Systemic symptoms in rheumatoid arthritis (RA) are mediated, at least in part, by elevated levels of circulating interleukin 6 (IL-6), which is a potent activator of the human hypothalamic-pituitary-adrenal (HPA) axis. In a recent study, we observed that the 24 h time-integrated plasma ACTH and cortisol, as well as urinary free cortisol levels of untreated RA patients were not significantly different from control subjects, in spite of their active disease. However, an earlier morning surge of plasma ACTH and cortisol in RA patients was found. Plasma ACTH and cortisol responses to oCRH were similar between RA patients and controls. Plasma IL-6 levels showed a pronounced circadian variation and were significantly increased in the RA patients, compared to control subjects. In the RA patients, we detected a positive temporal correlation between plasma levels of IL-6 and ACTH/cortisol, with IL-6 preceding ACTH and cortisol by 1 and 2 h, respectively. In the same patients, we detected a negative effect of cortisol upon IL-6 exerted with a delay of 5 h. In patients with early untreated RA--although endogenous IL-6 stimulates the ACTH and cortisol secretion--the overall secretory activity of the HPA axis remains "inappropriately" normal despite elevated plasma IL-6 levels. The resulting "inappropriately" normal cortisol levels are apparently insufficient to satisfactorily limit the inflammation in these patients. In patients with Sjögren's syndrome the ACTH and cortisol response after CRH stimulation has been found to be blunted. On the other hand, patients suffering from systemic lupus erythematosus, when subjected to insulin tolerance testing, showed a lower cortisol response compared to healthy controls. These data indicate a direct and/or indirect involvement of a defective HPA axis in the pathogenesis of certain autoimmune-related pathologic entities.