Morning symptoms in rheumatoid arthritis: a defining characteristic and marker of active disease.

Many human biological processes are regulated by circadian rhythms, which follow 24-h cycles and involve the neuroendocrine and immune systems. Pathological manifestations of this system may also follow circadian rhythms. In rheumatoid arthritis (RA), clinical symptoms of joint stiffness, pain, and functional disability are commonly most severe in the early morning. These symptoms closely follow the circadian rhythm of the pro-inflammatory cytokine, interleukin (IL)-6. In RA, the increase in nocturnal anti-inflammatory cortisol secretion is insufficient to suppress ongoing inflammation, resulting in the morning symptoms characteristic of RA. Established diagnostic criteria for RA include morning stiffness, although it is not part of the more recent classification criteria developed to guide early treatment decisions. Measures that are widely used to monitor disease control also omit morning stiffness. However, such measures may not capture all disease activity, and one in six patients in remission or with low disease activity still experiences prolonged morning stiffness. Such findings suggest that morning symptoms in RA remain an important marker of active disease that should continue to be monitored.