Relationship between interleukin-6 (IL-6) and hypothalamic-pituitary-adrenal axis hormones in rheumatoid arthritis

Systemic symptoms in rheumatoid arthritis (RA) are mediated, at least in pa rt, by elevated levels of circulating interleukin 6 (IL-6), which is a pote nt activator of the human hypothalamic-pituitary-adrenal (HPA) axis. In a r ecent study, we observed that the 24 h time-integrated plasma ACTH and cort isol, as well as urinary free cortisol levels of untreated RA patients were not significantly different from control subjects, in spite of their activ e disease. However, an earlier morning surge of plasma ACTH and cortisol in RA patients was found. Plasma ACTH and cortisol responses to ACTH were sim ilar between RA patients and controls. Plasma IL-6 levels showed a pronounc ed circadian variation and were significantly increased in the RA patients, compared to control subjects. In the RA patients, we detected a positive t emporal correlation between plasma levels of IL-6 and ACTH/cortisol, with I L-6 preceding ACTH and cortisol by 1 and 2 h, respectively. In the same pat ients, we detected a negative effect of cortisol upon IL-6 exerted with a d elay of 5 h. In patients with early untreated RA - although endogenous IL-6 stimulates the ACTH and cortisol secretion - the overall secretory activit y of the HPA axis remains "inappropriately" normal despite elevated plasma IL-6 levels. The resulting "inappropriately" normal cortisol levels are app arently insufficient to satisfactorily limit the inflammation in these pati ents. In patients with Sjogren's syn drome the ACTH and cortisol response a fter CRH stimulation has been found to be blunted. On the other hand, patie nts suffering from systemic lupus erythematosus, when subjected to insulin tolerance testing, showed a lower cortisol response compared to healthy con trols. These data indicate a direct and/or indirect involvement of a defect ive HPA axis in the pathogenesis of certain autoimmune-related pathologic e ntities.