Glasgow Molecular Pathology Node

Epigenetic stratification of rheumatoid arthritis patients for response to biological Disease Modifying anti-Rheumatic Drugs

The Node platform enables and supports a pipeline of novel diagnostics which is aimed at driving beneficial change in clinical practice for patients worldwide and benefitting the UK economy through the commercial exploitation of the diagnostics. The newest addition to this diagnostic pipeline is an epigenetic biomarker signature that can be used in a clinical laboratory-based QPCR test to predict whether or not rheumatoid arthritis patients respond to Disease Modifying anti-Rheumatic Drugs (DMARDs).

RA is the commonest inflammatory polyarthritis in the UK, affecting >600,000 people. It causes pain, stiffness and disability, and is associated with significant co-morbidity and premature mortality. It is also a major cause of work-related unemployment and attracts enormous costs for the patients, society and the NHS. For instance, biological disease-modifying anti-rheumatic drugs (bDMARDs) alone costs NHS Scotland approximately £25-30M pa. Unfortunately, up to 40% of patients fail to respond to their first bDMARD, and only a minority of patients attain low disease activity or clinical remission.

The ability to predict responsiveness will not only enhance ‘quality of life’ for the patients but also ease the burden of this disease on society and the NHS. The therapeutic options for patients have increased with the arrival of a number of targeted bDMARDs that represent a major therapeutic advantage (e.g. TNF inhibitors and B cell depleting antibodies). However, there is still a substantial proportion of patient who only partially respond or do not respond at all to their first bDMARD but, importantly, many of these patients subsequently respond to a different bDMARD. The ability to stratify patients a priori into responders and non-responders will be an invaluable clinical tool to select patients in whom one biological agent may confer advantage over another. Moreover, it should also be appreciated that in early RA, patients are initially treated with conventional DMARDs (cDMARDs) before they can ever receive bDMARDs. The response scenario to cDMARDs in early RA is similar to bDMARDs, in the sense that only a proportion of patients respond whilst others do not. Only after a period of non-responsiveness to cDMARDs can patient progress on to the more expensive biological therapies.

In a recent study, Professor Carl Goodyear and colleagues evaluated a molecular prognostic biomarker in early RA patients. In brief, they identified an epigenetic chromosome conformational signature that can differentiate cDMARD non-responders from responders. The question that the new project will address is whether the same modality can be used to predict whether cDMARD non-responders but bDMARD naïve patients will or will not respond to their first bDMARD. With the support of the Glasgow Molecular Pathology Node and Confidence in Concept funding the research team will investigate this over the next 12 months.

The overall aim of the research team is to create prognostic biomarkers that can be used at multiple points during a patient’s clinical journey. Importantly, the development of these tests will enable clinicians to identify the most optimal treatment regime for their patients. This will have a major impact not only on patients (e.g. quality of life) but also on the socio-economic impact this debilitating disease.

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First published: 23 April 2018