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

  • ReseaRch aRticle
  • Published 2011


Since their discovery [1], glucocorticoids have been used to treat rheumatoid arthritis (RA) through powerful anti-inflammatory [2,3] and antierosive [4,5] properties. In RA, symptoms such as pain, early-morning joint stiffness and joint swelling have a circadian rhythm, with maximum activity in the morning and minimum activity in the afternoon [6,7]. This phenomenon, often described as early-morning stiffness (EMS), is so characteristic of RA that it is considered a basic feature pointing to inflammatory polyarthritis [8]. The synovitis of RA is driven in part by deregulation of the inflammatory process and production of proinflammatory cytokines such as IL-6 and TNF [9]. Early studies by Arvidson et al. demonstrated that overnight plasma IL-6 is reduced by 15–20 mg of prednisolone [10] and that lower doses (5–7.5 mg) are more effective at lowering early-morning IL-6 when given at 2 am compared with 7 am [11]. In a recent clinical trial, Buttgereit et al. tested the timed-release formulation of prednisone in patients with RA against standard-release prednisone given in the morning [12]. In this timed-release tablet (TRT) formulation, prednisone is released into the gut lumen 4 h (±15 min) after ingestion. This allows patients to take the medication at 10 pm (before going to bed), while drug delivery occurs at 2 am, similar to the Arvidson study but without the need to wake the patients [13]. A significant reduction in early-morning joint stiffness was detectable in the TRT group after 2 weeks and was sustained for 12 weeks. In single morning blood samples taken at 12 weeks, IL-6 was also reduced. A wide range of systemic proinflammatory actions have been ascribed to IL-6 [14]. In RA patients, IL-6 is substantially elevated in serum and synovial fluid compared with healthy controls [15,16]. Serum IL-6 shows a clear circadian pattern of secretion, with a markedly exaggerated overnight peak reaching a maximum 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 nighttime 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-1b, 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-1b, IL-4 and TNF, neither IL-6 nor morning stiffness changed. Conclusion: Prednisone released at 2 am does suppress the pathological earlymorning 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.

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@inproceedings{aRticle2011AlleviationOM, title={Alleviation of morning joint stiffness by low-dose prednisone in rheumatoid arthritis is associated with circadian changes in IL-6 and cortisol}, author={ReseaRch aRticle}, year={2011} }