Focus on Birmingham
Published on 01 November 2011
RHEUMATOID ARTHRITIS: catching it early, hitting it hard
Professor Chris Buckley and his team. Professor Janet Lord is fourth from the left, with Dr Andrew Filer, Dr Mark Cooper, Professor Caroline Gordon and Dr Karim Raza to her right.
Our researchers in the Rheumatology Research Group in Birmingham are leading the way in the fight against early rheumatoid arthritis by catching and treating it quickly. Jane Tadman reports on their progress.
Catching rheumatoid arthritis early and treating it aggressively to reduce preventable joint damage is the mantra of most researchers and clinicians working in rheumatology.
However, reality has a nasty habit of getting in the way of such worthy aspirations. For one thing, many people with suspected rheumatoid arthritis don’t seek medical help quickly enough to take advantage of the three month ‘window of opportunity’ that is now generally accepted to be the best time to start effective medication. Nor are they always referred on quickly enough from their GP to the rheumatologist.
It is not yet possible to reliably predict which people with early signs of inflammatory arthritis will go on to develop rheumatoid arthritis, as, for some, their early symptoms resolve without the need for treatment. This remains a key challenge for researchers in the field.
Researchers at the University of Birmingham have been considering these thorny issues for several years now, from both the basic science and clinical research perspective.
In particular, Arthritis Research UK professor of rheumatology Chris Buckley and his team have been edging ever-closer to understanding more about the processes that go wrong in early disease. They’re doing this by using cutting-edge techniques such as high resolution ultrasound and analysing blood, urine and tissue samples taken from patient volunteers, which will help them to produce more accurate diagnostic and prognostic tests to predict the likely course of a patient’s disease, and in particular whether inflammation will persist or resolve.
In parallel, they are also developing ways of reducing delays and speeding up the assessment process so that patients can be “fast-tracked” for treatment.
Under the microscope: Arthritis Research UK professor of rheumatology Chris Buckley at the University of Birmingham
The basic science perspective
Research carried out largely by Professor Buckley and Arthritis Research UK clinician scientist and senior lecturer Dr Andrew Filer is concentrating on fibroblasts, a common connective tissue cell.
Working with patients recruited from the Birmingham Early Arthritis Clinic together with Dr Karim Raza, who set up the clinic in 2000, they are studying the mechanisms operating in the earliest clinically apparent phases of joint inflammation.
“There’s a different set of processes going on in early disease, and we really need to understand what’s going on in the tissue at that early stage,” explains Dr Raza.
“From the work we’ve done we’ve found that this stage of disease is driven by interactions between the white blood cells of the immune system, and fibroblasts.”
Fibroblasts, and their role in regulating the switches involved in whether arthritis resolves or persists, are of interest to the team because treatments such as the current biologic drugs aimed at targeting the body’s white blood cells - traditionally thought to be the villains in arthritis – have proven to be limited in their ability to repair damaged tissue. Fibroblasts could offer another targeting option.
Adds Dr Filer: “Using new ultrasound and biopsy methods we’re looking directly at fibroblasts from the joints of patients during the earliest stages of disease.”
"We’re testing to see if the differences we see in fibroblasts can predict the type of arthritis developed by patients. Using fibroblasts to predict diagnosis and outcome has radically changed cancer medicine, and we’re not that far behind. We aim to establish reliable and sensitive fibroblast markers which can enable doctors to predict the diagnosis for new patients at a very early stage - so enabling treatment to be correctly targeted in each case." - Dr Andrew Filer
Other important members of the team are career development fellow Dr Dagmar Scheel-Toellner, a basic scientist who with Dr Karim Raza and Dr Filer is investigating the inflammatory cells and the soluble products they produce in rheumatoid arthritis joints in the earliest stages of diseases. Together, with Dr Raza and Professor Buckley, senior lecturer Dr Steven Young is looking at the chemical signature in the blood and urine of patients with very early inflammatory arthritis that either gets better or goes on to develop into rheumatoid arthritis.
The clinical research perspective
Arthritis Today has previously reported on research by Dr Karim Raza and specialist nurse Kanta Kumar, which identified that the main reason for delay in starting early treatment for rheumatoid arthritis was not the failure of GPs in referring their patients to hospital, but delays in patients visiting their GP in the first place. With NHS funding, Dr Raza is now developing ways in which to reduce these delays nationally, by developing educational targets and information resources aimed at getting people with suspected rheumatoid arthritis to go to their GP earlier than currently.
