Prof. Mella - Autoimmunity and metabolism in ME/CFS (lecture)

Trish said:
Would it be ethical to put something in the placebo that induces mild transient nausea to help with blinding, provided patients were warned of this and gave permission?
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I think there is an impossible obstacle here. It would be very hard to be sure that a sham nausea inducing agent was adequately matched.

What might be the logical way around the problem is to do a dose response study with a range of cycle doses. If the drug works the effect will only show at certain doses so nausea-inducing low doses could be the controls. But even here there would not be reliable matching.

I have another problem with any further trials of cyclo having seen rituximab fail - cycle has very serious adverse effects, including bladder cancer. It would be unethical to have a low dose arm in a dose response study which you are pretty sure is not going to work for ME, because it might still cause bladder cancer in the study individuals.

I am not sure where researchers should be going from here but I do have one new thought. It seems that killing B cells does not have any useful effect - from the RituxME trial. Cyclophosphamide kills B and T cells. It may kill other cells like neutrophils but that is not going to be a means of getting long term benefit. If it works at all I think it must be working by killing T cells. In which case the logical thing to do is to treat patients with a T cell depleting antibody like Campath-1H.That would be a new departure but it would have logic to it.
 
Thanks for the post Milo and for doing such an important job. Having had chemo for breast cancer I have nothing but admiration for the nurses.

My experience was that I had Cyclophosphamide as part of the FEC-T regime. The nausea and vomited I experienced on the cocktail lasted for the entire 6 months of the treatment and now I still have a severe residual effect and a new onset severe motion sickness.

Not only did I react to the actual chemo drugs but the different ones that were prescribed for the nausea and vomiting. Also the Herceptin that I continued with and the steroids (I can't tolerate Dexamethosone anyway but my consultant didn't believe me).

My Oncologist and the team had no knowledge of ME and were gobsmacked to see someone react so badly to drugs and to have different nausea/vomiting drugs prescribed until we found some that made a difference but only at the end of treatment. They were also not used to a patient who was so affected by chemo (steroids, n&v drugs etc) that she could became bedbound and was unable to get to the hospital for the next infusion.

They were also not used to adverse reactions to n&v drugs and everything else.

As I had the Cyclo as part of a drugs combo it may be that these PWME won't have the severe reaction I had but if they do have nausea and vomiting it may be hard to get the right drugs to control this, they may react to the n&v drugs and anything else used as part of the regime such as steroids.

Then there is the risk of infection which I experienced with each chemo cycle and admittance to hospital.

I was gutted to come to the end of my chemo and find that I wasn't one of the lucky patients who had a ME remission and instead found myself even more disabled.
 
Hi @ukxmrv, I'm sorry to hear you had such an awful time with all those drugs. It sounds horrendous.

Jonathan Edwards said:
Cyclophosphamide kills B and T cells. It may kill other cells like neutrophils but that is not going to be a means of getting long term benefit. If it works at all I think it must be working by killing T cells. In which case the logical thing to do is to treat patients with a T cell depleting antibody like Campath-1H.That would be a new departure but it would have logic to it.
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Are you in touch with Prof. Mella to discuss this?
 
I was very impressed by this lecture, not only by all the research his team at Bergen are doing but also by his (their) intelligent, wide-ranging review of the best recent research in the field. Quite a good summary! As far as I understand, researchers are supposed to do this, a thorough review of the science in the field, but so many do not seem to, and then they get stuck in a corner which is not useful to us. Anyway, I found a great deal of intelligence in his talk, in their approach to doing research and expect we’ll see more results, informed hypothesizing, and collaboration from his team.

I am definitely rooting for the Norwegians!
 
For anyone reading this thread who hasn’t watched the video (I know it is hard for a lot of us to do—It was hard for me) Mella clearly advised patients not to try to get treated anywhere outside of a research study with Rituximab, or Cyclo, or any other major immunosuppressant with significant side effects.
 
Jonathan Edwards said:
I think there is an impossible obstacle here. It would be very hard to be sure that a sham nausea inducing agent was adequately matched.

What might be the logical way around the problem is to do a dose response study with a range of cycle doses. If the drug works the effect will only show at certain doses so nausea-inducing low doses could be the controls. But even here there would not be reliable matching.

I have another problem with any further trials of cyclo having seen rituximab fail - cycle has very serious adverse effects, including bladder cancer. It would be unethical to have a low dose arm in a dose response study which you are pretty sure is not going to work for ME, because it might still cause bladder cancer in the study individuals.

I am not sure where researchers should be going from here but I do have one new thought. It seems that killing B cells does not have any useful effect - from the RituxME trial. Cyclophosphamide kills B and T cells. It may kill other cells like neutrophils but that is not going to be a means of getting long term benefit. If it works at all I think it must be working by killing T cells. In which case the logical thing to do is to treat patients with a T cell depleting antibody like Campath-1H.That would be a new departure but it would have logic to it.
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Is there any way you, Dr Edwards, are able to toss this new idea around with the researchers doing studies? It would be interesting to hear what they say?

