Rheumatoid arthritis: circadian rhythms in disease activity, signs and symptoms, and rationale for chronotherapy with corticosteroids and other medications

Biological processes and functions at all hierarchical levels are organized in time as biological rhythms of discrete periods. Circadian (24-hour) rhythms, which are of direct importance to clinical medicine, are orchestrated by a set of clock genes of the master brain clock situated in the suprachiasmatic nuclei of the hypothalamus plus numerous subservient peripheral cellular clocks of all tissues and organs. Circadian rhythms are kept in step with the surrounding physical and social milieu by periodic external time cues, the most important one being the 24-hour environmental light-dark cycle. The circadian time structure gives rise to predictable-in-time day-night patterns in morbid and mortal events plus symptom occurrence and severity of common chronic conditions, including rheumatoid arthritis (RA). The circadian pattern of various cytokines and hormones in RA disease activity suggests a new treatment paradigm (i.e., chronotherapy-timing medications to 24-hour rhythms in disease pathophysiology) to improve desired outcomes. Since the 1950s, RA chronotherapy in the United States and Europe has involved several nonsteroid anti-inflammatory drugs (NSAIDs), certain disease modifying antirheumatic drugs (DMARDs), and various synthetic corticosteroid medications.