Why Do Gout Flares Start at Night? Save

The striking propensity for gout flares to initiate at night has been recognised for centuries. In 1683, Thomas Sydenham famously observed that the typical patient "goes to bed and sleeps in good health" only to be awakened around 2:00 AM by excruciating pain. More recent epidemiological research validates this observation, indicating that the risk of a gout flare is more than two times higher during the early morning hours compared to the daytime.

It is now well established that the NLRP3 inflammasome is the major pathway driving gout flares. Why gout flare initiation is more common at night is likely due to a combination of both diurnal and circadian factors culminating in a perfect storm of events that lead to a night-time susceptibility to inflammasome activation. 

Both diurnal and circadian rhythms are 24-hour rhythms linked to the day/night cycle. The distinction is that circadian rhythms are generated by an intrinsic circadian clock. They are synchronised to the day/night cycle but will persist even if there is no day/night cycle. The term “diurnal rhythms” is used to encompass rhythms that are not driven by the circadian clock machinery; but instead result from our personal daily timetable, e.g. the time of day we choose to eat meals or go to the gym. Understanding the intersection between circadian rhythms in physiology and diurnal rhythms in lifestyle may provide the key to understanding the nighttime risk of gout flare initiation.

Our immune system is heavily influenced by circadian control. The number of immune cells, e.g., leukocytes, oscillates over the course of a day; so too does immune cell activity. Of relevance for the gout flare, expression of NLRP3—the gene encoding one of the three major subunits of the NLRP3 inflammasome—as well as toll-like receptors, which are primary sensors initiating NLRP3 inflammasome activation, naturally varies throughout the day. This means that susceptibility of the NLRP3 inflammasome to activation is not uniform across a 24-hour period. Although most studies have been conducted in nocturnal rodents, there is evidence to suggest humans are naturally more sensitive to NLRP3 inflammasome activation at night than during the day. It is possible that this susceptibility is even greater in those with gout as a consequence of the effect of monosodium urate (MSU) crystals on the circadian clock in immune cells.

When most people talk about the circadian clock, they’re referring to the light-sensitive central circadian clock located in the hypothalamus, which is responsible for synchronising physiological activity with the light/dark cycle. However, clocks are also present in almost every cell in the body, including immune cells. These “peripheral” clocks are partially regulated by cues from the central clock but are also regulated by factors in the local cell environment. It is perhaps not surprising therefore, that peripheral clocks are often disrupted in cells in a diseased tissue environment. This may also be the case in gout. We found that exposure of macrophages to MSU crystals resulted in changes in the expression of core components of the macrophage circadian clock—particularly two components (BMAL1 and REV-ERBα) known to regulate the NLRP3 inflammasome. As a consequence, the magnitude of NLRP3 inflammasome activation generated by MSU crystal exposure in macrophages differed depending on the time of day of exposure. The presence of MSU crystals in a gouty joint is known to predispose to inflammasome activation, but our findings suggest the effects of MSU crystals extend beyond this, potentially helping drive the increased night-time susceptibility to NLRP3 inflammasome activation.

Circadian rhythms in susceptibility to NLRP3 inflammasome activation indicate that the timing of exposure to a potential gout flare trigger is important for dictating whether a flare initiates. Individual lifestyle choices dictate not only which potential triggers an individual may be exposed to, but also when. Considering diurnal rhythms in gout flare trigger exposure coupled with circadian rhythms in NLRP3 inflammasome sensitivity is likely important for understanding the triggers of a gout flare and how these differ between individuals.