Even in patients with apparently well-controlled RA, debilitating symptoms such as morning stiffness, fatigue and pain may occur. The key to controlling these symptoms may be in understanding their pathophysiology, which is probably most advanced for morning stiffness. Nocturnal plasma levels of the pro-inflammatory cytokine IL-6 are elevated in patients with RA and correlate with levels of morning stiffness. In these patients, it is suggested that endogenous cortisol secreted during the night is insufficient to counter the actions of IL-6. Consistent with this hypothesis, the beneficial effects of glucocorticoids on morning stiffness are enhanced by administration at 02:00 h compared with conventional administration around breakfast time, though it is inconvenient for patients to have to wake to take therapy. Modified-release prednisone has been developed to allow treatment to be taken at a convenient time (≈ 22:00 h), with programmed delivery of the glucocorticoid 4-6 h later, at a more appropriate time. Assessment of cytokine and cortisol levels over 24 h before and 2 weeks after treatment with modified-release prednisone 5 mg/day has confirmed the hypothesis. Clinical studies in patients with RA have shown that switching from conventional prednisone taken in the morning to modified-release prednisone at the same dose significantly reduced the duration of morning stiffness, without affecting tolerability. Furthermore, there are some indications that administration of glucocorticoid in accordance with the natural circadian rhythm may improve hypothalamic-pituitary-adrenal axis function. Further work is required to confirm these findings.