Invest in ME/Prof Jonathan Edwards statement on UK Rituximab trial, 30 July

[Jonathan Edwards]

Could I ask Prof Edwards if he could briefly explain the differences between treatment of RA using TNF-a inhibitors v B cell depletion using Rituximab as relates to the underlying disease mechanism(s) in RA.

I guess the question I'm asking is do the two treatment approaches overlap or are they addressing two different disease pathways?

As I understand it they address two steps in the same chain. B cells make autoantibodies that bind to antigens to form complexes that then bind to IgG Fc receptors on macrophages that trigger TNF production. Tiny Maini and Marc Feldman who were the first to try anti-TNF thought the macrophages were being activated by T cells but there are various reasons for doubting that, including the way patients respond to rituximab.

 

[Jonathan Edwards]

I thought rituximab depletes B cells but now I found this:

http://www.ncbi.nlm.nih.gov/pubmed/22674374

Rituximab mediates loss of CD19 on B cells in the absence of cell death.

I think this may be a case of not seeing the wood for the trees. If rituximab did not kill B cells nobody with B cell lymphoma would have got better - and an awful lot of people have. And they quote a 51% reduction in CD19 count in their blood analysis but when rituximab is used for autoimmune disease we like to see more than 98% depletion of CD19 positive cells. Moreover, that depletion can last long after rituximab levels have sunk away, in rare cases for years. And autoantibodies go down and the B cell growth factor that regulates B cell numbers goes way up, as if there are no B cells. There is no reason to think that rituximab does anything to any other cells, except perhaps a tiny strange population of T cells that have CD20, so I think this looks like a laboratory artefact.

 

[MeSci]

That's interesting - I didn't know that Fluge and Mella got their cases referred by neurologists. However, ME (properly defined by the CCC or ICC) is a neuroendocrine-immune disorder and all of us could probably request and get a neurological referral if we asked, based on our neurological symptoms (we often don't ask for all the appropriate referrals because we won't get treated). We could also probably get a referral to an endocrinologist, a rheumatologist, an immunologist, infectious diseases specialist, gastroenterologist...

If we had decent GPs, perhaps! I have been refused referral to both neurologists and infectious disease specialists.

 

[Marco]

As I understand it they address two steps in the same chain. B cells make autoantibodies that bind to antigens to form complexes that then bind to IgG Fc receptors on macrophages that trigger TNF production. Tiny Maini and Marc Feldman who were the first to try anti-TNF thought the macrophages were being activated by T cells but there are various reasons for doubting that, including the way patients respond to rituximab.

Many thanks

Would it be accurate then, if simplistic, to say that with both approaches result in reduced levels of TNF-a?

 

[MeSci]

The unusual things that strike me as unusual with ME/CFS is that people, over time, often don't get worse as you see in some autoimmune diseases which leads me to thinking that if there is auto-antibodies, then perhaps the target is non-specific as seen in things such as Lupus, or if it is more specific then the organ has the ability to self repair to a certain degree (as I believe some non-myelinated neurones can).

As the paper I linked to on how leaky gut can lead to autoimmunity states, autoimmunity is not a once-and-for-all event but an ongoing process. Auto-antibodies can stop being produced for various reasons, which will produce remission in autoimmune disease. There is info about the processes involved here for example:

http://www.birmingham.ac.uk/Documents/college-mds/facilities/cis/Essentialimmunology/Chapter4.pdf

So if we have an autoimmune disease, we are looking to achieve self-tolerance. There may be various ways to achieve this, and it can happen spontaneously. The Holy Grail is of course for such self-tolerance to be permanent. This may require more than one type of intervention, and perhaps some lifelong lifestyle changes.

 

[Kate_UK]

(In order to start making antibodies B cells rely heavily on other B cells having made antibodies before. For babies it is mother's antibodies from the placenta and in milk.

What about families where the mother and the children have ME? Does that mean the children could have ME because their B-cells learned wrong from the mother?

