Re-Evaluating the Treatment Plan for Diabetic Macular Edema Based on Early Identification of Response and Possible Biochemical Predictors of Non-Response After the First Intravitreal Ranibizumab Injection

<b>Background</b>: This study aimed to change the current concept of diabetic macular edema (DME) management through (1) early categorization of our DME patients into either responders or non-responders after the first intravitreal Ranibizumab (IVR) injection, and (2) finding a suitable clinical-biochemical diagnostic panel to identify the possible cause(s) of non-response in each non-responder and changing the treatment plan in each particular patient accordingly. <b>Patients and methods</b>: Our study included 64 eyes of 40 patients with DME <b>(Group A, DME patients)</b> and 40 eyes of 40 healthy individuals matched for age and sex <b>(Group B, controls)</b>. Blood and aqueous samples were collected from the study participants before and one month after IVR injection. The DME patients were further subdivided into responders and non-responders according to their response to the first IVR injection. Lymphocyte activation markers, NETosis markers, angiogenic factors, astrocytes, innate immunity, and inflammasome markers were assessed in both groups. <b>Results</b>: Multivariate regression analysis revealed that macular ischemia, aqueous levels of <i>hexokinase 1</i>, <i>SELL CD62L</i>, <i>ELANE</i>, <i>MPO</i>, <i>VEGFA</i>, <i>and SEMA4D</i> were the most significant factors affecting the response to IVR (<i>p</i> < 0.05). <b>Conclusions</b>: defining our DME patients as responders and non-responders after the first IVR injection, combined with potential utilization of a clinical-biochemical panel (macular ischemia- PCR array of combined <i>Hexokinase 1</i>, <i>MPO</i>, and <i>SEMA4D</i>) in each non-responder, may represent a good starting point for changing the current DME management strategy.