Title: Synovial B cells inform treatment response in Rheumatoid Arthritis (SyBRA)
Funder: Department of Health and Social Care

Abstract: My research will investigate the hypothesis that cellular and molecular signatures associated with B cell lineage in the disease tissue of Rheumatoid Arthritis (RA), i.e. the synovial membrane (SM), may be responsible for response / resistance to B cell targeted treatment (Rituximab - RTX), in comparison to anti-IL6 and anti-TNF.Despite the availability of powerful therapeutic options, up to 40% of patients with RA do not respond to current hugely expensive targeted biologic therapies. Since currently there are no biomarkers able to predict treatment response, the direct analysis of SM, obtained by minimally invasive ultrasound-guided biopsy, has gained much attention in recent years as a tool to potentially guide treatment choices in RA.My research project will aim at evaluating of B cell signatures in the SM at different disease stages, looking at their correlation with disease progression and treatment response.To this aim, the objectives will be:Objective 1. To test, replicate and validate cellular signatures of B cells (B cell rich/poor) in synovia. Histological analysis will be complemented by digital image analysis (DIA), to obtain an objective quantification of B cell presence in synovia.Objective 2. To analyse B cell signature at different disease stages. The B cell signature (B cell rich/poor, as defined above) will be compared at various stages, namely in patients nave-to-treatment, patients who failed first-line synthetic disease modifying anti-rheumatic drugs (sDMARDs), and patients who failed second-line biologic DMARDs (bDMARDs).Objective 3. To assess the association of B cell signature with treatment response to RTX vs anti-IL6 (TCZ) and anti-TNFa. Outcome measures will be compared in B cell rich and poor patients in the different cohorts.My research proposal capitalises on the biopsy-driven trials and observational cohorts available at the host institution. Altogether, these studies cover the whole spectrum of RA, as summarized in figure 1, providing a unique biomedical resource (a total of over 800 synovial biopsies), with matched peripheral blood samples longitudinally linked to clinical outcomes. These studies will complete recruitment before the start of the fellowship, which makes the post-hoc analysis and the delivery of the above objectives feasible within two years (see research timetable for details). The results of this research will be presented at international conferences (EULAR and ACR) and published on high impact journals, while being disseminated to general public, with the assistance of Queen Mary media team, and patients, with the assistance of QMUL's Centre for Public Engagement.Considering the costs (10K/patient/year) and side effects of current treatments, the identification of a B cell signature as predictor of treatment response could lead to huge savings for the NHS (6-8million/year, the estimated cost of RTX failure rate: ~40%), while decreasing risks for patients.

Lay abstract: Rheumatoid arthritis (RA) is the most common form of autoimmune disease, a condition in which the immune system, normally our defence against bacteria and viruses, attacks the body itself. More specifically, in RA there is an attack against the joints, which become painful and swollen. As RA is a chronic (long-lasting) condition, it will not resolve on its own and, if untreated, it can progress, potentially leading to joints destruction and disability.Luckily, powerful biologic medicines have become available in the last 20 years, with the ability to oppose the attack against the joints. However, biologic medicines have several disadvantages, including high costs, increased risk of serious infections and, most importantly, they do not work in all people (40% don't respond) and mechanisms for this remain unknown.Biologic medicines have been developed to target specific parts of the immune system. For example, the medicine named Rituximab (RTX) works by wiping out a type of immune cell called B cells, which normally produce antibodies that are like small bullets used by the immune system to fight infection. In RA, the antibodies are directed against own (self) proteins found in the joints, therefore, wiping out B cells will eliminate the source of this unwanted friendly fire against self-proteins. RTX is recommended by the National Institute for Health and Clinical Excellence (NICE) for use in RA and can be very effective in treating the disease. However, it only works in about 60% of patients, which means that 4 out of 10 patients will not respond, while being exposed to potential side effects.By studying the joints of people with RA, we have discovered that approximately half of them have very few B-cells infiltrating the joints. Therefore, we put forward the hypothesis that in patients with few/absent B cells in the joint a medication targeting B cells, such as RTX, would not work. To confirm this hypothesis, with the support of MRC/NIHR we are performing clinical trials examining a small piece (biopsy) of the disease tissue (synovium) from patients before starting the treatment, looking for factors that may help us understanding why only some patients respond to specific medications.With my fellowship, I will learn how to take and examine biopsies, which is an easy and well-tolerated procedure by patients, but requires training for the physician. I plan to learn this in the centre with the biggest experience in the world, with hundreds of procedures performed each year. At the same time, I will count the number of B cells from the tissues that have been previously collected, to assess if the above hypothesis is correct, i.e. if B cell presence can predict response to B cell targeted therapies. In addition, using samples which were collected at different times, I will look at the presence of B cells over time, which will also help understanding how early we should target these cells.If our hypothesis is confirmed, we will be able to identify in advance the patients with the highest chance to benefit from specific medications, so that we can use it earlier, while avoiding its use in patients who are unlikely to benefit from it choosing a different drug instead. Such approach has the potential to make a big difference to patients, the NHS and society in general. In fact, it could provide better care by choosing the most effective medicine earlier, preventing the unnecessary exposure to potentially toxic drugs, and, finally, as these are very expensive drugs, saving up to 6-8million/year to the NHS.

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM