Focus on Birmingham
Published on 01 January 2008
With funding of more than £1million from Arthritis Research UK and a healthy income from other major research bodies, the Rheumatology Research Group at Birmingham University is committed to tackling rheumatoid arthritis – the earlier the better.
"Rheumatoid arthritis is like a box of smarties; you have blue, red and orange ones."
Catching rheumatoid arthritis (RA) early and stopping its development by administering aggressive early treatment is a concept that has been occupying the minds of many researchers and medics over the past few years.
In Birmingham, it’s long been more than a concept. For the past few years researchers and clinicians at the university’s Rheumatology Research Group have been concentrating their combined efforts to test their hypothesis – that if you catch certain patients with rheumatoid arthritis early enough and treat them aggressively - you can effectively 'switch off' the condition in its tracks.
While other rheumatology research centres in the UK are pursuing similar work, what makes the Birmingham research different is that they have managed to carefully select a small cohort of patients with very early disease (within 3 months of onset of symptoms) in whom they have studied the processes operating in the inflamed joints.
As a result of the observations they have made, the group is now about to run a small clinical trial to treat these patients for 6 months with anti-TNF therapy. At the end of that time the expectation is that the patients will be symptom-free. If it works it could be hugely significant and have a big impact on how patients are treated.
This work is a perfect example of how basic science and clinical research are working together to provide translational research in which clinical practice is directly affected by what happens in the lab.
The Birmingham team, based in the MRC Centre for Immune Regulation, is headed by a basic scientist and professor in experimental rheumatology, Mike Salmon, and Arthritis Research UK professor of rheumatology, Chris Buckley, who has a dual role as a clinician and researcher. The pair have a close working relationship, and for the past few years have been involved in a series of Arthritis Research UK programme grants trying to address the seemingly intractable question of why inflammatory arthritis doesn’t go away.
Fifty per cent of people who develop joint pain and stiffness find their symptoms do in fact go away within a few months. But the remaining 50 per cent will go on to develop rheumatoid arthritis or another type of persistent inflammatory arthritis. The aim of the Birmingham group has always been to discover why this is so. Working with Dr Karim Raza, a former Arthritis Research UK clinical research fellow who now runs the rapid access early synovitis clinic at the City Hospital, Chris Buckley and Mike Salmon have made some important advances in this area.
“We know from our previous work that patients who do not get better tended to be in two groups: those who have a whole clutch of chemical messengers (cytokines) in common, and those who do not,” says Professor Salmon. “It was very interesting because all those in the group with a particular cytokine pattern in their joints developed rheumatoid arthritis. Those in the other group had persistent arthritis that didn’t fulfil the criteria to be rheumatoid arthritis; a mixture of reactive arthritis, psoriatic arthritis and other non-rheumatoid types, which was a surprise finding.”
Chris Buckley uses a fun analogy to clarify this process. “Rheumatoid arthritis is like a box of Smarties; you have blue, red and orange ones. People who present with these particular cytokines are the red Smarties, if you like; the cohort is very well-characterised. We are 99 per cent certain because of their cytokine profile that they will have rheumatoid arthritis. This has always been the challenge – to know which patients to treat with aggressive therapy early.”
Ultrasound to detect inflammation
An interesting new development that the team is utilising is ultrasound imaging, which helps to increase their ability to detect inflammation in the joint early on. This work, led by clinical lecturer Dr Andrew Filer, has the added advantage that it enables easy access to the joints to obtain fluid that otherwise can be quite difficult to aspirate.
The knowledge gained from the programme grant will be used to inform the small drug trial of etanercept over 6 months. “It is testing our core ideas at clinical level,” says Mike Salmon. “Other centres are treating all early rheumatoid arthritis patients with anti-TNF but a large number of them (up to half of the total) will get better anyway, with no treatment. So our reason for being restrictive is that we can really identify the right patients. If you treat everyone, you could never achieve the statistical power to show an effect.”
Although the focus of the Birmingham team’s work has been in understanding what is going on in the joints of patients with very early rheumatoid arthritis, it is clear that many patients are not actually being seen within the first few months of the onset of their symptoms.
With Arthritis Research UK funding, Dr Raza and clinical research nurse Kanta Kumar have been looking at the reasons for this. Their findings, some of which have been published in the journal Rheumatology, are fascinating if rather depressing. Their study showed that there was an average delay of nearly 6 months between the initial onset of symptoms and being assessed by a rheumatologist in hospital, and the majority of delays occurred because sufferers failed to seek medical advice at an early stage. On average people waited 3 months from the onset of symptoms before going to see their GP.
Kanta Kumar, Karim Raza and Andrew Filer.
“The main reason for this is that patients don’t recognise the significance of their symptoms,” says Karim Raza. “When their joints become painful, swollen and stiff they didn’t think that this is a serious condition for which effective treatments are available.
Many patients will go to their GP only when they get to the stage that they can no longer do the things they used to be able to do, and they go looking for symptomatic relief. In most cases they have no awareness of rheumatoid arthritis as a diagnosis and certainly do not link their symptoms to this condition.”
The Birmingham group has carried out a qualitative study to explore the reasons for the delay in seeking medical help. “People’s personalities often dictated whether they sought help – those who came early were often more proactive, with independent, busy lifestyles and self-initiative, possibly other co-morbidities and a family history,” adds Kanta Kumar. “One woman went to the GP within 24 hours of symptoms developing because she had cared for her mother who had rheumatoid arthritis for 20 years and therefore knew the signs. But such people were in a distinct minority.
“Most people who went to the GP had not heard of rheumatoid arthritis at the time. When we asked them the question: ‘If you’d known then what you know now would you have done something more quickly?’ They said ‘Yes, of course, but we didn’t know about rheumatoid arthritis like we did about heart disease or cancer. We’ve never seen any posters or seen anything about it on TV.’ There was a lack of awareness generally in these patients. They viewed their symptoms as an extension of the norm, perhaps aggravated by an activity such as gardening or decorating, or something at work.”
Dr Raza points out that that their study has its limitations. “West Birmingham and Sandwell is a socio-economically deprived inner-city area. We now need to look to see how generalisable these themes are. Would these same themes be replicated in affluent suburbs?
A big part of the population is missing out
"We’re going to develop a questionnaire based on themes that have come out of this qualitative study which we will distribute widely to study this area in a much broader way; something that is essential if we are to develop an educational campaign that really addresses the reasons patients delay in consulting their GP. A big part of the population is missing out on the opportunity for early intervention of new treatment because it takes so long before they can be assessed."
Another strand of the research, says Professor Caroline Gordon, who leads the Arthritis Research UK–funded clinical studies, is looking at rheumatoid arthritis and lupus patients’ beliefs about medicines via focus groups. A previous study done by the group highlighted that patients from an Asian background had more concerns about the medicines they took for rheumatoid arthritis or lupus, and viewed medicines as being more harmful and over-used than did patients of white British origin. This work has been taken forward by Kanta Kumar who is investigating the reasons for these views.
“Once we get people into the clinic, we want to find out the issues that determine whether they take their therapy,” adds Caroline Gordon. “The most important thing is to prevent complications of the disease, and the disability that ensues. We want to get to grips with what people believe about medicines to see how we can improve our educational programme and materials for our patients, to make sure they make the most of our recommendations. We want people to understand about their disease, their drugs, and why they have to take them.”