Long term relief from arthritis could evolve from B-cell targeted treatments

June 16, 2004

Long term relief for arthritis sufferers could be one step closer, thanks to a study of B-cell targeted therapy published today. The study from UCL reveals a major but hitherto poorly acknowledged role for B-cells in the most common and severe form of arthritis to affect younger people. By targeting B-cells, which are part of the body's immune system, it may be possible to break a key vicious cycle underlying the disease.

The drug trial, led by UCL Professor Jonathan Edwards, published today in the New England Journal of Medicine, explored the possibility of using a one-off drug treatment to banish the symptoms of rheumatoid arthritis form the body for months or years, with the ultimate aim of permanent relief, rather than relying on continuous drug therapy.

Of 161 patients involved in the study, 43% of those receiving a short course of B cell targeted therapy based on the drug rituximab found arthritic symptoms such as joint pain, swelling and stiffness were reduced by more than half as measured six months later, compared with 13% in the control group who took conventional drugs only.

The study was designed to assess improvement over six months but it was found that in many cases improvement was maintained for at least a year, confirming pilot studies at UCL suggesting an average benefit lasting over a year and sometimes as long as three years.

Previous laboratory research at UCL had led Professor Edwards and colleague Dr Jo Cambridge to suggest that antibodies directed against the body's own proteins might not only cause inflammation in rheumatoid arthritis but might also create a vicious cycle driving the disease on. Antibodies are made by B-cells and the idea was put forward that removing B-cells might cause the cycle, and the disease, to collapse.

Experience at UCL indicates that permanent relief from a single course of treatment is not yet possible. However, the fact that improvement can last for a period of years suggests that the approach is on the right track. Moreover, studies from UCL and elsewhere in other autoimmune diseases such as lupus are producing similar results.

Professor Edwards says: "This study provides clear evidence for the importance of B-cells in rheumatoid arthritis, heralding a major shift in our understanding of the disease.

"The cycle underlying autoimmune diseases such as rheumatoid arthritis may be similar to a bug in a computer that makes it loop and crash. B-cell targeted therapy is like rebooting the computer of your immune system to sidestep the bug.

"As is often the case, if you have not removed the bug completely the computer system may crash again. This seems to be where we are at present, possibly because the current treatment does not remove more than 80 to 90 per cent of B-cells, where the ideal treatment would knock out 100 per cent of cells.

"The challenge is to break the cycle once and for all. Many different B-cell targeted drugs are now in development and I am optimistic that long term benefit from a single treatment is achievable.

"People with arthritis desperately want to be free of painful, sleepless nights and fatigue and stiffness in the day. They also want to be free from the burden of long term drug treatment. This is what we should be aiming for."

Around a billion B-cells, or lymphocytes, are created every day by the body's immune system. B-cells generate antibodies to help fight infections. Each B-cell makes a different antibody by shuffling its antibody genes. B-cells that by chance make antibodies to the body's own proteins normally disappear. However, very rarely it seems that they can set up the vicious cycle that allows them to grow and produce damaging effects, known as autoimmunity.

Current B-cell targeted therapy works by knocking out 'bad' B-cells, but also knocks out useful B-cells for a period of months. The effect on 'bad' antibodies is greater than on useful antibodies but after repeated treatments levels of useful antibodies may be reduced.

This suppression of the useful side of the immune system, with a risk of infections, is a common problem with treatments for autoimmune disease. Experience at UCL suggests that chest infection may be more common during the months after B-cell targeted treatment.

For this reason further studies are needed to ensure the treatment is as safe as possible. It is also an incentive to develop B cell targeted therapy either to remove only disease-related B-cells or to ensure that treatment is powerful enough to avoid the need for repeated courses.

Over 350,000 people are affected by rheumatoid arthritis in the UK, which can start at any age from 15 onwards.

Professor Jonathan Edwards is Professor of Connective Tissue Medicine at University College London.
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University College London

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