The oRAcle Study - Predicting the risk of infection in RA

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The backgroundRheumatoid Arthritis (RA) is a long-term, incurable condition, affecting 1% of the adult population. It causes joint pain and stiffness, which overtime can result in damage. In RA the body's immune system (which is designed to defend against infection) becomes too active and mistakenly attacks the body's own tissue. Drug therapies that treat RA do so by targeting the immune system. These are called disease-modifying antirheumatic drugs (DMARDs). The problemPatients with RA experience frequent and severe infections, with twice as many hospital admissions compared to people without the disease. Serious infections are the tip of the iceberg, with over 30% of patients reporting non-serious infections each year. When a patient has an infection, their clinician will stop their DMARDs. Without treatment for RA, disease activity worsens and the disease may 'flare'. Interrupted treatment regimens are associated worsening disease and increased joint damage. The research questionCurrent belief is that the increased risk of infection in patients with RA is a side effect of drug therapy. However, we propose that the active inflammatory process in RA is an important cause of susceptibility to infection. We believe that this is because chronic inflammation paradoxically suppresses the immune system, putting patients at greater risk of infection. This is supported by clinical experience where patients with more severe disease experience more infections. It is currently not known how much the disease state contributes to the body's ability to resist infection. We want to answer this question.Study aimOur research will address how much the disease state contributes to infection susceptibility. Our goal is to study the clinical and laboratory features of a large group of RA patients to identify which of these characteristics put them at greatest risk of infection, independent of drug therapy. Study planThe TACERA (Towards A Cure in RA) dataset has acquired extensive clinical information and blood samples on 270 patients with newly diagnosed RA prior to starting treatment. It is one of the richest datasets generated in recent years combining large amounts of clinical and laboratory data. Importantly, this is "real life" data because patients were treated as they would be in routine clinical practice. All infectious events have been captured throughout the study, and so the high risk group has already been identified. In this study we will compare the patients who have had an infection with those who did not. Initial work will identify any differences in their clinical characteristics (e.g. age, smoking, disease severity). The TACERA dataset has detailed analysis of the patients' blood samples prior to starting DMARDs, with the measurements of the expression of thousands of genes that control the way the immune system functions. We can look at this data and see if there are any specific differences between patients that developed infections compared to those who did not. This will help identify patterns associated with the risk of infection. We will then investigate changes in the blood after starting DMARDs, to identify changes in the immune system associated with an increased risk of infection. We will compare these patterns to those seen before therapy was started. This will enable us to assess the relative contribution of the drug and the disease on the risk of infection.Study impactWe anticipate being in a position to use a combination of blood test results with clinical features to determine for every patient their risk of developing an infection. This test may contribute to a scoring system that considers other risks factors for infection, and may be relevant to patients with many inflammatory disorders. In clinical practice this means we could identify high risk patients and personalise their care, preventing infection, improving safety of treatment, and optimising long-term outcomes.