CIRCADIAN RELATIONSHIPS BETWEEN INTERLEUKIN (IL)-6 AND HYPOTHALAMIC-PITUITARY-ADRENAL AXIS HORMONES - FAILURE OF IL-6 TO CAUSE SUSTAINED HYPERCORTISOLISM IN PATIENTS WITH EARLY UNTREATED RHEUMATOID-ARTHRITIS

Systemic symptoms in rheumatoid arthritis (RA) are mediated, at least in part, by elevated levels of circulating interleukin (IL)-6, and thi s cytokine is also a potent stimulus of the hypothalamic-pituitaryadre nal axis. To evaluate the 24-h circadian secretory dynamics of ACTH, c ortisol, and IL-6 and their interactions in patients with early untrea ted RA, we recruited and studied five newly diagnosed, untreated RA pa tients early in the course of their disease and five age-, gender-, an d race-matched control subjects. We collected serial blood samples ove r 24 h and measured plasma ACTH and cortisol every 30 min and IL-6 eve ry hour. The 24-h collection was followed by administration of ovine C RH (oCRH) and post-oCRH serial blood samples over 2 h. We analyzed the 24-h overall levels of these hormones and their circadian variations and performed time-lagged cross-correlation analyses among them. The u ntreated RA patients had 24 h time-integrated plasma ACTH, plasma cort isol levels, and urinary free cortisol excretion that were not signifi cantly different from control subjects, in spite of their disease acti vity. However, an earlier morning surge of plasma ACTH and cortisol in the patients was suggested. Plasma ACTH and cortisol responses to oCR H were similar in RA patients and controls. IL-6 levels were significa ntly increased in the RA patients compared with control subjects durin g the early morning hours (P < 0.05). There was pronounced circadian v ariation of plasma 11-6 levels. In the RA patients, we detected a posi tive temporal correlation between plasma levels of IL-6 and ACTH/corti sol, with elevated levels of IL-6 before the elevations of ACTH and co rtisol 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. Th e data presented here suggest that although endogenous IL-6 may stimul ate secretion of ACTH and cortisol, overall activity of the hypothalam ic-pituitary-adrenal axis remains normal and apparentry is insufficien t to inhibit ongoing inflammation in early untreated RA patients.