New Rituximab ME/CFS open-label phase II study with rituximab maintenance treatment

[Jonathan Edwards]

Hi professor Edwards. This is my very first post on Phoenix Rising, I have been sick for a little over year now avidly following this site for most of that time, and I just want to say I am beyond grateful for everything you do, you give people hope. Just so I can be clear on what you are saying though, in theory if I were to get rituximab and respnd positively but then relapse, I would be able to keep taking it whenever I have a relapse in the future? Also, would you say it realistic for me to think that Rituximab will be available in the US within the next ten years?

In RA, some patients have had repeated courses of rituximab as required over a period of up to 15 years. Some develop low Ig levels and need to switch to other treatments. The policy at present in ME is to give repeated top up courses for about 18 months to prevent any early relapse. It seems that a proportion of people will manage without further doses for quite long periods. But generally speaking yes, rituximab can be repeated if needed.

Whether rituximab becomes available for ME in the next ten years depends firstly on whether its effect is confirmed in the phase 3 trial. If it confirmed that will be in about 2 years time. And if confirmed then I think it likely that because rituximab is available for use in other conditions there will be a number of physicians prepared to use it off label. Reimbursement through insurance or health care systems is another matter and is hard to predict at this stage. Normally further trials would be done before official licensing but I have a feeling that in this case things might move forward a bit more rapidly - since there is no other treatment available.

 

[trails]

@Jonathan Edwards, Hoping you can tell me whether or not the success of the Rituximab trials and all of the resultant CFS disease theories (autoimmune disease, etc.) completely negate or decrease the plausibility of the "older" mitochondrial theories postulated by Dr. Myhill and others? Thank you so much.

 

[Jonathan Edwards]

@Jonathan Edwards, Hoping you can tell me whether or not the success of the Rituximab trials and all of the resultant CFS disease theories (autoimmune disease, etc.) completely negate or decrease the plausibility of the "older" mitochondrial theories postulated by Dr. Myhill and others? Thank you so much.

I never quite got what Dr Myhill's mitochondrial theory was. When I looked into the background research there was rather little and there did not seem to be enough detail of a theory to evaluate. There did not seem to be any good reason why mitochondria all over the body should suddenly function abnormally. And I find it hard to see how it would really fit with the clinical illness. So I guess I rated the plausibility low anyway. The rituximab and autoimmune stuff is still at the stage of being speculation so it does not change things. There may of course be several sorts of ME so one theory does not really negate another.

 

[Kati]

Hi professor Edwards. This is my very first post on Phoenix Rising, I have been sick for a little over year now avidly following this site for most of that time, and I just want to say I am beyond grateful for everything you do, you give people hope. Just so I can be clear on what you are saying though, in theory if I were to get rituximab and respnd positively but then relapse, I would be able to keep taking it whenever I have a relapse in the future? Also, would you say it realistic for me to think that Rituximab will be available in the US within the next ten years?

welcome to the forums @bctjr1993.

 

[Eeyore]

I think the mitochondrial theory isn't on very solid footing in general. Doctors see fatigue as the defining symptom of ME because of the inappropriate use of the term CFS or even CFIDS. This prevents them from really understanding the disease. If you say there is a problem with fatigue, it's not hard to get to the point of thinking there is a problem with energy production, and of course we all learned in biology 101 that mitochondria are responsible for energy production, so we blame mitochondrial dysfunction.

There are a number of diseases with mitochondrial function (genetic in origin, passed mother to child generally). They do not look much like ME.

I think one possible explanation for reduced exercise capacity and VO2 max may be poor delivery of blood to tissues. There are many possible explanations for this, but endothelial dysfunction (being studied by the Norwegians in the phase III trial) is among them. Some kind of a vasculitis could be involved, as could problems with angiogenesis (there are some small studies showing reduced VEGF in ME patients and quite a few showing reduced plasma volume).

 

[alex3619]

If you say there is a problem with fatigue, it's not hard to get to the point of thinking there is a problem with energy production, and of course we all learned in biology 101 that mitochondria are responsible for energy production, so we blame mitochondrial dysfunction.

The mitochondria are almost certainly not working right in us, but as you point out this might have nothing to do with the mitochondria themselves. The exact mechanism still eludes us. However we do need to keep the scientists investigating all the options.

I am currently of the view that fatigue is not much of a clinically useful symptom. Its like saying pain, or depression, or feeling unwell. It tells you something may be wrong, but does not identify what that is. Figuring out the neurological or biochemical pathology is very very hard to do.

