| Abstract |
Diseases such as rheumatoid arthritis (RA) relapse and remit. In other words, symptoms come and go unpredictably. This adds to the physical and psychological burden for patients because, even when they are well, they face the prospect of a sudden deterioration in their health. Imagine, for example, the impact of such an event when starting a new job or when about to go on a long-awaited vacation. Joint inflammation also causes joint damage which in turn causes disability, as well as contributing to conditions such as heart disease and stroke. So every flare has added potential consequences for long-term health. Despite advances in understanding of the causes of RA, we understand almost nothing about what leads to disease 'flare' (an alternative term for relapse). There are a number of possibilities, one of which involves the white blood cells. RA is a so-called autoimmune disease in which the body's immune system turns inwards and starts to attack the joints and other tissues. So, when the disease is inactive the immune system may revert back to the normal state, only to become triggered again leading up to relapse. There are a number of different types of white blood cell that contribute to the immune system, several of which could be implicated in a flare. Although some white blood cells are damaging, others can regulate the immune response, and the balance between these two types of cells appears to be critical in diseases such as RA. Also, some of the 'bad' cells produce autoantibodies (proteins that can damage the tissues), and changes in these autoantibodies could trigger flares. Because flares occur unpredictably they are difficult to study scientifically. However, we have developed a human 'model' which allows us to study the underlying processes. As already implied, up to a third of patients with RA enter periods of remission, which can last for months or years. Many patients then ask whether they can stop their medicines and, if they do, about a half flare and the remainder remain well, for variable periods of time - although currently we cannot tell which patients will flare. In a recently completed study we asked 118 patients with RA, in remission, whether they would like to stop their medicines. If they did, and they agreed to take part in our research, we assessed them at intervals for 6 months after stopping treatment - initially fortnightly, then less frequently. Each time we saw them we took a blood sample for analysis in the laboratory. Now, by comparing samples from patients who flared and those who remained in remission we will be able to gain a better understanding of the immune reactions that trigger flare. In the proposed work we will use the samples we have collected from ten patients who remained in remission after stopping treatment with samples from ten patients who flared, to look for differences in their white blood cells at different timepoints. We only plan to look at a selection of patients at first because the tests we employ are sophisticated and will provide highly detailed information on the proteins that are on the surface of each blood cell, as well as the genes that are switched on inside each cell, and the proteins on their surface that are responsible for recognising and discriminating 'self' from the outside world of bugs etc - mistakes in which underlie the autoimmune attack. If this work proves to be informative then we will seek funding to extend the analysis to samples from a broader set of patients. We hope this work will help us to understand the mechanisms that underpin flare. In the longer term this should allow us to develop treatments that prevent or interrupt flare, as well as to predict the patients who are most likely to flare, in whom it is less safe to stop treatment. We believe that this could lead to new treatment approaches for such patients, enhancing their quality of life and long-term health. |
