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.

Giant cell arteritis (GCA) is the commonest primary systemic vasculitis. Ischaemic complications, including visual loss, occur in 19%. Large-vessel vasculitis leads to stenoses and aneurysms. GCA is difficult to diagnose; to prevent blindness, suspected GCA is treated empirically with high-dose glucocorticoids. However blood and imaging tests can normalize within days of therapy, whereas temporal artery biopsy is insensitive. 86% of patients have adverse effects with glucocorticoids. Glucocorticoids can trigger psychosis or arrhythmia within days, prompting further admissions and treatments. Many other adverse events accrue over time and 50% still need glucocorticoids at 2-3 years. There is little trial data to guide adjunctive immunosuppression, and these data are equivocal due to patient heterogeneity and imprecision of outcomes.
We will develop methods for phenotyping patients to accurately identify the severity of organ involvement, the dominant immunological pathways, and risk factors for glucocorticoid toxicity. Integrating this information, leveraging existing and current datasets, will allow modelling of the most appropriate treatment pathways and rational patient stratification. We will also use outcome measures to identify good prognosis, non-relapsing groups in order to minimize therapy and reduce toxicity in these patients. Refinement of the molecular and immunological phenotype will also allow rational patient selection for early-phase clinical trials of selected biological therapies supporting drug repurposing, subject to target validation.
In parallel, we will generate contemporary epidemiological data to support clinical adoption of emerging biomarkers or therapeutic strategies through incorporation of health economic and cost-effectiveness analyses and engagement with NICE. Future work will include the development of virtual training material and expert centres, supported by NHS England, through specialist commissioning centres.

Our overarching vision is to improve health and reduce health inequalities for patients with GCA. To achieve this, we recognise the need to understand and identify our end users' needs and to map these against our interdisciplinary strengths in translational research and provide focus for our work. We identify our main beneficiaries as clinicians delivering care, patients and users of health services, government and healthcare policy makers who determine the configuration and funding of health services and healthcare related industries, especially in the pharmaceutical, devices and informatics sectors. Our main impacts are on the clinical and cost effective delivery of health services and on the economy and commercial activities of healthcare related industries. We recognise that the strongest potential for impact arises when our strengths in clinical, biomedical and applied health research converge to address important clinical challenges.

Patients, Government and Healthcare Policy makers: The impact of developing new diagnostic and stratification algorithms that will identify those patients most likely to require and respond to a specific therapy, in the absence of serious toxicities, will revolutionise the delivery of GCA healthcare services. Permanent loss of vision and stroke can have a major impact on quality of life and ultimately independence, particularly in this elderly population. The societal impacts and social inclusion for individuals with the disease and their relatives is immense. More timely and accurate diagnosis and efficacious and/or cost-effective treatment, would have significant impacts on the NHS and Social Services and thus ultimately the UK economy.

UK Economy and Industry: The UK is a world leader in life sciences. Medical technology development and innovation is a growing business sector that has the potential to stimulate the UK economy and revolutionise healthcare provision through accelerated delivery of stratified medicines. The University of Leeds has restructured its innovation services to align with 14 industry sectors and the newly established Stratified Medicine Hub (part of the Healthcare Innovation Hub) and its team of innovation professionals will play a key role in establishing links between our Partnership and potential commercial partners by using existing networks and developing new contacts to provide support for stakeholder engagement. At the time of application six industrial partners have signed up and discussions are ongoing with three additional pharmaceutical companies. Opportunities for collaboration will be identified through knowledge of partnership members, review of commercial product pipelines, clinical trial databases and patent searches. In addition to the direct contact with industry in the preparation of this application, Prof Luqmani and Dr Jayne are in ongoing discussions with NOCRI to facilitate clinical trials in GCA, through the Translational Research Partnership.

GCA is also of interest to diagnostic companies, as the potential for identifying disease-specific markers of risk or treatment response, as well as general markers of inflammatory disease, is appealing. Alongside the mechanisms listed above, the partnership will utilise its network to identify and engage new partners and can also promote the partnership through contacts within the British In Vitro Diagnostics Association (BIVDA). A workshop with BIVDA including representation from the Technology Strategy Board and Precision Medicine Catapult was held in June 2014, with 15 companies attending that led to three industrial partners supporting this application. We will continue to engage with the Precision Medicine Catapult once this has been fully implemented.