Fatigue in chronic inflammation - a link to pain pathways

Abstract

Fatigue is a frequent symptom in several inflammatory diseases, particularly in rheumatic diseases. Elements of disease activity and cognitive and behavior aspects have been reported as causes of fatigue in patients with rheumatoid arthritis. Fatigue could be associated with activity of inflammatory rheumatism. Indeed, biologic agents targeting inflammatory cytokines are effective in fatigue. Fatigue is also associated with pain and depressive symptoms. Different pathways could be involved in fatigue and interact: the immune system with increased levels of pro-inflammatory cytokines (interleukin-1 and -6 and tumor necrosis factor alpha), dysregulation of the hypothalamic-pituitary-adrenal axis and neurological phenomena involving the central and autonomic nervous systems. A pro-inflammatory process could be involved in pain and behavioral symptoms. Inflammation could be a common link between fatigue, pain, and depression.

Fig. 1

Model of interactions between fatigue, pain and psychological disturbance. (a) Conceptual model of clinical interactions between fatigue, pain and psychological disturbance in inflammatory arthritis. (b) Conceptual model of physiological interactions between fatigue, pain and psychological disturbance in inflammatory rheumatism. The potential mechanisms of action in each domain are listed. The increase of inflammatory cytokine levels could be involved in fatigue, pain and mood disorders. HPA, hypothalamic-pituitary-adrenal; IFN, interferon; IL, interleukin; TNF, tumor necrosis factor

Fig. 2

Mechanisms of interaction between peripheral inflammation, the nervous system and the hypothalamic-pituitary-adrenal (HPA) axis involved in the fatigue process. In the HPA axis, the hypothalamus contains neurons that synthesize corticotropin-releasing hormone (CRH), which regulates adrenocorticotropic hormone (ACTH) by the pituitary gland. ACTH stimulates the synthesis of glucocorticoids such as cortisol by the adrenal cortex and catecholamines by the adrenal medulla of the adrenal gland. Cortisol could have a negative feedback mechanism on the brain. Glucocorticoids inhibit many functions of leukocytes and the production of pro-inflammatory cytokines (interleukin (IL)-6 and IL-1) by immune cells. ACTH and CRH have pro-inflammatory properties and IL-1, IL-6 and tumor necrosis factor (TNF)-α activate the HPA axis. The peripheral nervous system can affect inflammation: the sympathetic neurons of the autonomic nervous system (ANS) secrete pro- and anti-inflammatory neuropeptides. These pro-inflammatory cytokines could enter central nervous system (CNS) areas by the permeable blood–brain barrier or facilitate the release of second messengers to induce cytokine activity in the brain. With excess inflammation, the activity of some CNS neurotransmitters could be altered