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

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.

Flares of immune-mediated inflammatory diseases, such as rheumatoid arthritis (RA), are a major burden for patients. They occur unpredictably, adding to the physical and psychological burden of the condition, and contribute to joint damage and comorbidities, such as cardiovascular disease. Flares are difficult to study, precisely because of their unpredictable timing. However, we have established a human model that generates a 'synchronized' population of RA patients in clinical remission, of whom about 50% flare within 6 months, the remainder maintaining remission. We propose to carefully study such a population to better understand the factors that determine disease flare.

Up to a third of patients with RA achieve disease remission with aggressive therapy. Many wish to discontinue therapy at this point and, if they do, about 50% flare in the subsequent 6 months. We will follow such a population prospectively, to study the biological processes underpinning flare. We will study 150 patients in clinical remission for at least 6 months, and prepared to discontinue treatment. After treatment cessation patients will be studied intensively, with blood sampling at weeks 2, 4, 6, 12 and 24. Patients will also undergo ultrasound-guided biopsy of 'flaring' synovium before reinstatement of previous treatment (with which patients readily regain remission). We will also obtain biopsies from consenting patients at baseline and in remission at 6 months.

In blood we will study immune cell subsets and their activation status; autoantibody profiles; and epigenetic profiles. Synovial biopsies will allow us to examine the cell lineages present, including stromal cell subtypes, as well as inflammatory mediators. We will additionally examine metabolic profiles in blood, urine and synoivum.

Using multivariate statistical techniques we will develop a model that predicts impending flare in RA, highlighting tractable therapeutic pathways and informative biomarkers.

The successful conclusion of this work will have wide-ranging impacts. By unravelling the causes of flare in rheumatoid arthritis it will suggest novel pathways for intervention, to prevent flare as well as improving our ability to predict flare. In turn this will enable the targeted withdrawal of therapy from patients in remission - to avoid flares in the 50% (approx) of patients who continue to need these drugs. Furthermore, this research is likely to have implications for the immune-mediated inflammatory diseases in general. These include psoriasis, psoriatic arthritis, ankylosing spondylitis, inflammatory bowel disease (Crohn disease, ulcerative colitis) and the connective tissue diseases (systemic lupus erythematosus, systemic sclerosis, Sjogren's syndrome, polymyositis, systemic vasculitis). All of these diseases remit and relapse and the underlying mechanisms are likely to be related. Thus, the beneficiaries of this research will include:

PATIENTS with the above diseases - flare is an enormous burden to patients. Not only do they have to live with a life-long inflammatory condition but the unpredictable nature of these diseases significantly hampers planning, both in relation to work and leisure time. For example the impact of a flare at the start of a new job or preceding a long-awaited vacation is massive. Flares also lead to incremental organ damage and increase susceptibility to comorbidities such as cardiovascular disease. Therefore an ability to predict and prevent flare and, indeed, to stop drugs in patients who do not need them, would greatly improve quality of life for patients.

SCIENTISTS working on these diseases. The identification of flare pathways will catalyse new work programmes in these and related areas, both in ACADEMIA and in INDUSTRY. In particular the ability to target these pathways in an informed way could lead to the development of medicines to prevent or disrupt flare - ie medicines that could be taken prophylactically or immediately a patient senses an impending flare. The coupling of these drugs to predictive biomarkers should enable flares to be both predicted and prevented in a stratified manner. This could therefore develop into a new branch of 'preventative' medicine, with benefits to both academia and industry.

The HEALTH AND WEALTH of the nation. The ability to prevent flares, or to intervene early, will improve the health of the nation whilst also maintaining productivity by keeping patients in work. It will also provide new therapeutic targets and pathways, and companion diagnostics, for our partners in Industry. Furthermore, the ability to discontinue drugs in patients who don't require them will result in tangible savings in direct healthcare costs.

POLICY MAKERS. Quality Standards have hugely improved the outlook for patients with early arthritis (and other inflammatory diseases). However, if a patient achieves remission then they move out of medical focus until they flare again. This can feed their insecurity and reduces their quality of life, even during 'good' spells. In contrast, understanding the science of flare should lead to new policies aimed specifically at this patient group. For example, the intermittent measurement of biomarkers informed by the proposed work will enable the prediction and curtailment of flares, as indicated above, and this should result in new guidelines and policies for this stage of the disease.

The MRC have invested heavily in immune mediated inflammatory diseases, and the proposed work would link in with the outcomes of several of these ongoing projects, such as RA-MAP, MATURA and PSORT, many of which are linked with national and international industrial partners. The successful conclusion and integration of these projects will send a strong signal from the UK in terms of our capabilities in the Life Sciences, attracting inward investment and enhancing the global economic performance and competitiveness of the United Kingdom.