Qualification of ultrasonography as a biomarker of prognosis and response to therapy in rheumatoid arthritis

Lead Research Organisation: Imperial College London
Department Name: Dept of Medicine

Abstract

Rheumatoid arthritis is a progressively disabling disease affecting about 1% of the population. There have been considerable advances in treatment, although the new biologic therapies are not effective in about one-third of patients. Furthermore, biologic treatments such as anti-TNF are administered by injection and are very costly, such that there is rationing in the UK. Only those patients with the most active disease become eligible, despite the particular effectiveness of this type of treatment in preventing progressive joint damage. There is an unmet need to develop biomarkers that will allow a doctor to accurately predict which patients are likely to have rapid and progressive joint destruction, so that these patients can be treated with the most effective preventative treatments available without having to wait until they have had disease for some time, by which stage the damage is already done and largely irreversible. Firstly, we want to look at a simple, non-invasive ultrasound technique that gives information about blood flow as such a predictive tool to identify poor prognosis patients. Secondly, because not all patients respond to the available therapies and the expensive ones are not as widely available as would be ideal, there is a need for new, affordable drugs. However, the drug development process itself is very costly and it is not always straightforward to prove that any improvements in disease after drug intervention are due to the drug itself without testing it on very large numbers of patients. Therefore, we seek to investigate the potential of ultrasound measures of blood flow to give a sensitive, early, and reliable indication of response to new treatments in smaller numbers of patients. If this approach is successful, the findings will have wider implications for more cost-effective approaches to new drug testing in future to (a) make new drug discovery for rheumatoid arthritis more efficient, and (b) minimize patient exposure to drugs that have turned out to have no significant benefit.

Technical Summary

Research objectives
1) To develop ultrasonographic imaging biomarkers that can inform management decisions on an individual patient basis.
2) To develop ultrasonographic measures of joint inflammation as a safe and reliable biomarker of efficacy, that can be used in early studies of novel therapeutics in patients to enable go/no-go decision making for further large scale clinical trials and to compare this with MRI.

Experimental design and Methodology
The work proposed is two phases. In phase 1, a cohort of at least 100 consenting newly diagnosed, seropositive patients meeting classification criteria for RA will undergo power Doppler ultrasonographic assessment of all ten metacarpophalangeal joints (MCPJ) in order to measure synovial vascularity. An image analysis programme will be used to measure the number of colour pixels in a region of interest in each MCP joint and the count in all 10 MCPJs will be summed to give the quantitative power Doppler Area (PDA). All patients will have radiographs of the hands and feet at baseline and one year. These will be scored for erosions and joint space narrowing by the modified van der Heijde-Sharp method. We will investigate relationships between baseline PDA and change in vdH-Sharp score using Spearman correlation. In parallel with this major objective, we will also collect serum- and whole blood-derived RNA to undertake a hypothesis-generating study to investigate the prognostic potential of candidate bioinformatics-based algorithms (signatures) of proteins and expressed genes using a small panel of candidate markers.
In phase 2, we will investigate the utility of quantitiative power Doppler imaging as a sensitive early efficacy measure in the context of a double-blind, randomized, placebo-controlled trial at intervals up to16 weeks of repeat dosing with a test drug from the portfolio of AstraZeneca, the industrial partner for this application. Power calculations indicate that 15 patients will need to be recruited into each arm.

Application and exploitation of the research results
The findings of these studies will be presented at national and international rheumatology meetings and will be written up with a view to submission for in publication in peer-reviewed journals. Positive findings of phase 1 will have implications for best management of early RA patients and positive findings in phase 2 will have implications for more cost effective approaches to future new drug testing in RA.

Publications

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Title Ultrasonographic 3D quantification of vascular signal within small joints 
Description Development of quantitative measurement of vascular signal within MCP and wrist joints as assessed by power Doppler technology. Pilot data show this to be a useful and novel technique for prediction of prognosis in rheumatoid arthritis. 
Type Of Material Physiological assessment or outcome measure 
Provided To Others? No  
Impact After conclusion of this study and completion of data capture, it is expected that this technique will inform clinical practice and prognostication of patients with early rheumatoid arthritis. 
 
Title Ultrasonographic quantification of synovitis 
Description Quantitative and 3 dimensional Grey scale ultrasound and power Doppler methodologies have been developed for rapid assessment of rheumatoid arthritis disease activity and prognostication. 
Type Of Material Physiological assessment or outcome measure 
Provided To Others? No  
Impact This research is expected to inform clinical trial design and rationalise treatment prescribing of biologic agents for management of rheumatoid. 
 
Description AstraZeneca 
Organisation AstraZeneca
Department Research and Development AstraZeneca
Country United Kingdom 
Sector Private 
PI Contribution Intellectual contribution by Principal Investigator to Astra Zeneca R&D
Impact Outputs mainly relate to MRC-funded work, in particular pilot data from the study and manuscript still in preparation as study comes to a conclusion and data capture is completed.
Start Year 2007
 
Description Crescendo Biosciences 
Organisation Myriad Genetics
Department Crescendo Biosciences
Country United States 
Sector Private 
PI Contribution Access to data
Impact Outputs from Crescendo still ongoing and relate to testing of peripheral blood biomarkers as part of this study.
Start Year 2008