levels of ICAM-1 (intercellular adhesion molecule-1) and a favourable anatomic response to ranibizumab therapy. The clinical research study, conducted by investigators at the Department of Ophthalmology, St. Michael’s Hospital, Toronto, showed that an increasing baseline level of aqueous ICAM-1 appeared to associate with a reduced macular volume on SD-OCT at 3 months. In addition, increasing baseline aqueous VEGF appeared to associate with a less favorable SD-OCT macular volume response at 3 months. As a result, characterization of such biomarkers may assist in selecting positive responders for ranibizumab treatment as early as possible, thereby optimizing patient outcomes and minimizing needless ocular injection regimens for patients unlikely to respond.


While the efficacy of anti-VEGF agents in the treatment of DME has been established and validated in clinical use, not all patients respond identically. Some patients can experience rapid resolution of edema, coupled with functional visual gains, while other show little or no benefit. The specific reasons remain unclear although the heterogeneous effect may in part derive from the complexity of the disorder at a molecular level where the pathogenesis is driven not only be VEGF, but also by other cytokines including ICAM-1 and IL-6, among others. To understand the process further, the Canadian research group aimed to determine if there might be any association between baseline aqueous levels of VEGF and ICAM-1 and the anatomic response brought about by ranibizumab treatment in DME patients. 48 DME patients were recruited, each receiving monthly injections of ranibizumab, 0.5mg, for 3 months while 0.2ml of aqueous fluid was obtained for cytokine analysis at baseline and repeated at the 2-month visit. A variety of measurements were performed including those for VEGF, placental growth factor, transforming growth factor beta 2, intercellular adhesion molecule 1 (ICAM-1), interleukin 6 (IL-6), IL-8, IL-10, vascular intercellular adhesion molecule, and monocyte chemo-attractant protein 1.


Results of the study showed that a number of cytokines were lower at month 2 compared to baseline including ICAM-1 (median change, −190.88; interquartile range [IQR], −634.20 to −26.54; P < .001), VEGF (median change, −639.45; IQR, −1040.61 to −502.61; P < .001), placental growth factor (median change, −1.31; IQR, −5.99 to −0.01; P < .001), IL-6 (median change, −38.61; IQR, −166.72 to −2.80; P < .001), and monocyte chemo-attractant protein 1 (median change, −90.13; IQR, −382.74 to 109.47; P = .01). When the data was controlled for age, foveal avascular zone size, and severity of retinopathy, a multiple linear regression analysis indicated that increasing baseline aqueous ICAM-1 associated with a favorable anatomic response, in terms of reduced SD-OCT macular volume at 3 months, whereby every additional 100 pg/mL of baseline ICAM-1 associated with a volume reduction of 0.0379mm3; P = .01). In addition the researchers were also able to demonstrate that increasing baseline aqueous VEGF associated with a less favorable SD-OCT macular volume response at 3 months, in this case, every additional 100 pg/mL of baseline VEGF associated with an increase of 0.0731mm3; P = .02), and associated with lower odds of being a central subfield thickness (CST) “responder” (odds ratio, 0.868; 95%CI, 0.755-0.998). In other words, higher ICAM-1 levels appeared to be associated with a better therapeutic response – in particular, for every 100pg/mL increase in ICAM-1, the odds of a macular volume response increased by 27%, while for every 100pg/mL increase in VEGF there was a 20.7% decrease in the odds of a macular volume response. While the authors of the study identified a number of limitations, the study concluded that the data gathered introduced “the novel paradigm of cytokine-guided treatment algorithms whereby clinicians might tailor therapy by choosing among a variety of therapeutic agents based on a patient’s individual intraocular cytokine profile. Furthermore, our findings suggest ICAM-1 may be not only a biomarker of disease severity and anatomic response but also a potential therapeutic target in DME, recognizing that in patients with DME, there is not always a direct correlation between anatomic and visual acuity response.”