Archive Articles

Dr Geraldine Cambridge

• Article in Newsletter 58, March 2005
• Writing in Newsletter 53, December 2002
• Writing in Newsletter 51, March 2002

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» Research

Article printed in Newsletter 58 March 2005.

Results of an Open-Label Pilot Study using Rituximab in the Treatment of Dermatomyositis - USA

The Support Group has funded the cost of Rituximab for a pilot study of this B-cell depletion therapy in unresponsive Dermatomyositis patients at University College London. The trial was completed at the end of last year and we are awaiting publication of the results. Dr G Cambridge said, “The beneficial effects of Rituximab in this subset of patients looks a promising therapeutic option but a larger trial is needed.” You may be interested to read about a similar study conducted by Todd Levine in the USA. He has recently published in the Arthritis & Rheumatism journal promising data.

The following is an extract of the findings from the USA study: “The results of this study help to establish the critical role of B cells in the pathophysiology of DM and indicates that B cell depletion with rituximab appears to be effective in the treatment of this condition. These results suggest that this approach is well tolerated, convenient, safe, and without complications such as increased infection rates. However, the optimal therapeutic dose of rituximab in DM is currently unclear, and the schedule for re-treatment, based on the return of signs and symptoms of the illness, has not been evaluated in this pilot study. Therefore, further investigation to understand the processes involved and to ascertain the effect of retreatment at relapse is warranted from larger controlled clinical trials.

In this small open-label study of patients with DM, rituximab consistently depleted B cell levels. This corresponded to an improvement in the symptoms of the illness. These results are sufficiently encouraging to prompt a more formal evaluation of the role of B cells in the pathophysiology of DM, and the value and place of rituximab in its treatment.”

Potential New Therapies for the Treatment of DM/PM

Dr Cambridge, our Charity President, is an immunologist working on B cell depletion therapy for the treatment of Rheumatoid Arthritis at University College London.

Dermatomyositis and polymyositis both result in muscle weakness (there are exceptions). However, the immunological cells which predominate in the muscle and carry out the series of events that leads to muscle damage are different between the two diseases (this can be seen by muscle biopsy). Because of the nature of these immunological events B cell depletion therapy will theoretically be more effective in dermatomyositis than polymyositis. However, B cell depletion therapy is one of many new emerging therapies that could be future treatment for myositis.

B cell depletion therapy has been demonstrated to be effective in Rheumatoid Arthritis patients and Dr Cambridge believes that this therapy has the potential to treat dermatomyositis sufferers. This type of therapy is novel and in its very early stages. No trials have yet been performed in Myositis patients to demonstrate whether it is more effective than conventional therapy. Small scale testing of the therapy is soon to be carried out and Dr Cambridge is optimistic that it may become a therapy for sufferers of dermatomyositis.

In dermatomyositis, B cells (rather than T cells in polymyositis) are thought to govern the series of inflammatory events. B cells are the white blood cells which when mature develops into ‘plasma cells’ which make antibodies. As well as being a very selective and effective way of defending the body from attack by bacteria and viruses, antibodies can also turn ‘bad’. It is thought that such a ‘bad’ population of antibodies result in the inflammation of joints and other tissues in patients with Rheumatoid Arthritis. Although there is less evidence for such aberrant antibodies underlying the disease process in dermatomyositis, the nature of the disease suggests that they may play a role. B cell depletion therapy removes a large quantity of the B cell population for from 4 to 9 months. In patients with Rheumatoid Arthritis, the patients can remain disease-free for up to 3 years after a single treatment. Thus, this treatment unlike conventional drugs does not have to be given continually.

One of the drugs in the limelight at the moment is Entercept. Entercept is the name given to one of the anti-TNF drugs. Research in RA and other inflammatory diseases has shown that TNF may be an important mediator in the inflammatory events of the joint. Macrophages are the main source of TNF but activated T cells can also release TNF. TNF is a powerful inflammatory mediator that can perpetuate and amplify the disease process.

If TNF is released by macrophages, which we know are present in muscle then Entercept and other anti-TNF drugs could benefit dermatomyositis and polymyositis sufferers. However, it is not yet known whether macrophages in the muscle of myositis sufferers release large quantities of TNF, but raised levels of TNF have been found in the blood of patients. The really good news is that a clinical trial of this therapy is underway in the USA.

Although the anti-TNF drugs are not being widely prescribed in the UK, some patients here have tried the therapy with mixed responses. Anti-TNF drugs are not cures but very effectively block a potentially key player. Until we know what actually underlies the disease process in myositis (both PM and DM), we can only try to target our treatment at the most likely immunological candidates. Future research will need to be adopted to determine whether TNF is important in myositis and to ensure that treatment is given wisely, determined by what type of sufferers are likely to benefit.

However, until there is a proper controlled trial of B cell depletion or indeed any of the anti-TNF drugs in myositis, we have to be cautious in our optimism. But at least there is some progress and a general feeling that more good options for treatment may be available in the near to very near future.

“As mentioned at the last AGM, at The King’s Fund, Professor Jo Edwards (Dr M Leandro and myself) has been carrying out pilot studies on a new treatment for patients with Rheumatoid Arthritis, this treatment is at present the subject of a large controlled trial in Europe, the UK and Australia. It is based on the idea, for which we believe there is a lot of evidence, that the disease causing process is dependent on the production of particular antibodies, called Rheumatoid factors in these patients. What we do is selectively remove the population of blood cells, B- lymphocytes which produce antibodies, in our pilot study of 23 patients, the way this was done was to inject with 2 doses of a monoclonal antibody directed against the B-lymphocytes, together with some steroids and sometimes cyclophosamide within a two week period. After that, there was not other treatment, the majority of the Rhuematoid patients have remained well after this single course of treatment from 6-36 months! We have had not real problems with infections or any side effects, the results of the big trial will be revealed later in the year.

Now, for Dermatomyositis. A Dr Levine in the States has been treating DM patients in a similar way but without the cyclophosamide and has reported excellent results. Unfortunately, Dr Levine has recently been taken ill himself so I have no more information at present but know that a publication is on its way.

Many years ago, we at UCL, came to the conclusion that B –lymphocytes were the likely culprits in DM so we aren’t too surprised at his success. Hopefully, someone here will follow up on Dr Levines work.”

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