Simvastatin inhibits cytokines in a dose response in patients with rheumatoid arthritis

To evaluate the effects of simvastatin in peripheral blood mononuclear cell (PBMC) cytokines profiles and correlate with the disease state of rheumatoid arthritis (RA) patients. The PBMC from 22 RA patients were purified and stimulated or not stimulated with phorbol myristate acetate/ionomycin and were treated with simvastatin in different doses. Cytokine levels were quantified by ELISA and patients were assessed for clinical and laboratory variables. This assessment included disease activity measures [Clinical Disease Activity Index (CDAI), Disease Activity Score for 28 joints (DAS28)] and a Health Assessment Questionnaire. The IL-17A, IL-6, IL-22 and IFN-gamma were significantly reduced in a dose response after simvastatin treatment (50 mu M, p = 0.0005; p < 0.0001; p < 0.02; p = 0.0005, respectively). The IL-17A and IL-6 cytokines were also significantly reduced in lower concentrations of simvastatin (10 mu M) compared to controls (p = 0.018; p = 0.04) and compared to the standard drug (p = 0.007; p = 0.0001). The results also showed that only RA patients with severe disease (DAS28 > 5.1 and CDAI > 22) had poor response to simvastatin in reducing cytokines levels, mainly for IL-17A and IL-22 cytokines (p = 0.03; p = 0.039, respectively). The RA patients in clinical remission, mild or moderate had lower levels of all cytokines analyzed after simvastatin treatment, showing that these patients have better response to treatment. Our findings suggest that the simvastatin therapy modulates different cytokines in a dose dependent manner and its effect is associated with stratification of patients according to disease activity.