In ME though there is a marked crash in energy production. That is a more useful sign than just fatigue. It gives us things that can be tested, at least in a research setting. Its not currently so useful clinically due to the unavailability of many useful tests.

Biochemistry includes vast networks of causal effects that have feedback and other issues. In some case the chemistry is reversible, so the effect can go in both directions. Its a mess. When something goes wrong we hypothesize about what it is, but it takes careful science to really figure it out, and this is the kind of thing that science is not good at. Science is still the best process for how to answer these questions, but the complexity makes it a difficult and prolonged process of figuring out what is what. Systems biology offers hope that we might be able to more rapidly generate reliable hypotheses to test. Advances in medical technology can change this picture very rapidly.

 

[Eeyore]

I favor impaired delivery of oxygen, which will of course decrease mitochondrial ATP production, so we will cross the AT earlier when we exercise. I think the push/crash in ME is most interesting re: fatigue. That's not at all common. Fatigue is a nearly universal sign of illness. Heart disease, cancer, PBC (which Julia Newton studies), anemia, FFI (very rare prion disease), sleep apnea, influenza, rheumatoid arthritis, old age, hypothyroidism, etc. all cause fatigue. Most illnesses in fact do.

I think scientists have largely forgotten how to think. We have way too much testing w/o enough formation of coherent hypotheses to test in the first place - as if we've forgotten the first steps of the scientific method! First, create the hypothesis to test. It shouldn't be something dumb like "X chemical is low" - that's now a hypothesis. That's a prediction from a hypothesis that can be tested. There needs to be coherent theory of disease - and this requires long hard thought.

 

[BurnA]

The problem with drawing parallels within autoimmunity is that each autoantibody produces its particular disease in a completely different way, so there are almost no rules. And since autoantibodies accumulate by a gradual process of expansion of B cell clones over many years the disease onset can be sudden or gradual. Moreover, the susceptibility of autoantibody producing cells to rituximab varies so response varies.

Can you explain more about the accumulation of autoantibodies over several years ?
Could this mean that the initial offending event could in fact happen several years before symptom onset it have I picked this up wrong ?
How would the accumulation of autoantibodies tie in with an infectious trigger ?
Thanks.

 

[Jonathan Edwards]

Can you explain more about the accumulation of autoantibodies over several years ?
Could this mean that the initial offending event could in fact happen several years before symptom onset it have I picked this up wrong ?
How would the accumulation of autoantibodies tie in with an infectious trigger ?
Thanks.

Yes autoantibodies often appear five to ten years before symptoms - gradually accumulating stepwise over that time.
As we have discussed on other threads, if autoantibodies in ME sensitise danger signal responses so that they are induced by trivial insults then what seems to be an infectious trigger may just be the first insult to trip the sensitised response, which was already present.

 

[BurnA]

Yes autoantibodies often appear five to ten years before symptoms - gradually accumulating stepwise over that time.
As we have discussed on other threads, if autoantibodies in ME sensitise danger signal responses so that they are induced by trivial insults then what seems to be an infectious trigger may just be the first insult to trip the sensitised response, which was already present.

Thanks.
Is there a general time frame of accumulation or is it unknown and random ?
With my limited knowledge I understand it can take 2-3 weeks for antibody generation to an antigen, it this a completely different response mechanism unrelated to autoantibody production ? Curious because it has been suggested that if onset is 2-3 weeks post a viral infection it could suggest autoantibodies, just wondering if this is a valid suggestion or not relevant.

If there was an identified offending autoantibody, for any disease, could it be detected in theory at low levels in advance of symptoms to prevent the disease from developing?
Thanks.

 

[Jonathan Edwards]

Thanks.
Is there a general time frame of accumulation or is it unknown and random ?
With my limited knowledge I understand it can take 2-3 weeks for antibody generation to an antigen, it this a completely different response mechanism unrelated to autoantibody production ? Curious because it has been suggested that if onset is 2-3 weeks post a viral infection it could suggest autoantibodies, just wondering if this is a valid suggestion or not relevant.

If there was an identified offending autoantibody, for any disease, could it be detected in theory at low levels in advance of symptoms to prevent the disease from developing?
Thanks.

The time frame is random - some fast some slow, some this direction, some that.

You raise an interesting point. We have discussed before that it takes 2 weeks for antibodies to be generated in bulk to a new antigen. Autoantibodies cannot have anything to do with that because the antigen is never new. So it seems that the rate limiting step is quite different. I think it is the rare generation of clones that can subvert negative control. But the interesting point is that getting symptoms 2-3 weeks after a virus is AGAINST new autoimmunity at that time and in favour of some sort of reaction involving a normal antibody response to virus complicated by something else.

