Fatigue is a common symptom in patients with rheumatoid arthritis and contributes to the cost of clinical care, reasons for primary care consultation, and even loss of employment. Patients with rheumatoid arthritis report rates of fatigue that are 4 to 8 times higher than the general population.1 In a review of current studies, however, fatigue is a poorly understood and poorly managed symptom.

While specific studies designed to investigate disease activity or the inflammatory biomarkers related to fatigue in rheumatoid arthritis are few, prognosis is generally limited to factors of pain, mental health, disability, and sleep. These general factors consistently drive outcomes of fatigue, and along with other disease-specific processes, warrant a closer look in elucidating the mechanism of fatigue. The ability to comprehensively and robustly understand the mechanism of fatigue in rheumatoid arthritis can provide insight into optimal treatment approaches, which may further benefit a number of other chronic diseases.

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The Role of Disease Activity and Inflammation

Disease-specific processes, including those of inflammation and joint damage, are historically related to symptoms of fatigue. In fact, the pro-inflammatory cytokines associated with the inflammation response are thought to trigger fatigue in many chronic illnesses. However, this relationship is much more complicated, as evidenced by a number of studies with differing results that correlate fatigue with global measures of disease activity vs traditional markers of inflammation.

In studies analyzing the relationship between disease activity and fatigue, a direct association was made between fatigue and disease activity scores for 28 joints (DAS-28).1 But when DAS-28 was substituted for specific inflammatory measures, including common clinical markers of C-reactive protein or erythrocyte sedimentation rate, the relationship between disease activity and fatigue disappeared.1 The investigators suggest that the relationship may be partly influenced by patient self-reports of joint pain included in the DAS-28 assessment.

Because rheumatoid arthritis is an inflammatory disease, inflammation-focused interventions are commonly recommended. However, it is notable that fatigue often persists in patients despite receiving anti-inflammatory treatments,1 so the role of inflammatory disease processes in predicting fatigue is also limited. Future studies should target the pro-inflammatory cytokines not typically considered in clinics, but those that have been indicated in other disease groups associated with fatigue, including TNF-α, IL-1, IL-6 and IFN-γ.

Pain as a Possible Predictor of Fatigue

Many studies have investigated the role of pain as a possible predictor of fatigue in rheumatoid arthritis. A number of studies have shown that an increase in joint pain is associated with a greater magnitude of fatigue; pain also seems to mediate the effect on disease activity and fatigue outcomes.1 To this extent, the investigators suggest that pain, not disease activity, drives fatigue.

On the other hand, greater fatigue associated with concurrently higher pain has been reported by patients despite achieving disease remission.1 The investigators explain this consequence as being due to a possible shared etiology between pain and fatigue symptoms, rather than the previously discussed cause-and-effect relationship. Regardless of the true relationship, pain management should be a central focus in treating fatigue.

Sleep Problems Linked to Chronic Fatigue

Though similar in description, sleepiness and tiredness are distinct symptoms from fatigue, making the predictive relationship between sleep and fatigue difficult to assess. Some studies have reported an association between the number of sleep problems and the magnitude of fatigue; other studies indicate, however, that the relationship between sleep problems (or use of sleep mediations) and fatigue is not significant.1

Perhaps the most useful insight into the nature of the relationship between sleep and fatigue has been demonstrated in experimental studies, which experimentally induced sleep deprivation is associated with increased fatigue.1 But whether sleep has a direct or indirect effect on fatigue is unknown, and it is possible that poor sleep is mediated through elevated pain levels, which in turn cause greater fatigue.1

Although it has been difficult to discern the relationship between sleep and fatigue, a study focused on sleep problems and chronic fatigue in patients with rheumatoid arthritis demonstrated that an exercise intervention prescribed for this population can improve both sleep quality and fatigue outcomes.2

Mental Health Predictive of Fatigue Prognosis

Several studies show that poor mental health is associated with fatigue, whereby higher depression scores and dysphoria ratings along with a history of depression have been linked with a failure to improve, or worsening of, fatigue.1 Other studies indicate that a decline in mental health complaints is frequently associated with concurrent improvement in fatigue, and mental health remains poor among those who experience persistent fatigue despite rheumatoid arthritis disease management.1

It is important to note that fatigue is included in the clinical criteria for depression, so the predictive relationship between depression and fatigue is complex, such that poor mental health both predisposes an individual to, and perpetuates, fatigue.1

More studies are needed to investigate the relationship between fatigue and other mental health disorders or symptoms, such as anxiety and stress, but in general it may be safe to assume that poor mental health is predictive of a fatigue prognosis. In a systematic review, certain psychological variables were indicated as potential targets in the treatment of fatigue, including mood and cognitive functioning.3 The ability to cope with stress and having a social support system have also been linked to improvements in fatigue.3

Fatigue Affects Physical Functioning (and vice versa)

The level of physical disability in rheumatoid arthritis is consistently associated with a patient’s likelihood to experience an improvement in fatigue, experience persistent fatigue, or report greater progressive fatigue.1 Considering that progressive joint damage is a hallmark of rheumatoid arthritis, the increased effort required to complete daily tasks undoubtedly leads to increased fatigue over time.

In contrast, fatigue is considered a disabling symptom and has a significant effect on a patient’s physical functioning. It is therefore unclear to what extent fatigue affects disability measures in patients with rheumatoid arthritis. In a study exploring the relationship between fatigue and work disability, fatigue independently predicted certain dimensions of disability, including activity impairment.4 These findings suggest that managing symptoms of fatigue may improve a patient’s functioning.

References

1. Druce KL, Basu N. Predictors of fatigue in rheumatoid arthritis [published online August 21, 2019].  Rheumatology. doi:10.1093/rheumatology/kez346

2. Durcan L, Wilson F, Cunnane G. The effect of exercise on sleep and fatigue in rheumatoid arthritis: A randomized controlled study. J Rheumatol. 2014;41(10):1966-1973.

3. Matcham F, Ali S, Hotopf M, Chalder T. Psychological correlates of fatigue in rheumatoid arthritis: A systematic review. Clin Psychol Rev. 2015; 39:16-29.

4. Druce KL, Aikman L, Dilleen M, Burden A, Szczypa P, Basu N. Fatigue independently predicts different work disability dimensions in etanercept-treated rheumatoid arthritis and ankylosing spondylitis patients [published online May 29, 2018]. Arthritis Res Ther. doi:10.1186/s13075-018-1598-8