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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

The Inflammatory Joint Diseases Section (L.J.C., K.T.K., J.W., K.S.K., R.L.W.), Arthritis and Rheumatism Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases; the Developmental Endocrinology Branch (G.M., M-A. M., G.P.C.), National Institute of Child Health and Human Development; and the Clinical Neuroendocrinology Branch (K.T.K., P.W.G.), National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland 20892

Address all correspondence and requests for reprints to: Leslie J. Crofford, M.D., Department of Internal Medicine, University of Michigan, R4570 Kresge I, 200 Zina Pitcher Place, Ann Arbor, Michigan 48109-0531.

Systemic symptoms in rheumatoid arthritis (RA) are mediated, at least in part, by elevated levels of circulating interleukin (IL)-6, and this cytokine is also a potent stimulus of the hypothalamic-pituitary-adrenal axis. To evaluate the 24-h circadian secretory dynamics of ACTH, cortisol, and IL-6 and their interactions in patients with early untreated RA, we recruited and studied five newly diagnosed, untreated RA patients early in the course of their disease and five age-, gender-, and race-matched control subjects. We collected serial blood samples over 24 h and measured plasma ACTH and cortisol every 30 min and IL-6 every hour. The 24-h collection was followed by administration of ovine CRH (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 untreated RA patients had 24 h time-integrated plasma ACTH, plasma cortisol levels, and urinary free cortisol excretion that were not significantly different from control subjects, in spite of their disease activity. However, an earlier morning surge of plasma ACTH and cortisol in the patients was suggested. Plasma ACTH and cortisol responses to oCRH were similar in RA patients and controls. IL-6 levels were significantly increased in the RA patients compared with control subjects during the early morning hours (P < 0.05). There was pronounced circadian variation of plasma Il-6 levels. In the RA patients, we detected a positive temporal correlation between plasma levels of IL-6 and ACTH/cortisol, with elevated levels of IL-6 before the elevations of 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. The data presented here suggest that although endogenous IL-6 may stimulate secretion of ACTH and cortisol, overall activity of the hypothalamic-pituitary-adrenal axis remains normal and apparently is insufficient to inhibit ongoing inflammation in early untreated RA patients.

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