He acknowledges that there could be a knock-on effect if more people with suspected rheumatoid arthritis seek their GP’s advice. “If you start raising awareness you will get people going to their doctor earlier and earlier with more and more undifferentiated symptoms – stiffness, aches and pains - so in parallel with getting people into the system more quickly there have to be more robust strategies to predict the outcomes for people with early arthritis.
That’s where using ultrasound comes in. “You can pick up signs of inflammation that you cannot spot clinically,” explains Dr Raza. “For example you can confirm that someone has arthritis in their knee, but you can also spot inflammation in other joints which are asymptomatic. If you put that together with blood tests and other clinical tests and it helps make a swift diagnosis - and if you treat people in the early stage you will slow down the rate of progression.”
Professor Buckley and his team have an eye to the future. Ultimately they want to prevent rheumatoid arthritis from occurring in the first place.
“Prompt treatment is essential once patients have developed rheumatoid arthritis,” he says. “However, ideally you would want to identify individuals at risk of rheumatoid arthritis and intervene to prevent them developing the condition in the first place. But we need to know which cells to hit as those processes that are important in the very early stages of arthritis may not be the same as those later on. That’s where fibroblasts might prove to be interesting new therapeutic targets.”
And Dr Raza continues: “We now aim to extend our inflammatory arthritis research cohort to include new individuals and their relatives, who are at risk of developing rheumatoid arthritis, so that we can study this phase of disease in more detail.”
Other related research
The Rheumatology Research Group are also involved in a brand new EU-funded translational study to find out how gum disease is implicated in the development and progression of rheumatoid arthritis.
Around 10 per cent of rheumatoid patients are thought to suffer from moderate to severe periodontal gum disease. Clinical lecturer Dr Paola de Pablo and Dr Dagmar Scheel-Toellner are working with colleagues in the School of Dentistry in Birmingham to explore how bad gums might lead to worse arthritis and whether better dental hygiene will improve the symptoms of patients with rheumatoid arthritis.
Working alongside Professor Buckley is Professor Caroline Gordon, respectfully known in rheumatology circles as the “Queen of lupus”. As well as her clinical work – she is an acknowledged expert in the field of pregnancy and inflammatory autoimmune conditions - Professor Gordon runs a number of commercial trials testing new drugs that target lupus, and until recently was the lupus lead on the Arthritis Research UK autoimmume clinical studies group. She is also involved in research, also charity funded, that is looking to develop a quality of life tool to be used in people with lupus that captures their worries and concerns as their disease progresses; an instrument that demonstrates patients’ quality of life as well as for measuring disease activity.
In their work on novel predictive approaches and therapeutic strategies, Dr Raza and Dr Filer are working closely with colleagues, endocrinologist Dr Mark Cooper and immunologist Dr David Sansom. Both men are Arthritis Research UK-funded; Dr Cooper to investigate alternatives to steroids, and Dr Sansom in looking at the anti-inflammatory properties of vitamin D in rheumatoid arthritis.
Just over the way in the brand new Queen Elizabeth Hospital is the Centre for Translational Inflammation Research and Centre for Healthy Ageing Research, Professor Janet Lord is heading research that looks into what keeps our immune systems healthy in old age. Another academic with a good line in snappy one-liners, Professor Lord subscribes to the adage: “old age should be enjoyed rather than endured.” Among her many projects is a study looking at the effects of stress and depression in hip fracture patients, which has shown that old people’s stress responses are up to seven times higher than younger people.
FOCUS ON BIRMINGHAM
Birmingham is a major centre of Arthritis Research UK-funded work, currently in receipt of £1.5 million. The Rheumatology Research Group is based in the school of Immunity and Infection in the College of Medical and Dental Science, and researchers are also active in the MRC Centre for immune Regulation. Team members also now work in the new Centre for Translational Inflammation Research in the brand new Queen Elizabeth Hospital, and run clinics throughout Birmingham. Chris Buckley, Arthritis Research UK Professor since 2002, who has a good line in sound bites, says: “We don’t have an institute of rheumatology. We collaborate with minds; not places.” He heads a team of academic and clinical rheumatologists, GPs, biological and social scientists and allied health professionals, with the aim of improving clinical outcomes for those with, and at risk of developing, rheumatoid arthritis.