The morning stiffness and pain of rheumatoid arthritis (RA) is accompanied by a rise in serum interleukin-6 (IL-6) from 2 am to 7 am. Using a formulation that releases prednisone at 2 am (after ingestion at 10 pm), we studied the circadian dynamics of serum IL-6, other cytokines, and cortisol in 9 patients before and after 2 weeks, therapy. Significant improvements occurred in morning stiffness, pain, disease activity, and the acute-phase response. Only IL-6 showed measurable cytokine circadian variation, its high pretreatment peak was abolished, and changes in IL-6 correlated with the changes in morning stiffness. Following treatment, afternoon and evening serum cortisol was reduced, but in the early morning cortisol peak concentration increased. Thus the severity of morning symptoms is related to nocturnal serum IL-6 concentration. The specific timing of the medication, linked to the interaction between IL-6 and the hypothalamic-pituitary-adrenal (HPA) axis, may correct a postulated deficiency in HPA control in RA.

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In rheumatoid arthritis (RA), nocturnal release of pro-inflammatory cytokines is not adequately counteracted by endogenous glucocorticoid, and is associated with symptoms of morning stiffness and pain. Taking exogenous glucocorticoid during the night reduces morning stiffness significantly more than treatment at the conventional time in the morning, though waking to take tablets is unacceptable for patients. Modified-release prednisone tablets have beenwas developed to allow administration at bedtime for programmed delivery of glucocorticoid during the night. Single centre crossover studies were conducted, each in ≥24 healthy subjects, to compare the pharmacokinetics of a single 5 mg oral dose of modified-release prednisone and conventional prednisone, and the effect of food on bioavailability. There was no substantial difference in pharmacokinetic parameters of the formulations apart from the programmed delay in release of glucocorticoid from the modifiedrelease tablets (Cmax 97%, AUC0-∞ 101%, 90% confidence intervals within the requisite range for bioequivalence). Administration after a full or light meal did not affect pharmacokinetic characteristics, but bioavailability was reduced under fasted conditions. Pharmacokinetic evaluation in nine patients with RA confirmed that modified-release prednisone tablets taken at bedtime (around 22:00 h) with or after an evening meal result in programmed release of glucocorticoid 4-6 hours after intake.Paper revised following submission to J Clin Pharmacol 16Nov11The circadian pattern in symptoms is a well-known feature of rheumatoid arthritis (RA). Furthermore, working ability may be impaired, with severity of morning stiffness a key factor in early retirement from work in the 3 years after RA diagnosis. 3,4 Yet despite the widespread occurrence of morning stiffness and its impact on patients, treatment is often unsatisfactory. 5There is increasing awareness of the underlying pathophysiology of morning symptoms in RA.6, 7Nocturnal levels of the pro-inflammatory cytokine, interleukin-6 (IL-6) correlate with morning stiffness. 8,9 In patients with RA, the normal nocturnal increase in endogenous cortisol appears to be insufficient to counteract increased nocturnal levels of IL-6. 6, 7, 10 Exogenous glucocorticoid may be given to supplement endogenous glucocorticoid. 7, 11 Prednisone and its therapeutically-equivalent metabolite, prednisolone, are oral glucocorticoids commonly used in RA. 11, 12 Both glucocorticoids have a short half-life of approximately 2 hours and are usually administered in the morning. 13However, efficacy with respect to morning stiffness and pain is improved if treatment is given during the night, 14 before the peak in IL-6, though it is unacceptable in the long term for patients to have to wake to take medication.To facilitate delivery at the optimal time, in accordance with circadian rhythms, a modified-release formulation of prednisone has been developed. 15 These tablets, consisting of an active drug core inside an inert coat, are designed ...

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