Alleviation of morning joint stiffness by low-dose prednisone in rheumatoid arthritis is associated with circadian changes in IL-6 and cortisol

Aim: The effect of prednisone on the morning joint stiffness of rheumatoid arthritis (RA) is enhanced by night-time (2 am) administration. It has been hypothesized that this may be due to suppression of the pathological early-morning rise in plasma IL-6, but this has not yet been measured. A theoretical disadvantage of night-time prednisone is increased suppression of the hypothalamic-pituitary-adrenal axis and reduced peak plasma cortisol levels, usually attained at approximately 7 am. This study measured 24-h variations in IL-6, other cytokines and cortisol in patients before and after a 2-week course of night-time prednisone to address both these questions. Materials & methods: Nine patients with active RA were clinically assessed and had 24-h blood sampling before and after a 2-week course of timed-release tablet (TRT) prednisone (5 mg per day). Patients took the TRT orally at 10 pm and the prednisone was released at 2 am. Changes in circadian variation in cortisol and IL-6 and clinical measures were compared using regression modeling and Wilcoxon matched-pairs signed-rank test. Cytokines IL-1 receptor antagonist, IL-1β, IL-4 and TNF were also measured. Results: Significant alterations in the circadian profiles and concentrations of IL-6 and cortisol were observed following TRT prednisone. The estimated peak value of IL-6 fell from 42.2 to 21.3 pg/ml and occurred earlier (8:05 am compared with 1:21 am; p < 0.005). Following TRT prednisone, the peak value of cortisol increased from 14.1 to 19.3 μg/dl and the trough fell from 2.9 to 2.1 μg/dl (p < 0.001). Clinical symptoms, particularly morning stiffness (p = 0.028), were reduced, but in three patients with high concentrations of IL-1 receptor antagonist, IL-1β, IL-4 and TNF, neither IL-6 nor morning stiffness changed. Conclusion: Prednisone released at 2 am does suppress the pathological early-morning rise in plasma IL-6 in RA. The nocturnal rise in plasma cortisol was not suppressed but was enhanced, consistent with a changing relationship between hypothalamic- pituitary-adrenal axis and immune system activation. A subset of patients with high concentrations of several cytokines did not respond to prednisone.