Overnight variations in IL-6 in synovial fluid and plasma in patients with active rheumatoid arthritis

Aim: To investigate for the first time overnight variations in absolute values and patterns of synovial fluid IL-6, and other proinflammatory cytokines including IL-1 and TNF, and to relate them to blood concentrations of cytokines and cortisol in rheumatoid arthritis. Patients & methods: Six people with active rheumatoid arthritis and large knee effusions who had received no recent glucocorticoids were admitted overnight. Blood and synovial fluid samples were obtained at 13 time points between 21:00 and 10:00. Results: The geometric mean synovial fluid IL-6 concentration increased significantly from 1483 pg/ml at 21:00 to 5084 pg/ml at 08:00 (repeated measures ANOVA p < 0.001). The geometric mean plasma IL-6 and cortisol concentrations increased significantly overnight. In a random coefficient model including data from all participants, the estimated mean synovial fluid IL-6 value began to rise approximately 6 h before the estimated mean plasma IL-6, which in turn began to rise approximately 3 h before plasma cortisol. In the modeled results the three peaks occurred at approximately 09:00, 09:00 and 11:00, respectively. Conclusion: In people with active rheumatoid arthritis of varying disease duration there are high concentrations of IL-6 in synovial fluid that rise significantly during the night, rise before plasma IL-6 and are higher than plasma concentrations at all time points. This suggests that intrinsic synovial fluid IL-6 production is the main driving force for the overnight blood IL-6 changes and future investigation into the source of the IL-6 should focus on the underlying synovial pathology.