 

[Roy S]

Jonathan Edwards -- Thanks for your participation here. For what it's worth your past contributions have been appreciated on this forum.

http://forums.phoenixrising.me/inde...h-needed-letter-in-plosone.12955/#post-219033

 

[lilpink]

Help! I was hoping to post one or two more responses to interesting suggestions and what with being offline for 36 hours I now find it takes all my time to read the next lot of interesting suggestions. I will try to fire off a few responses that seem easy to do quickly. In response to lilpink, remission in pregnancy I think we should take careful note of. It was remission of rheumatoid arthritis in pregnancy that made Hench look for an anti-inflammatory hormone and discover cortisone. It turns out not to be the reason for the effect but it laid the bedrock for research into inflammation. The reason why taking sex hormones does not work seems to be because more complicated cumulative changes occur in pregnancy, maybe in part due to chorionic hormones (i.e. from the baby). One of them is the production of pregnancy associated glycoprotein, but there are many. The situation is further complicated by the fact that some autoimmune diseases get worse in pregnancy (e.g. lupus). But that does not bother us here; what is interesting is that there seems to be a well recognised pattern of change which would fit with an antibody mediated process.

I think the answer may well be yes, brilliant idea, pregnancy-related remission might be a good marker of B cell related ME, rather than one of the probably several other sorts of ME. It is probably not something we could factor in to a scientific study prospectively but it would definitely be something to take note of and check correlation with response to B cell therapies.

Thank you so much for this very interesting reply. I must say that's the most supportive response I've ever had to this query over the last 26 years since I noticed the effect during my two pregnancies in 1987 and 1988. I'm very glad that my own notions of cause and effect (if only theoretical) might indeed have a biological basis. It's such a change to be able to have this sort of interaction with someone who doesn't only reply in terms of 'probably not' or 'we just don't know'. Many thanks indeed!

 

[Jonathan Edwards]

Many thanks

Would it be accurate then, if simplistic, to say that with both approaches result in reduced levels of TNF-a?

Yes, although measuring it may not be that easy.
What I forgot to add is that the pathway from antibody to TNF is important in rheumatoid arthritis but may not figure at all in other conditions. In lupus the antibodies may deposit in blood vessel walls. In thrombocytopenia they cause phagocytosis of platelets. In thyroid disease they may stimulate hormones. In some neurological diseases they interfere with neurotransmission. On the other hand there are diseases that involve TNF but not antibodies - like psoriasis.

 

[Jonathan Edwards]

What about families where the mother and the children have ME? Does that mean the children could have ME because their B-cells learned wrong from the mother?

Brilliant thought Kate. I would need to think hard about that but I think the answer is probably no, judging by other autoimmune diseases (assuming we can extrapolate). When mothers have autoimmune disease their babies can get sick in the womb because the mother's antibodies cross the placenta - it happens in lupus, myasthenia and Sjogren's. It does not happen in rheumatoid because complexes do not cross the placenta I think. However, the effect wears off in a matter of days or weeks. And as far as I know there is no evidence that the baby's immune system then starts making its own autoantibodies. You might then ask why, considering the story I told a while ago, and I don't think anybody knows. Maybe its because the mother's antibodies are not actually being produced in the baby's bone marrow where the B cells are developing. That would be a neat answer but I would like to think about it more. Not that many scientists ask these interesting questions, in my experience. I will have to see if Jo Cambridge or Amolak Bansal have a neater answer!

 

[Esther12]

Several people have commented that the current proposal for a trial seems too small. However, trials only need to be large if the statistical analysis needs it because you are looking for a small change or one that shows up in a small proportion of cases (like for preventing stroke with blood pressure drugs). Large multicentre trials actually have a Catch 22. With big trials (especially international ones) quality control of recruiting and assessment drops so you need an even bigger trial to get an answer. On the face of it what we want to see is whether quite a big change in 60% of cases can be repeated. The only worry is that we may start treating people with a different sort of disease and only get an effect in a few cases. If so, I think a big trial first off would be a waste of resources. If only one person in ten is going to respond we only need to treat a small number to discover we are not in the same ball park. On the other hand if 60% respond in a small study there is a strong case to do further studies. Even these may not need to be big. I think there is a requirement for a certain number of cases to be treated for licensing but I don't think we are that far ahead just yet. Moreover, I do not think that the UK is obliged to foot the bill for all of that.

Thanks for all your responses. I tend to avoid reading research involving the immune system because it all seems so complicated, but the Samurai training story was right on my level!

re concerns about a small trial: My concerns are largely in light of the report that the larger Norwegian trial is no longer being held up, and is under-way (I'm not sure if this has been officially confirmed or not, if this is wrong, most of this post will be redundant). I don't want to talk down this proposed trial, as it seems like a more worthwhile area of research than most CFS studies that end up being funded, but I don't think I really understand why you think a small trial is the right way to go at the moment, so hoped you could respond and expand on this.

