Asymmetric and Symmetric Dimethylarginine Concentration As an Indicator of Cardiovascular Diseases in Rheumatoid Arthritis Patients: a Systematic Review and Meta-analysis of Case-control Studies

Rheumatoid arthritis (RA) is the most common type of inflammatory arthritis leading to joint damage and physical disability. Cardiovascular diseases (CVDs) are considered a common comorbidity in patients with RA. However, the mechanism underlying its pathogenesis is not definitively explained. Endothelial dysfunction caused by impaired nitric oxide synthesis is an early indicator of cardiovascular disease. Asymmetric and symmetric dimethylarginine (ADMA and SDMA, respectively) the inhibitors of endothelial nitric oxide synthase (NOS) have emerged as novel CVD risk factor determiners. Concerning the unmet need to identify a salutary biomarker for CVD prediction, the purpose of this meta-analysis was to assess the serum/plasma ADMA and SDMA levels in RA patients compared with the healthy controls. A thorough literature search was performed in PubMed, Scopus, Web of Science, and Google Scholar to identify all studies reporting ADMA and/or SDMA levels in RA patients compared with healthy controls. The quality of studies was evaluated using the Newcastle-Ottawa scale (NOS). Pooled standard mean difference (SMD) with 95% confidence interval (CI) was used as the effect size in this study. We also conducted stratified analysis based on assay methods and median age of the participants. Fourteen articles were included. The pooled serum/plasma levels of ADMA were higher in RA patients compared with those of healthy controls (SMD = 1.02, 95% CI = 0.49 to 1.55); However, no statistical differences between RA patients and healthy controls in serum/plasma SDMA levels was seen (SMD = 0.57, 95% CI = -0.21 to 1.36). Subgroup analyses suggested that participants aged > 50 years had higher levels of ADMA rather than controls and the measurement method was a source of heterogeneity for ADMA. According to the results of this meta-analysis, ADMA measurement but not SDMA, can be useful for assessment of endothelial dysfunction as a predictor of CVD risk in RA patients. Prospero registration number: CRD42019121126.