A study of circadian variation in PMR found that plasma concentrations of IL-6, IL-8, TNF-α, and IL-4 peaked between 4 and 8 am in both untreated patients and controls, although levels of those cytokines were higher throughout the day in patients. The peak in cytokines matched the early-morning peak of pain and stiffness in untreated patients. In addition, melatonin levels were consistently higher in patients than in controls and varied with time, peaking around 2 am, suggesting that melatonin stimulates cytokine production, which in turn accounts at least partly for PMR symptoms. [14]