MICA: Treatment According to Response in Giant cEll arTeritis (TARGET)

Rare diseases like the autoimmune disease giant cell arteritis (GCA) are at risk of not getting the attention they deserve in research funding. In GCA, blood vessels become inflamed and blocked. Without treatment, this can lead to blindness, strokes and tearing or bursting of major blood vessels, such as the aorta. However, this does not affect all patients and this disease shows great variation in severity between different individuals. Prompt treatment is critical in order to prevent permanent tissue damage and loss of vision but, because the disease is rare, the symptoms can be unfamiliar to busy family doctors and early warnings of this diagnosis can be missed for some weeks or months. Currently all patients are treated with steroids at high doses, but this is a non-specific treatment that causes dangerous side effects in a very large proportion of patients (86%). These include high blood pressure, diabetes, mental-health problems, muscle weakness and fragile skin and bones, leading to breaks. This is particularly serious because GCA affects older people (>50 years) who often have other medical conditions. There is virtually no clinical trial evidence to guide doctors as to how quickly they should be reducing the steroid dose, how long treatment should be continued and the benefits of using other immune-suppressing drugs to minimise steroid requirements. Treatment trials traditionally lump all GCA patients together and have so far failed to convincingly demonstate improved outcomes when these alternative treatments have been added to steroids. We propose that by accurately classifying patients in terms of their pattern of disease, dominant immune pathway and risk for developing steroid side effects, will allow us to identify subgroups of patients who will respond better than others to newer therapies. We will also use outcome measure assessment to identify good prognosis, non-relapsing groups who may require lower steroid doses for shorter durations; allowing us to minimize therapy and reduce toxicity in those patients whose disease is under better control. GCA is sufficiently rare that no single centre can access sufficient numbers of patients to perform the analyses required at the necessary scale. There is therefore a compelling need for a national partnership approach, capitalising on key UK strengths and building on recent experience of succesful delivery of large, collaborative studies in other rare diseases that have already delivered new treatments for use in the NHS. Our proposed partnership will bring together specialist GCA clinicians and researchers from across the UK so that they can work together to tackle the causes, diagnosis and treatment of GCA. We already have the consent and active engagement of many patients with GCA and the partnership will expand this to create a comprehensive patient network across the UK. The funding will provide state-of-the-art infrastructure, including equipment and staff to manage the clinical data collected, x-rays and scans, along with data collected from blood and tissue biopsies; irrespective of whether the tests were performed within the NHS or for research. The Partnership will make use of a substantial MRC investment in computing power and bioinformatics at the University of Leeds and Leeds Teaching Hospitals NHS Trust to safely store and manage these data. The proposed research activity will make a world-leading contribution to the discovery of better diagnostic tests for use in the NHS. It will also attract investment and research to the UK from the pharmaceutical industry who will work closely with the partnership to develop new treatment strategies for GCA. The approach developed by the partnership will provide an exemplar to inform future consolidation of rare disease research around state-of-the-art bioinformatics infrastructure.