Focus on University College London: B cells and beyond
Published on 01 April 2008
New B cell treatments, which are having a profound effect on people with severe rheumatoid arthritis and lupus, were pioneered at University College, London.
The team at the Centre for Rheumatology with Professors David Isenberg (left) and Michael Ehrenstein (right) in the foreground.
It was in 1999 that a rheumatologist from University College London (UCL), Jo Edwards, had his Eureka moment. Professor Edwards had realised that a drug then used for Non-Hodgkin’s lymphoma may also be effective in treating patients whose severe rheumatoid arthritis (RA) was uncontrolled.
With a colleague, Jo Cambridge, he set up a small trial of 5 later expanded to 22 patients and such was the positive response to the drug that Professor Edwards started seriously talking about rituximab as a possible RA cure.
Nine years and several national and international drug trials later, rituximab is approved by NICE for patients whose RA does not respond to anti-TNF therapy.
While not the cure that Professor Edwards predicted, it is an effective treatment, cheaper than anti-TNF and is administered much less frequently.
Arthritis Research UK professor of rheumatology at UCL David Isenberg, who heads a large academic rheumatology team, and a close colleague of Professor Edwards, says that although rituximab is now an accepted treatment, at the time its use for RA and lupus was controversial, and thought by the mainstream of academic rheumatology to be way off the mark.
B cells work by knocking out white blood cells
This was because, unlike most RA drugs at the time, rituximab was a B-cell therapy, not a T-cell therapy. It works by knocking out the body’s B cells (white blood cells that defend the body against viruses and bacteria by making antibodies). Patients have two infusions one to two weeks apart, with a second course of treatment when its effects start to wear off – anything from 6 months to 3 years later.
As with anti-TNF therapy, the main aim now is to refine the use of the drug and to predict who will respond most effectively, and to treat patients with early disease, rather than wait until they have failed on conventional therapies.
Now Arthritis Research UK has awarded a programme grant of more than £745,000 to Professor Isenberg’s colleagues, Dr Claudia Mauri and Professor Michael Ehrenstein, to carry out research which could lead to the design of a more selective drug and could mean removing some but not all the body’s white blood cells, leaving patients less open to infections.
“There are some patients who have been given rituximab on several occasions and have started getting chest infections, so there might be problems with giving repeated infusions,” explains Michael Ehrenstein.
Recent UCL experiments have shown that not all B cells are pathogenic (ie disease-causing). In fact a small subset called regulatory B cells are actually beneficial, capable of suppressing autoimmune disorders.
So the programme grant team is aiming to identify this particular subset, using animal models, healthy volunteers and RA patients from UCL. According to Dr Mauri, once this subset has been identified it could be clinically feasible to take out the good B cells along with the bad, increase their number in the laboratory, and then re-introduce them back into patients, whose immune system would then be less compromised, leaving them less prone to picking up infections.
"We thought we knew everything about B cells, but we don't"
Dr Mauri has been working in this field for many years, since she was at the Arthritis Research UK’s Kennedy Institute, and says it is only recently that this line of inquiry has been getting the attention it deserves from the rheumatology community. “We thought we knew everything about B cells, but we really don’t. The recognition of a B cell subset capable of suppressing disease as well as pathogenic B cells has important implications, providing novel treatment as well as refining the therapy.”
In a separate but related strand of research, Professor Ehrenstein has been working on MRC-funded work to see if it is possible to predict who will respond to anti-TNF therapy. He is now seeking Arthritis Research UK funding to take this further, in order to develop a diagnostic test which will predict overnight if a patient with early RA is likely to respond, and is therefore likely to go into remission.
Arthritis Research UK funds a raft of important research at UCL, with two non-clinical fellowships and a clinical fellowships on top of the programme grant, several project grants, infrastructure support and David Isenberg’s Professorship. The Centre for Rheumatology in the Windeyer Building in central London, where academic rheumatology is based, also has funding from the Medical Research Council, the Wellcome Trust, and the Department of Health and other bodies. Working alongside David Isenberg at the Windeyer is Professor Pat Woo, doyenne of research into childhood arthritis, whose clinical base is Great Ormond Street Hospital. Another strand of UCL/Arthritis Research UK academic rheumatology is based at the Royal Free Hospital in Hampstead, where the names of Professor Carol Black, Chris Denton and David Abrahams are synonymous with research into scleroderma and Raynaud’s phenomenon.
David Isenberg has been at the academic helm of the centre for rheumatology since 1996 and sees his role if not exactly that of an elder statesman, then certainly as a “talent-spotter, nurturing talented basic and clinical scientists who want to work in autoimmune diseases.”
So as well as Michael Ehrenstein and Claudia Mauri, the current Arthritis Research UK team includes Dr Mark Lazarus, looking at how B cell depletion works in lupus, Dr Liz Jury working on lipids and the immune system in lupus patients, and Dr John Ioannou, currently working in Australia on warning signals that contribute to inflammatory arthritis. Other leading members of the team and ex-recipients of charitable funding are former fellow Dr Ian Giles, and rheumatologist and educationalist Dr Anisur Rahman, both of whose academic specialist area is antiphospholipid syndrome, the blood clotting disorder allied to lupus.
On the clinical side, the stylish new University College Hospital, which cuts a fine dash on the Euston Road, is the centre for the treatment of the whole gamut of rheumatic diseases, from chronic pain and hypermobility and osteoporosis, although lupus and RA predominate. It sees more than 3,000 new patients and 15,000 follow ups a year.
Rituximab is effective in treating lupus
Lupus has long been Professor Isenberg’s particular area of expertise, and he is delighted that rituximab, while neither licensed nor NICE-approved for this condition, is so effective in treating it.
“It’s simply not worth their while for drug companies to gain a licence for lupus. It affects around 30,000 people as opposed to the 400,000 who have RA in the UK,” he says. However the UCL team have had relatively little difficulty in getting primary care trusts to pay for rituximab treatment. Until recently this was just for severely ill lupus patients – they have just treated their 50th patient – but clinicians have just been given the go-ahead to treat newly diagnosed patients.
“There is excellent data on the efficacy of rituximab from the literature, and it’s no more expensive than other therapies such as intravenous immunoglobulin or cyclophosphamide infusions,” adds Professor Isenberg. “As long as it is used with due care and is very effective and well-tolerated.”