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Fatigue in inflammatory rheumatic diseases: current knowledge and areas for future research

Abstract

Fatigue is a complex phenomenon and an important health concern for many people with chronic inflammatory rheumatic diseases, such as rheumatoid arthritis, psoriatic arthritis, primary Sjögren syndrome and systemic lupus erythematosus. Although some clinical trials have shown the benefits of cognitive behavioural therapy in fatigue management, the effect of this approach is relatively modest, and no curative treatment has been identified. The pathogenesis of fatigue remains unclear. Despite many challenges and limitations, a growing body of research points to roles for the immune system, the central and autonomic nervous systems and the neuroendocrine system in the induction and maintenance of fatigue in chronic diseases. New insights indicate that sleep, genetic susceptibility, metabolic disturbances and other biological and physiological mechanisms contribute to fatigue. Furthermore, understanding of the relationships between psychosocial factors and fatigue is increasing. However, the interrelationships between these diverse mechanisms and fatigue remain poorly defined. In this Review, we outline various biological, physiological and psychosocial determinants of fatigue in inflammatory rheumatic diseases, and propose mechanistic and conceptual models of fatigue to summarize current understanding, stimulate debate and develop further research ideas.

Key points

  • Fatigue is a common and disabling symptom of inflammatory rheumatic diseases.

  • The mechanisms of fatigue in inflammatory rheumatic diseases are not fully understood but are likely to involve multiple biological, physiological, psychosocial and behavioural mechanisms.

  • The mechanisms of fatigue in inflammatory rheumatic diseases might change over time and vary between individuals.

  • Fatigue might reflect the body’s resource management strategy in response to chronic stressors, favouring rationing and storage over expenditure.

  • Studying fatigue has many challenges; consensus on a study framework for fatigue research and a multidisciplinary approach are essential.

  • Optimal management of fatigue requires a personalized and holistic approach.

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Fig. 1: Putative mechanisms implicated in the pathogenesis of fatigue.
Fig. 2: The role of the nervous system in fatigue.
Fig. 3: Mechanistic model of fatigue.

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Glossary

Recall period

The period over which people are asked to recall a prior event (for example, their fatigue experiences, thoughts and/or behaviours).

Sickness behaviour

Adaptive behaviours (such as social withdrawal, reduced activity and increased sleep) developed by animals and humans during an acute infection that are presumed to be beneficial for recovery and survival.

Anhedonia

Loss of interest in activities that were previously enjoyed and a decreased ability to feel pleasure.

Neural drive

The activation signals from the central nervous system delivered to the innervating motor neurons of the muscle.

Hypothalamic–pituitary–adrenal (HPA) axis

Refers to the connections and interactions between the hypothalamus, pituitary gland and adrenal glands.

Hypothalamic–pituitary–gonadal axis

Refers to the connections and interactions between the hypothalamus, pituitary gland and the gonads.

Hypothalamic–pituitary–thyroid axis

Refers to the connections and interactions between the hypothalamus, pituitary gland and the thyroid glands.

Dysautonomia

An umbrella term used to describe conditions attributable to malfunctioning of the autonomic nervous system.

Sleep disturbances

An umbrella term used to describe the spectrum of sleep disorders, such as difficulty falling asleep, frequent wakening and sleep apnoea.

Somatic focus

Heightened attention to physical symptoms.

Learned helplessness

An attributional style whereby a person perceives that they have little control over the events in their life and so responds passively to the challenges that they face.

Mindfulness

The ability to be fully aware of one’s thoughts, feelings and sensations without being overly reactive.

Socratic questioning

The technique of asking focused, probing, open-ended questions that encourage reflection.

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Davies, K., Dures, E. & Ng, WF. Fatigue in inflammatory rheumatic diseases: current knowledge and areas for future research. Nat Rev Rheumatol 17, 651–664 (2021). https://doi.org/10.1038/s41584-021-00692-1

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