Interview: Professor Jonathan Edwards on the UK Rituximab trial

Prof Jo Edwards
Professor Jonathan Edwards

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 Mella believe 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 of Lost 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.

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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.

Sasha: Does having smaller numbers make more detailed biological measurements before, during, and after treatment more affordable?

Prof. Edwards: Yes, cost is always a factor and although doing twice as many samples may not cost twice as much the dyes used for B cell studies are costly, as is the labour for the procedures, and there is not much saving with bulk. That is probably not a critical factor for the trial design, however. For that I think the key question is about making sure we are doing the right thing by the people who are volunteering to be involved.

Sasha: Could samples from the initial Haukeland trial be studied at UCL to understand why those patients who responded did so?

Prof. Edwards: The Haukeland team may be oncologists but they have been very quick to see the immunological implications of their findings and follow them up. They will be looking at everything they can think of in their samples. However, the studies I think we want to look at in more detail require fresh preparations of B cells analysed within 24 hours, so the first Haukeland study will not help. And even if further patients are treated in Norway I do not think it is practical to study those cases in the UK because samples need to be processed all in exactly the same way, with control samples run alongside at the same time. It is a bit like getting your photos printed in different shops – the colours for each batch can come out quite different.

Sasha: Do you have a sense already of what to look at to distinguish between responders and non-responders?

Prof. Edwards: There are some clues but my feeling is that it is going to be important to do a little more preliminary lab work at UCL before deciding on a trial design. I have some ideas about what measurements might split patients into groups. As to which is the more likely to respond I could not say for sure. But that need not matter. The logic that appeals to me is that if we can show that groups separated on B cell measurements have statistically significant differences in responses then we know that there are real responses going on.

Sasha: Does it make sense to recruit severe cases for the trial because the clinical effect size and change in markers might be expected to be bigger?

Prof. Edwards: I think severe cases should be included if it is practical. In fact my experience is that clinical benefits tend to be most obvious in moderately severe cases, perhaps because really severe cases have resistant disease, but excluding severe cases from trials is in general terms a recipe for getting an unhelpful result.

Sasha: Is being on Phoenix Rising helping you?

Prof. Edwards: Yes, I am learning a lot about the problems people with ME experience and I am also learning a lot of science from those who have researched things themselves.

Sasha: Is there anything else we can do that will be useful to you (aside from fundraising)?

Prof. Edwards: Not really, other than continue the dialogue. I guess that will go in bursts a bit. We have already covered a lot of ground and it may be time for things to quieten down. But I am interested in anything new coming up – like the paper on eye movements [referred to on the forum] – so I am hoping things will hot up again from time to time.

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I’m very grateful indeed to Professor Edwards for generously answering our questions and I suggest that for continuity, any additional questions for him be added to the original discussion thread.

This is clearly a story that will run and run as Invest in ME tries to raise the £350,000 needed for the trial. As ever, if we want the science, we have to pay for it. But with over £50,000 raised by Invest in ME and £60,000 ringfenced for the trial by the ME Association, we’ve already got nearly a third of the way there in three months. Please donate and help get the trial the rest of the way.

Remember that Phoenix Rising costs money to run and needs your donations to support it. Please hit the button below and donate!

Further resources

Invest in ME’s Rituximab trial site

Phoenix Rising article on the Rituximab trial

 

 

 

 

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