The efficacy and safety of combined methotrexate with anti-vascular endothelial growth factor therapy in treatment of diabetic macular edema: A protocol for systematic review and meta-analysis

Objective There is no review or meta-analysis to compare the efficacy and safety of methotrexate plus anti-vascular endothelial growth factor (anti-VEGF) therapy in patients with diabetic macular edema (DME). It is worthy to critically review the evidence of the assessment of combined therapies to inform clinical practice. Therefore, the purpose of this study was to compare the efficacy and safety of methotrexate plus anti-VEGF therapy in the treatment of DME and to provide evidence for clinical practice. Methods The electronic databases of EMBASE, PubMed, Cochrane Library, and Web of Science were searched from the inception to April 2021 using the following key terms: "diabetic macular edema," "methotrexate," and "anti-vascular endothelial growth factor," for all relevant studies. Additionally, the reference lists from published original articles and relevant reviews were assessed to identify more relevant studies. Only English publications were included. Data were extracted by review of each study for population, mean age, gender, follow-up duration, study design, publishing date, characteristics, and outcomes assessment. The present study was performed using Review Manager (RevMan Version 5.3, The Cochrane Collaboration, Copenhagen, Denmark). Results We hypothesized that combined therapies would provide better therapeutic benefits compared to single method. Osf registration number 10.17605/OSF.IO/APD6 V.