If there is a 60% response rate, then this will be shown by the larger trial.
If there is a lower response rate, then this is more likely to be picked up by the larger trial than a small one,and this could also lead to data that would allow for more useful small replications in the future.
If there is no positive response to rituximab, then the larger trial will be more useful for revealing this.

Is the benefit of a small trial the speed? That a small study be likely to be completed and published long before the larger study? Is it political?: eg, researchers/doctors/funding bodies seem to have more respect for research from their country that elsewhere. Maybe just having different groups working on this in slightly different ways increases the chances of something useful turning up? Is it just that, as the cost is relatively low and it's thought that there's a good chance of a 60% response rate, it's worth trying to get an independent replication in now?

When I heard the expected cost of the Norwegian study I did think 'maybe do another smaller study first?', but if the large study is under-way, I'm unsure about the value of running a small study concurrently, while we still have a poor understanding of which patients are most likely to benefit.

 

[Sasha]

My concerns are largely in light of the report that the larger Norwegian trial is no longer being held up, and is under-way (I'm not sure if this has been officially confirmed or not, if this is wrong, most of this post will be redundant).

Everything I've read says that the Norwegian trial will begin in January 2014 and (I think) would take an estimated two years to complete.

I assume a UK trial of 30 patients could be completed much faster, especially given that potential patients will be thundering like wildebeest towards UCL so recruitment could be pretty quick.

 

[Bob]

...patients will be thundering like wildebeest towards UCL...

They'd better watch out for the Samurai!

I'm loving the metaphors in this thread!

 

[Dolphin]

Everything I've read says that the Norwegian trial will begin in January 2014 and (I think) would take an estimated two years to complete.

I assume a UK trial of 30 patients could be completed much faster, especially given that potential patients will be thundering like wildebeest towards UCL so recruitment could be pretty quick.

Always nice to see optimism.
However, outside the US, where some people with deep pockets occasionally donate 6- and 7-figure sums, £400,000 is a lot of money to raise in the ME world.

What the ME and You Foundation did was exceptional.

 

[Sasha]

Always nice to see optimism.
However, outside the US, where some people with deep pockets occasionally donate 6- and 7-figure sums, £400,000 is a lot of money to raise in the ME world.

What the ME and You Foundation did was exceptional.

I refer the honourable gentleman to the answer I gave some moments ago:

http://forums.phoenixrising.me/inde...uximab-trial-30-july.24499/page-6#post-376996

 

[Dolphin]

I refer the honourable gentleman to the answer I gave some moments ago:

http://forums.phoenixrising.me/inde...uximab-trial-30-july.24499/page-6#post-376996

My guess, could be wrong, is the CFSRF won't give anything: they like to fund studies exclusively.

Not sure whether AfME have much if any money left currently: the biobank has been expensive and they gave out grants for research fairly recently.

The MEA have pledged £60,000, but £50,000 of that money was raised over a reasonable period (i.e. only around £10,000 since launching the ring-fenced money).

Not sure how long it took Invest in ME to raise £100,000 for their first study - maybe 2-3 years? I expect they may well raise money faster than that this time of course.

Other money may come in also, but just pointing out that grants in the ME world outside the US are usually measured in five figures so I wouldn't expect the money will be raised before January 2014. But who knows. I just don't want anyone to get complacent.

 

[Sasha]

My guess, could be wrong, is the CFSRF won't give anything: they like to fund studies exclusively.

Not sure whether AfME have much if any money left currently: the biobank has been expensive and they gave out grants for research fairly recently.

The MEA have pledged £60,000, but £50,000 of that money was raised over a reasonable period (i.e. only around £10,000 since launching the ring-fenced money).

Not sure how long it took Invest in ME to raise £100,000 for their first study - maybe 2-3 years? I expect they may well raise money faster than that this time of course.

Other money may come in also, but just pointing out that grants in the ME world outside the US are usually measured in five figures so I wouldn't expect the money will be raised before January 2014. But who knows. I just don't want anyone to get complacent.

Hard to know. I think IiME raised that £100k in two years.

I think we're into a new game with being able to donate to specific projects with a clear funding goal rather than the bottomless pit of a charity's general fund. That £8k from a single donor, I believe, came within days of the MEA announcing that they'd ringfenced that £50k. Supporters of the other charities might do similarly.

I wouldn't underestimate the enthusiasm among patients that this trial is going to generate, especially after the example that Maria set. I think those coffers could get topped up pretty quickly.

