Glucocorticoid chronotherapy in rheumatoid arthritis

In today’s Lancet, Frank Buttgereit and colleagues report a double-blind randomised trial of modifi ed-release prednisone for rheumatoid arthritis. The tablets release the drug about 4 h after ingestion (a special coating bursts due to penetration of water). The tablets are ingested in the evening and thus prednisone release is adapted to the circadian rhythm of cortisol. In the study, the duration of early morning stiff ness was lower than when the same dose of prednisone (standard pill) was taken early in the morning. Many biological processes have cyclic variability (ie, chronobiology). Plasma cortisol concentrations have a circadian rhythm: they peak at 0600–0800 h and have a nadir at 2200–0200 h. In patients with early untreated rheumatoid arthritis, cortisol concentrations begin to increase at 2300–0200 h (fi gure). This earlier rise is preceded and possibly caused by a rise in concentrations of the proinfl ammatory cytokine interleukin 6. This cytokine has a pleiotropic role in the pathogenesis of rheumatoid arthritis, including stimulation of the hypothalamic–pituitary–adrenal axis. In healthy people, no rise in interleukin 6 concentration is seen. The peak in rheumatoid arthritis probably contributes to the typical pattern of joint pain, swelling, and stiff ness, which is most severe on waking and decreases as the morning progresses. Early morning stiff ness is characteristic of infl ammation in rheumatoid arthritis and its duration and severity are measures of disease activity. The suppression of rheumatoid arthritis by drugs that target interleukin 6, and the results of Buttgereit and colleagues’ study, support this pathophysiological model. Buttgereit and colleagues’ results are in line with those of an earlier study, in which low doses of prednisolone taken at 0200 h had more eff ect on severe morning symptoms of rheumatoid arthritis than the same dose at 0730 h. However, patients had to be awakened in the middle of the night, which on its own will infl uence the hypothalamic–pituitary–adrenal axis. So the modifi ed-release formulation of prednisone is a step forwards, enabling intake at bedtime and release of drug around 0200 h. Buttgereit and colleagues’ results are clearly relevant for daily clinical practice. In early rheumatoid arthritis, the advantages of low doses of glucocorticoids outweigh the disadvantages, because this therapy not only suppresses signs and symptoms but also signifi cantly slows the progression of radiological joint destruction, including in the long term. Additionally, several adverse events of low doses can be managed. Thus glucocorticoids are currently part of the fi rst-line treatment of early rheumatoid arthritis. Although treatment has progressed in important ways in the past decade as biological agents became available, many countries cannot aff ord these new drugs. Furthermore, when older drugs (eg, methotrexate and glucocorticoids) are used early in rheumatoid arthritis they are more eff ective than previously thought. The aim of treatment in each individual patient with rheumatoid arthritis is total suppression of disease with individualised tight-control combination therapy. The gain with the modifi ed-release formulation in effi c acy and decreased concentrations of inter leukin 6 could lead to reductions in glucocorticoid doses and exposure, and thus to fewer adverse events. Unfortu nately, Buttgereit and colleagues did not fi nd clear ad vantages in other symp toms of disease activity, but the study period of 12 weeks was short. Concentrations of osteocalcin, a marker of bone metabolism, did not change, which suggests that the eff ect on bone of the modifi ed-release formu lation is similar to that of standard-release prednisone These results pose several relevant research questions. Does effi cacy persist? Does the eff ect on radiological joint destruction equal that See Articles page 205