Fatigue is probably the systemic manifestation of RA that rheumatologists have the least confidence in with respect to their approach, and it is a systemic manifestation that patients are profoundly concerned about. The importance of fatigue in RA is underscored by several studies that have concluded that patients may value a day without fatigue as much as a day without pain.

Fatigue is a complicated quality-of-life domain in patients with RA, and there are many things that can influence this. For example, when the disease is active and patients have a lot of inflammation and pain in their joints, they are less likely to exercise, and exercise is clearly inversely related to fatigability. The more you exercise, the less fatigued you are, and that has been demonstrated both experimentally and epidemiologically. Secondly, if you are experiencing significant pain, particularly at night, then you sleep poorly. And it has been shown experimentally that if sleep is disrupted or if the patient has partial insomnia (ie, trouble falling asleep or waking up too early in the predawn hours), then inflammatory markers tend to be increased, especially interleukin 6. For those with RA, the disease scores will rise over several days of sleep disruption. Lastly, patients with RA are more likely to have intercurrent mood disorders, including varying degrees of depression and anxiety. In addition to anhedonia and abulia, common symptoms of depression include pain and fatigability. So, these are areas in which we are very interested in exploring other therapies.

From the pharmacologic perspective, there is great interest in determining whether certain agents, such as interleukin-6 inhibitors, may have something more to offer patients with fatigue, and there are some supportive data to suggest that this may be true for some individuals. Clinically meaningful patient-reported benefits on fatigue have been observed in randomized clinical trials with both sarilumab and tocilizumab.

However, patients need more than just pharmacologic intervention. They need wellness interventions, whether this involves coaching on exercise, cognitive behavioral therapy, sleep therapy, and/or stress modification. Interestingly, as reported by Hewlett and colleagues, there are systems that can be developed that can reduce fatigue over both the short- and long-term. The authors concluded that teams consisting of rheumatology nurses and occupational therapists using cognitive behavioral approaches reduced multiple RA fatigue impacts. Rheumatologists do not currently have access to such systems, but I think that this is an area that is ripe for partnership with the pharmaceutical industry. That is, with the help of industry and its resources, such systems might be developed to improve fatigue and perhaps other outcomes of interest as well.