Chronic fatigue – “an overwhelming sense of tiredness, lack of energy and feeling of exhaustion” (Krupp 1996) – is a frequent phenomenon in chronic inflammatory and autoimmune diseases, cancer, and neurodegenerative diseases. It is often rated by patients as their worst complaint, the most difficult problem to cope with, and the most important reason for work disability. Fatigue must not be mistaken for normal tiredness, and as such does not respond to rest or sleep. Fatigue is a major problem not only to the individual patient, but also to society with high societal cost due to medical expenses, sick leave and loss to the working force.
Roughly 70-80% of patients with diseases such as rheumatoid arthritis, systemic lupus erythematosus, and primary Sjøgrens syndrome (pSS) report fatigue. These numbers are highly dependent on the fatigue instruments used, and the cut-off to separate normal from abnormal scores.
Some studies in chronic inflammatory diseases indicate that the higher the disease activity the more fatigue. A number of studies don't support this view. Especially studies that have used fatigue instruments without elements of disease activity indicate a separation of these two elements. How can this be explained if inflammation is the trigger for fatigue?
It is well known that mental depression influences fatigue, but also pain, sleep disorders, and social factors have been associated with the severity of fatigue. There is growing evidence that biological factors play important roles in generation and regulation of fatigue. Activation of the innate immune system and cellular stress responses seem to be central elements.
A model for understanding of fatigue is the “sickness behavior model” in animals. Sickness behavior is a survival-enhancing strategy, observed during infection and inflammation, and is highly conserved during evolution. It is characterized by sleepiness, social withdrawal and loss of appetite, and is a complex and automated behavior believed to protect the sick individual from predators (Dantzer 2008). Sickness behavior has many elements of fatigue.
Chronic inflammatory and autoimmune diseases can be regarded as a “chronic infection”, and activation of innate immunity cells like macrophages leads to production of pro-inflammatory cytokines such as interleukin (IL)-1β. This cytokine is passively and actively transported over the blood-brain-barrier, resulting in sickness behavior through activation of specific receptor complexes on neurons in the brain. Fatigue in humans can be considered a component of sickness behavior, and observations in humans confirm several of the results from animal studies. Studies in pSS show that the IL-1 system is activated in the cerebrospinal fluid and also that blocking of IL-1 with an IL-1receptor antagonist drug is able to relieve fatigue in pSS (Norheim 2012). These observations strengthen the view that IL-1 plays a significant role in fatigue.
Another possible cause of fatigue is oxidative stress. Oxidative stress is a term used to refer to an imbalance with increased production of free radicals compared to the compensatory mechanisms that inhibit or repair the damage that may occur. Molecular mechanisms that protect against cellular stresses may be “fatigue generators” that act on the brain through unknown pathways.
Recent studies indicate that there is a genetic basis for fatigue, and that genetic variation and genetic regulation determine the severity of fatigue in the individual subject.
Dantzer R, O'Connor JC, Freund GG, et al. From inflammation to sickness and depression: when the immune system subjugates the brain. Nat Rev Neurosci 2008;9:46-56.
Krupp LB, Pollina DA. Mechanisms and management of fatigue in progressive neurological disorders. Curr Opin Neurol 1996; 9:456-60.
Norheim KB, Harboe E, Gøransson LG et al. Interleukin-1 inhibition and fatigue in primary Sjögren's syndrome–a double blind, randomized clinical trial. PLoS One 2012;7:e30123.
Disclosure of Interest R. Omdal Shareholder of: Photocure ASA, Nordic Nanovector ASA, Grant/research support from: R.O. has received an unrestricted grant of NOK 100,000 from Pfizer for research on fatigue in RA and AS., Speakers bureau: Pfizer, Roche, GSK, BMS
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