I understand research works at its own pace, but there are some young people who are suffering horrifically.
 
ukxmrv said:
Thanks for the post Milo and for doing such an important job. Having had chemo for breast cancer I have nothing but admiration for the nurses.

My experience was that I had Cyclophosphamide as part of the FEC-T regime. The nausea and vomited I experienced on the cocktail lasted for the entire 6 months of the treatment and now I still have a severe residual effect and a new onset severe motion sickness.

Not only did I react to the actual chemo drugs but the different ones that were prescribed for the nausea and vomiting. Also the Herceptin that I continued with and the steroids (I can't tolerate Dexamethosone anyway but my consultant didn't believe me).

My Oncologist and the team had no knowledge of ME and were gobsmacked to see someone react so badly to drugs and to have different nausea/vomiting drugs prescribed until we found some that made a difference but only at the end of treatment. They were also not used to a patient who was so affected by chemo (steroids, n&v drugs etc) that she could became bedbound and was unable to get to the hospital for the next infusion.

They were also not used to adverse reactions to n&v drugs and everything else.

As I had the Cyclo as part of a drugs combo it may be that these PWME won't have the severe reaction I had but if they do have nausea and vomiting it may be hard to get the right drugs to control this, they may react to the n&v drugs and anything else used as part of the regime such as steroids.

Then there is the risk of infection which I experienced with each chemo cycle and admittance to hospital.

I was gutted to come to the end of my chemo and find that I wasn't one of the lucky patients who had a ME remission and instead found myself even more disabled.
Click to expand...
Without going too far off-topic, I am sorry @ukxmrv that you had to go through a very difficult chemo protocol. FEC is on of the tough one, and the most difficult drug is epirubicin (the E of FEC) but the 3 drugs combined means that the side effects amplify. The ‘ risk of infection’ is because this particular protocol makes your white blood cells (neutrophils) go down to almost zero after each and every chemo treatment. I am not sure how low patients with ME go with single agent, low dose Cyclophosphamide goes.

Essentially, this FEC protocol for breat cancer is a tough one, and hard to compare with low dose, simgle agent cyclophosphamide. There would be side effects for sure, and as @Jonathan Edwards mentioned, there are also more risks than for Rituximab. It may not be for everybody.
 
Jonathan Edwards said:
I am not sure where researchers should be going from here but I do have one new thought. It seems that killing B cells does not have any useful effect - from the RituxME trial. Cyclophosphamide kills B and T cells. It may kill other cells like neutrophils but that is not going to be a means of getting long term benefit. If it works at all I think it must be working by killing T cells. In which case the logical thing to do is to treat patients with a T cell depleting antibody like Campath-1H.That would be a new departure but it would have logic to it.
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If I remember correctly Mark Davis found some problems with T cells.
 
Mella said in the lecture above that the research on ME is showing it not to be an autoimmune disease, not primarily autoimmune. Is the point of doing further research on strong immunosuppressants of any kind to elucidate more about what is going on in ME? That idea seems sound enough. Or is the point of this area of research to find good, effective treatments? Then what I would question is how a strong immunosuppressant could be a good treatment given that ME is known as a lifelong, not immediately fatal condition in which such a drug would need to be taken indefinitely, since it would not be addressing the cause.

Any thoughts?
 
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Anybody looked at what he was saying about endothelial disfunction and their findings tying up with findings from research done in Edinburgh in 2011. I struggle to understand the science but it seemed like something I’ve not seen mentioned before (quite likely due to my lack of knowledge/education so ignore if not particularly interesting)
 
I also wonder what the vascular and endothelial problems are such that body tissues aren’t as well served by the circulatory system as they need to be? This can lead to damage/destruction of small nerve and autonomic fibers. Mella didn’t refer to that in his brief overview, but the autonomic nervous system problems could come from nerve damage/destruction at their ends, where the small capillaries are supposed to be serving these nerves. I hope I am understanding this correctly.
 
This video was even better than I expected. Maybe the rituxime results allows him more time to talk more about other items, or maybe he just can't say much about the trial yet.

Either way, it was interesting to hear about the muscle cells reacting to serum, has that ever been mentioned before?

He still seems keen on endothelial dysfunction as an explanation, so whatever about rituximab, I get the impression he is still very focused on solving ME.
 
@BurnA

I think Dr Ron Davis had mentioned a while back that it is something in the serum. Did Dr. Newton notice this too? Maybe someone else will remember.
 
ukxmrv said:
My Oncologist and the team had no knowledge of ME and were gobsmacked to see someone react so badly to drugs and to have different nausea/vomiting drugs prescribed until we found some that made a difference but only at the end of treatment.
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May I ask: what turned out to be helpful for you?
 
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