MICA: BIOlogical Factors that Limit sustAined Remission in rhEumatoid arthritis (the BIO-FLARE study)

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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 longterm 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. 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 white blood cells 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 cell 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. Alternatively, we now understand that there are cells in the joint (synovial fibroblasts) that can influence the activity of the immune system, and which therefore could be important in determining when a flare happens. Just like the immune cells, fibroblasts themselves can also exist in 'good' and 'bad' forms. Lastly, all of the cells mentioned above can undergo 'epigenetic' modification. This is a process that influences the activity of the DNA in a cell and determines whether a particular gene is switched on or off. We believe that epigenetics is an important determinant of whether someone develops RA, and also of how severe their disease is. Similarly, epigenetic changes could influence whether or not a patient flares.Because flares occur unpredictably they are difficult to study scientifically. However, we have developed a human 'model' which will allow 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. We will ask patients with RA, in remission, whether they would like to stop their medicines. If they do, and they agree to take part in our research, we will assess them at intervals for 6 months after stopping treatment - initially fortnightly, then less frequently. Each time we see them we will take a blood sample for analysis in the laboratory. When they initially stop their medicines, and again if they flare, we will also ask to take a sample of the lining of their inflamed joint in a simple procedure which does not require admission to hospital.We will use the samples we have collected to address the various possibilities for flare listed above. By comparing samples from patients who flare and those who don't we will be able to gain a better understanding of the pathways that trigger 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.