Plasma asymmetric dimethylarginine in active rheumatoid arthritis: links with oxidative stress and inflammation

Endothelial dysfunction and accumulation of asymmetric dimethylarginine (ADMA) have been identified as independent predictors of future cardiovascular events in patients with coronary artery disease.

The aim of the study was to investigate the factors that determine increased accumulation of ADMA, an endogenous inhibitor of nitric oxide synthesis, in patients with rheumatoid arthritis (RA).

We studied 46 consecutive patients with RA (39 women, 7 men; mean age, 57 years [range, 23-75 years]) with active disease (mean Disease Activity Score 28 [DAS28], 5.2), without clinically overt cardiovascular disease and 50 controls matched for age, sex, hypertension, blood cholesterol, and glucose. We assessed the plasma levels of ADMA, symmetric dimethylarginine (SDMA), L‑arginine, and the marker of oxidative stress, 8‑iso‑prostaglandin F2α (8‑iso‑PGF2α).

ADMA and SDMA levels were significantly higher in the RA group than in controls (0.58 ±0.081 vs. 0.46 ±0.045 μmol/l, P <0.0001; 0.45 ±0.07 vs. 0.36 ±0.046 μmol/l, P <0.0001; respectively). ADMA levels in the RA group correlated positively with fibrinogen (r = 0.70, P <0.00001), C‑reactive protein (CRP; r = 0.88, P <0.00001), DAS28 (r = 0.44, P = 0.002) and Health Assessment Questionnaire scores (r = 0.39, P = 0.008), but not with age, renal function, or the medications used. 8‑iso‑PGF2α correlated positively with ADMA (r = 0.82), SDMA (r = 0.72), CRP (r = 0.76), fibrinogen (r = 0.57) (all, P <0.0001) and DAS28 (r = 0.44, P = 0.003). Regression analysis models showed that CRP was the only independent predictor of 8‑iso‑PGF2α and ADMA levels in RA.

Our study is the first to show positive associations between plasma ADMA levels and the production of 8‑isoprostanes and CRP in RA.