Dysregulation of the in vivo production of interleukin-1 receptor antagonist in patients with rheumatoid arthritis. Pathogenetic implications.

Abstract

Patients with rheumatoid arthritis (RA) have defective hypothalamic responses to inflammation, possibly because of excessive production of cytokine inhibitor, which could blunt the effects of cytokines on the hypothalamus, or because of an imbalance between interleukin-1 beta (IL-1 beta) and interleukin-1 receptor antagonist (IL-1Ra), which could create a mainly proinflammatory state. The present study was undertaken to investigate these possibilities. The in vivo kinetics of IL-1 beta and IL-1Ra secretion were studied in patients with RA, osteoarthritis (OA), and chronic osteomyelitis (OM), and in normal controls before and after surgery. The 24-hour levels of IL-1Ra were significantly increased in RA (P < 0.001), but there was no diurnal variation in any group. Preoperative levels of IL-1Ra were higher in RA and OA sera (P = 0.001). After surgery, IL-1Ra behaved like an acute-phase reactant protein in all subjects. IL-1 beta was 10-20 times higher in RA than in OM and OA patients at baseline, but the percentage increase in all groups postoperatively was the same. RA patients had an IL-1Ra:IL-1 beta ratio of 26.2 +/- 3.7 (mean +/- SEM) at baseline (OM patients 89.2 +/- 5.8 and OA patients 1,310 +/- 363); this increased to 66.5 +/- 19.8 after surgery (OM patients 120 +/- 6.7 and OA patients 325.8 +/- 106). RA patients have a dysregulation of IL-1Ra production, and it seems unlikely that the defective hypothalamic response seen in RA is due to a functional deficit of IL-1 beta.