The error in logical sequence is to assume that rheumatic fever is autoimmune, which nobody has ever demonstrated satisfactorily. That does occur 2-3 weeks after infection but the tissue injury looks likely to be a side effect of a normal response to a foreign antigen - maybe immune complex deposition. It is a non-autoimmune postinfective reaction. A pre-existing autoimmune process would be just as likely to latch on to the early innate response in the first few days.

 

[lansbergen]

We have discussed before that it takes 2 weeks for antibodies to be generated in bulk to a new antigen.

How long would it take if a carrier of a low virulent strain of a pathogen gets infectred with a more virulent strain?

 

[Jonathan Edwards]

How long would it take if a carrier of a low virulent strain of a pathogen gets infectred with a more virulent strain?

Generally speaking all antibody responses to new antigens take 2-3 weeks because they are chain reactions and once started reach full blast in about the same time.

 

[lansbergen]

Generally speaking all antibody responses to new antigens take 2-3 weeks because they are chain reactions and once started reach full blast in about the same time.

If plasma cells makng antibodies against a low virulent strain are activated by a more virulent strain it will take 2 to 3 weeks to full blast?

 

[BurnA]

The time frame is random - some fast some slow, some this direction, some that.

You raise an interesting point. We have discussed before that it takes 2 weeks for antibodies to be generated in bulk to a new antigen. Autoantibodies cannot have anything to do with that because the antigen is never new. So it seems that the rate limiting step is quite different. I think it is the rare generation of clones that can subvert negative control. But the interesting point is that getting symptoms 2-3 weeks after a virus is AGAINST new autoimmunity at that time and in favour of some sort of reaction involving a normal antibody response to virus complicated by something else.

The error in logical sequence is to assume that rheumatic fever is autoimmune, which nobody has ever demonstrated satisfactorily. That does occur 2-3 weeks after infection but the tissue injury looks likely to be a side effect of a normal response to a foreign antigen - maybe immune complex deposition. It is a non-autoimmune postinfective reaction. A pre-existing autoimmune process would be just as likely to latch on to the early innate response in the first few days.

Thanks again.
You lost me in the middle somewhere...
If you don't mind what do you mean by the antigen is never new ?
And when you say 'complicated by something else' ...any thoughts ?
And finally, what do you mean by "a pre existing autoimmune process would be just as likely to latch on to the early innate response in the first few days ?"
Sorry, my knowledge is very limited I need very basic explations.
Thanks.

 

[Jonathan Edwards]

If plasma cells makng antibodies against a low virulent strain are activated by a more virulent strain it will take 2 to 3 weeks to full blast?

Plasma cells do not get activated. A new response to a more virulent strain will need to involve a response to a new antigen (maybe causing the virulence) involving fresh B cells from bone marrow. Responding to any new antigen takes roughly the same time. If there is no new antigen involved and all that is happening is expanding a memory B cell pool then the response should be slightly quicker.

 

[Jonathan Edwards]

Thanks again.
You lost me in the middle somewhere...
If you don't mind what do you mean by the antigen is never new ?
And when you say 'complicated by something else' ...any thoughts ?
And finally, what do you mean by "a pre existing autoimmune process would be just as likely to latch on to the early innate response in the first few days ?"
Sorry, my knowledge is very limited I need very basic explations.
Thanks.

A self antigen is never new because it is there in your body all the time. So the time of development of autoantibodies has nothing to do with the time of availability of antigen - it was always there.

The other bits take quite a long time to explain - but have been discussed before in previous threads. I am afraid I am not sure which ones. If you really want to understand all this you probably need to do an immunology course. There is an awful lot of background stuff that has to be factored in.

 

[BurnA]

A self antigen is never new because it is there in your body all the time. So the time of development of autoantibodies has nothing to do with the time of availability of antigen - it was always there.

The other bits take quite a long time to explain - but have been discussed before in previous threads. I am afraid I am not sure which ones. If you really want to understand all this you probably need to do an immunology course. There is an awful lot of background stuff that has to be factored in.

Ok thanks!

 

[lansbergen]

If there is no new antigen involved and all that is happening is expanding a memory B cell pool then the response should be slightly quicker.

Is it known how many days at most?

 

[Marky90]

Ok thanks!

The channel "khan academy" has some nice videos if you tire easily from reading..