Biomarker signature and US profile in Rheumatoid Arthritis.v1
Research type
Research Study
Full title
Biomarker signature and musculoskeletal ultrasound (MSUS) profile in Rheumatoid Arthritis (RA) patients: a pilot observational study.
IRAS ID
149600
Contact name
Peter Taylor
Contact email
Sponsor organisation
University of Oxford
Research summary
Summary of Results
Study title: Biomarker signature and musculoskeletal ultrasound profile in Rheumatoid Arthritis patients (BMUS Study): a pilot observational study
Funding for the study
This Study was funded by UCB Pharma
Who carried out the study?
It was carried out by the research group of Professor Peter Taylor at the Botnar Research Centre, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, UK. Collaborators included colleagues in the Department of Chemistry, University of Oxford, UK and the Harvard School of Public Health, USA.
Who participated in this study?
This pilot study involved the recruitment of 43 people with a confirmed diagnosis of Rheumatoid Arthritis (RA) from rheumatology clinics within the Oxford University Hospitals NHS Trust. We would like to express our gratitude to all study participants who generously gave of their time to support this research.
What were the key research questions?
A key objective of this study was to generate an archive of information about how people with rheumatoid arthritis respond to different kinds of drug treatment by means of a) sensitive ultrasound scanning of their joints and b) detailed measurements of cells or molecules in the blood, urine or stool. The next objective was to analyse this data and look for patterns that might predict response to treatment. This archive of information could then be used in the future to compare how these measures change in subjects participating in clinical trials of a new generation of treatments in order to give clues as to which treatments being tested are the most promising. We also set out to identify markers in blood or urine that might help distinguish whether pain reported in rheumatoid arthritis is due to inflammation or due to wear and tear of joints or other mechanical causes.
Why was this research needed?
In the last quarter century, there have been several important breakthroughs in understanding the different types on inflammation in the body that can lead to rheumatoid arthritis. As a result, new treatments have been developed which aim to switch off one of these types of inflammation. These are sometimes referred to as advanced therapies and each of them are similarly efficacious, having significant benefits in about two-thirds of patients treated. But it is not clear which patients will respond best to a particular type of advanced therapy. Five different classes of advanced therapies are now available on the NHS in patients meeting certain criteria as defined by the National Institute of Clinical Excellence (NICE). However, the clinical approach to selection of treatment for any given individual is undertaken more or less on a “trial and error” basis to see if a particular treatment works or not. Therefore, there is research need to develop new ways of determining if a treatment is going to work optimally as soon as possible after it has been started, rather than waiting many months before deciding that it does not work! There is also a research need to find substances we can measure in samples such as blood, urine and even in faeces that might help predict which treatment approach will give the best chances of success for an individual living with rheumatoid arthritis. This is particularly the case for people living with rheumatoid arthritis who experience pain because pain may be due to inflammation or to other causes such as wear and tear. This is important to know as the treatment approach may be different depending on the cause of pain. However, it can be very difficult in clinical practice to determine whether inflammation is the cause of all the pain or not.
What were the findings?
a. Ultrasound measurements
Our research has shown that ultrasound measurements of blood flow are a very sensitive way of demonstrating an early response to treatment in rheumatoid arthritis. But these tests can be so sensitive that they do not correlate well with clinical assessments of disease activity which are based on composites of several parameters including counts of the number swollen and tender joints as well as an overall score of disease severity (on a 0-100 scale) as assessed by the patient and separately assessed by the doctor.
b. Blood biomarkers
Using a technology called “CyTOF™” which provides information about the effects of inflammation in individual cells, we identified a potential association between treatment with a drug used early in the course of rheumatoid arthritis called methotrexate and a decrease in expression of a molecule called PD1 on the surface of two important types of immune cells (T cells) in blood. This finding may help us in future studies to understand whether a patient will respond well to methotrexate or whether an advanced therapy is needed early on. We also gained important new insights into how methotrexate works. We identified 12 immune cell subsets (CD8 T-cell subsets) and found that levels of a molecule called perforin were lowered in these cells after successful treatment with methotrexate.c. Urine biomarkers
We used a technology called nuclear magnetic resonance spectroscopy to measure a signature of chemicals in the urine and blood of patients with rheumatoid arthritis and to compare the findings to the amount of pain that each patient reported. We discovered a signature of chemicals in the urine that is associated with subjective pain intensity but unrelated to inflammation. But this was not the case in blood measurements. This may lead to a new urine test that could be used in the clinic to help determine the most suitable type of treatment for a patient with joint pain and avoid the risk of causing immunosuppression by overtreating inflammation with advanced therapies.d. Faecal biomarkers
We were unable to detect any reduction in faecal inflammatory cell markers after treatment for rheumatoid arthritis, potentially due to a lack of gut inflammation in patients. However, it was possible to measure reduction in inflammatory molecules. We identified several families of gut microbes significantly associated with inflammation, diagnosis, and anemia in rheumatic diseases but we were not able to confirm the involvement of one type of gut microbe (Prevotella copri) that has previously been found in stool samples in treatment-naïve patients newly diagnosed with rheumatoid arthritis.Summary of research
This research has generated a data repository providing a “high resolution” view of immune function at baseline and following initiation or change of treatment at different stages after presentation of rheumatoid arthritis. In undertaking this work, we have created a resource that permits exploration of the way in which a diseased immune system which is no longer in balance causes the physical and mental sequelae of rheumatoid and we have begun to identify measures in the blood and urine which help predict subsequent therapeutic responses of these various features of disease to different treatments.
REC name
South Central - Oxford B Research Ethics Committee
REC reference
14/SC/0266
Date of REC Opinion
25 Jul 2014
REC opinion
Further Information Favourable Opinion