Friday, September 6, 2013

Interview: Professor Jonathan Edwards on the UK Rituximab trial

SEPTEMBER 3, 2013 by Sasha:

The charity Invest in ME’s plans for a UK Rituximab trial got a substantial boost at the end of July when Jonathan Edwards, Emeritus Professor of Connective Tissue Medicine at University College London (UCL), agreed to act as their advisor for the study.

‘No UK expert is better placed than Professor Edwards to advise us on setting up a Rituximab trial for ME patients’, stated the charity, and it’s hard to argue with that. Drs Fluge and Mellabelieve that the timing of ME patients’ response to Rituximab-induced B cell depletion indicates that ME may be an autoimmune disease, and it was none other than Professor Edwards who proposed, in a 1999 paper in Immunology, that self-perpetuating B lymphocytes drive human autoimmune disease. He followed that up with Phase I and ‘proof of concept’ Phase II studies of Rituximab for rheumatoid arthritis published in the New England Journal of Medicine in 2004 that established empirically the role of B cell depletion in autoimmune disorders.

In order to set up the Rituximab studies for rheumatoid arthritis in 1998, all he had to do, he says, ‘was to write a letter saying I was wanting to do it and get a letter back that just said, in effect, “in this case we will not say no”.’ But by 2010, ‘the bureaucratisation and commercialisation of the NHS had got to such a stage that I concluded I would never be able to get involved in anything as productive again. So I took early retirement to do other things.’ And with the ME Rituximab trial? ‘I am now hoping to prove myself wrong.’
Professor Edwards has suggested his old Rituximab research team, led by Dr Jo Cambridge, to run a small trial of about 30 patients at University College London. He clearly understands the need for this research in this most neglected of diseases. In a statement to Invest in ME, he said, ‘After the Invest in ME Conference I began thinking about my personal experience of patients and friends with ME/CFS. I was sent a copy ofLost Voices by Invest in ME, which made me think more. It struck me that, whether or not results are positive, further trials of Rituximab for ME/CFS should be encouraged not only because impact on life for those affected can be so severe but also because further trials could give clues to disease mechanism.’

We’ve been very fortunate on Phoenix Rising in that, shortly after making this statement, Professor Edwards joined the forum here and has been generously answering questions and explaining the science behind the effects of Rituximab. He very kindly agreed to be interviewed about the trial, and the questions below include those from members of Phoenix Rising posted in response to an earlier article about the study.


Sasha: How does Rituximab make sense as a treatment for ME?

Prof. Edwards: Illnesses due to immune system malfunction tend to look like infections but with no persistent infection to find. ME would seem to fit that. True autoimmune diseases are due to B cells making antibodies against the body’s own molecules. In many we have found the autoantibodies, but that was not always so and some have only been discovered recently. There are also common conditions like polymyalgia that may well be autoimmune but for which no autoantibodies have been found. Even in multiple sclerosis we know antibodies are being made in the wrong place but not exactly what they are against. In several autoimmune diseases the antibodies cause inflammation with a rise in blood tests like CRP but not in all. So it would not be so surprising if ME included one or more diseases due to autoantibodies that have not yet been discovered and for which we have no good markers for effects, like CRP.
If this is so we might expect to find some changes in B cell life history in ME and although the findings are subtle, we do have such evidence from Dr Bansal’s work. There is also some evidence of altered NK function but I think this is more difficult to interpret. Moreover, it is hard to see why NK function should suddenly change in a person who was previously well, unless secondarily to some other immune problem. In contrast we know that B cell malfunction often starts up in previously well people.
Many autoimmune diseases respond to Rituximab and we would not expect anything other than B cell related diseases to respond, so the Norwegian finding of a response to Rituximab is strong evidence for an autoimmune basis in at least some patients.

Sasha: How does the way that Rituximab might work for ME relate to the design of the planned trial?

Prof. Edwards: What I am currently thinking is that plans for a trial should focus on trying to link the evidence from Norway for a B cell basis for at least a proportion of cases with the evidence for B cell dysregulation from the study from Dr Bansal. Dr Bansal’s work suggests that young B cells are coming out of bone marrow under different rules. That fits well with an autoimmune process. Changes in immune regulation can make numbers either go up or go down and it can be difficult to see why it is one rather than the other. So my feeling is that what is important here is not so much the particular change seen but the suggestion that there may be some consistent change that we could use as a clue and a marker to relate further research to.

Sasha: Is a study of only 30 patients large enough to be of value, when there will be 140 in the Haukeland trial?

Prof. Edwards: I think the second Haukeland trial is big because there are specific requirements for numbers of patients being treated for licensing authorities. There is no good scientific reason for requiring these numbers but all regulators like rules. I think it may be largely a safety issue. I think a good small study can take the science forward. I also think it would be wrong to recruit more patients than we need for a specific purpose. In some ways I see the important objective not so much as ticking license boxes as getting scientific evidence that makes it so clear that B cells are involved (if they are) that further research will have a rock-solid base from then on. It would also be much more easy to justify compassionate, off-label use for severe cases pending formal licensing.

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Karen Robins said...

When is the UK trail likely to start?

Karen Robins said...

apologies, of course i mean 'Trial'


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