Towards a cure for early rheumatoid arthritis

Joint inflammation may either resolve spontaneously or evolve into rheumatoid arthritis (RA). RA is a chronic disease which causes joint pain and swelling, and ultimately deformity and disability. People with RA who are diagnosed and treated early do much better than those in whom diagnosis and treatment are delayed. They have less joint damage and long term disability. The best possible response to a drug, a clinical state called remission in which there are no detectable signs or symptoms of arthritis, is only achieved in a minority of people. New research is urgently needed to identify which subgroups of people with arthritis are most likely to achieve clinical remission without the need for drug therapy, or in response to arthritis drugs. This would mean that only those people who need treatment receive it, thus reducing the costs of treatment and the risk of side effects. The aims of our research project are to enable the delivery of the right treatment to the right patient at the right time. We aim to establish how to measure the state of clinical remission not only at the bedside but also in the laboratory (eg using new ways to visualise affected joints and combining these with blood tests that assess the health of the immune system), and to identify individuals who may be at risk of developing RA in the future. To achieve these objectives, we will work closely with the pharmaceutical industry to collect information about all clinical studies that have been undertaken in patients with RA. We will then study the characteristics of patients with RA who have been recruited to clinical trials and received either (a) placebo (a lookalike drug but with no effects), or (b) active drug, and use this information to see if we can identify the factors that predict spontaneous or treatment-induced clinical remission. We will also set up a new, UK-wide research study of early RA patients to investigate this in more detail. These patients will receive treatment according to nationally approved guidelines. We will observe them in detail, collecting information about their arthritis and how they respond to teatment. Finally, we will undertake some studies to see if it possible to identify healthy individuals who are likely to develop RA in the future. This could pave the way for new ways to treat, or even prevent, early arthritis.

New cases of inflammatory polyarthritis (IP) may either resolve spontaneously or evolve into rheumatoid arthritis (RA). Early diagnosis and prompt therapy with tight control have been shown, in clinical trials, to alter the long-term course of early RA towards a more benign outcome by limiting structural damage and long term disability. Nonetheless, clinical remission is only achieved in a minority of subjects with early RA, and sustained drug-free remission remains a rare event. There is therefore a major unmet need to identify the characteristics of those individuals most likely to achieve clinical remission either spontaneously or in response to specific drug therapies so that new and existing therapies can be targeted to the right patient populations. Thus, identification of accurate predictors of spontaneous resolution, mild disease in early RA, and treatment response would prevent patients being exposed unnecessarily to potentially toxic therapies and permit stratification of patient populations in clinical trial and clinic settings. There is also a need to accurately define clinical and biological outcomes that unambiguously reflect drug efficacy. The aims of this research are to establish reproducible and clinically relevant criteria for ?biological remission states? that incorporate imaging and immune phenotypes, to establish the key predictors of clinical remission in early IP and RA patients and to identify individuals at high risk of developing RA in whom prognostic factors for remission and ongoing active disease can be validated. To achieve these objectives, we will first assemble an inventory of relevant UK clinical cohorts and clinical trials. We will then collate anonymised patient-level data from RA patients randomised, in controlled clinical trials, to receive (a) placebo or (b) active drug, and use this information to establish the characteristics, frequency, duration and clinical consequences of spontaneous and drug-induced clinical remission. A new, UK-wide longitudinal observational study of early RA patients will be established, in which patients will receive intensive treatment according to NICE guidelines. Clinical, imaging and immunological assessments, including novel in vivo assays of resolution, will be undertaken, and the data used to identify further biological predictors and descriptors of the remission state. Finally, we will undertake a feasibility study using existing EPIC/NOAR and UK Biobank cohorts to characterise individuals captured prior to RA onset based on demographic, genotypic and autoantibody profiles. This will provide novel insights into the very earliest phase of the disease and provide a framework for disease prevention strategies in the future.