Tired all the time? Fatigue can get you down so what is it, and what causes it? WOrds: Peter Stannett Fatigue is more than simply feeling tired. it can make your limbs seem as if they are very heavy, causing you to feel very tired. it can affect you psychologically, and have an impact on your mood, motivation and concentration. Fatigue is also one of the most difficult aspects of inflammatory arthritis to treat. What causes fatigue? There are many contributory causes including: inflammation; anaemia; the side effects of some drugs; long-term pain; poor diet; stress; depression; levelof disease activity; and lack of sleep and exercise. informAtion Peter stannett is information officer at Arthritis Care; visit www.arthritiscare.org.uk Focusing on inflammation People with inflammatory diseases, such as rheumatoid arthritis, have inflammation in the joints. inflamed tissue produces small proteins called cytokines, which coordinate cells to produce an immune response, which then leads to fatigue. This can occur in a number of ways: 1 The central nervous system it is thought that, during inflammatory states, cytokines act on the brain to cause drowsiness, loss of appetite, decreased physical activity and socialwithdrawal. Cytokines produced in the body can act on the brain via fourpathways: n activation of certain nerves arriving into the brain, including the vagus nerve, which extends from the brain to the abdomen n Transport across the blood-brain barrier a permeable barrier between the blood and the brain n increased secretion from cells in the blood system in the brain n increased secretion by cells in the blood-brain barrier 2 The hypothalamus-pituitary-adrenal axis The hypothalamus-pituitary-adrenal (HPa) axis is a hormone system connected with stress. The HPa is involved in releasing a hormone called cortisol, which influences wellbeing, so may play a role in fatigue. There is a complex relationship between the immune system and the HPa. in animal studies, some cytokines help stimulate the release of cortisol, which suppresses the immune system when there is a raised level of it in circulation. in patients with chronic fatigue syndrome, it has been found that the HPa does not work so well. 3 Oxidative stress The production of energy using oxygen produces reactive molecules that can causedamage. The body is usually able to neutralise these reactive molecules; however, an imbalance in the ability to neutralise these reactive molecules is calledoxidative stress. oxidative stress is frequently found in chronic inflammatory diseases and may be associated with fatigue. exactly how oxidative stress leads to fatigue is unknown, but it could involve the mitochondria, a part of the cell which produces energy. 4 Genetic factors There is some evidence that specific genes may act as markers in chronic fatigue syndrome, although better studies are required. Further genetic studies are also needed on inflammatory arthritis, to give a better understanding of genetic factors infatigue. Fatigue has a major impact on the lives of people with inflammatory arthritis, so understanding some of the causes may help those with arthritis to know why fatigueoccurs. Cytokines produced in the body can act on the brain via four pathways