The CFSRF is a dark horse but every now and again, they drop an absolute ton of money on something. They will have people with ME who will want to get well as fast as the rest of us. If they see this opportunity, who knows...

Of course, there's nothing to stop someone in the US donating or pledging to this trial, if they see an advantage in getting a small trial done quickly rather than (or as well as) a large trial done over a longer timeframe.

And let's not forget the MRC - this would be chickenfeed to them. And even the feeble £700k or so that ME gets a year from them would more than cover this trial.

Lots of reason for optimism - and it's optimism that brings the money in!

 

[Firestormm]

I agree with Dolphin I also think that when UCL have confirmed a Trial as being worthwhile and produced a proposal, and said proposal meets the separate charities (or a collaboration thereof) peer review: THEN you might see some momentum.

Individual charities are unlikely to invest with IiME fundraising pot until such time as this is produced - their is also the issue of ownership to be resolved or raised. IiME cannot take funds from a separate charity and expect to control them; or to hold onto them in the event of this UCL venture not proceeding for any reason. Their literature thus far produced claims that in such a situation the funding would be reallocated to the general 'biomedical' fund.

Personally, though, I still think you'll be hard pressed to reach £400k before the Norwegian Trial has been completed. If I had the money, I would I think at this point, hold fire until I saw what that revealed.

But it depends also on what comes out of UCL by way of a proposal - and if that proposal is good enough - you might see an application to the MRC being honoured; which could change the landscape.

For me - the interest is in learning how this drug appears to have worked (and not worked) at this point.

 

[Bob]

I'm open minded to the idea that ME is an autoimmune disease, but I wonder if the illness can be as simple as the production of an auto-antibody.

The main reason that I question it is because of post-exertional malaise.

Post-exertional malaise is a very specific reaction to exertion. Simply put, when we exert ourselves (i.e. use energy) all of our symptoms increase, often with a delayed reaction of 12 to 24 hours, and our illness deteriorates.

I wonder how and why the symptoms would increase in reaction to exertion, if it's an autoimmune disease.

If looking at it from the point of view of autoimmunity, what happens when we use energy, that would provoke an autoimmune response? And then why would the reaction be long-lasting once we stopped exercising?

Exploring the issue hypothetically, let's say that a unique molecule is produced (or enters our bloodstream) when we use energy, and that provokes an auto-immune response. Then why doesn't the autoimmune response diminish once we stop exerting ourselves, or why is there a long-lasting reaction? Post-exertional malaise can last for months, or longer, after we over-exert ourselves. Symptoms do not increase and decrease in direct proportion to energy used.

If auto-antibodies are produced in reaction to exertion, how long can they last in the body? Can they last a very long time after they are produced? Could this be an explanation for long-lasting reaction to exertion? Or can dysfunctional B-cells last for a very long time after they are created?

I'm out of my depth here, scientifically, but I can't help feeling that it's more complex than an auto-antibody at play, and that we have a more complex immune dysfunction.

Hypothetically, again, perhaps there is some sort of destructive biological loop at play, and an auto-antibody is targeted at a part of the immune system. So that when an auto-immune response is provoked or triggered, by exertion, the auto-antibody attacks a part of the immune system which makes the immune system dysfunctional. And perhaps this immune dysfunction causes, or allows, the auto-immune response to take place in the first place. So it's a destructive feedback loop.

I'm sure I'm talking absolute nonsense, in terms of actual science, but I'm just trying to get my head around the possibilities.


Another thought is Julia Newton's recent (as yet unpublished) research in which she found that muscle tissue taken from ME patients produces 20 times as much (lactic?) acid as muscle tissue from healthy people. How would this come about in terms of auto-immunity? I imagine that there might be an interplay between auto-antibodies and something within the cellular mechanism that produces energy (i.e. related to the mitochondria.) Are the mitochondria an integral part of the immune system? Could this explain a possible destructive feedback loop? (Dysfunctional mitochondria could potentially explain both the profound fatigue/exhaustion, and the post-exertional malaise in ME patients.)

Here's an interesting article about the relationship between the immune system and mitochondria, which discusses how mitochondria can mediate/trigger a systemic inflammatory immune response to 'trauma'. (The article doesn't mention ME, but perhaps ME could be described as a systemic inflammatory immune response to 'trauma' or 'stress'?):
http://www.nature.com/scitable/topicpage/mitochondria-and-the-immune-response-14266967


I wonder if Jonathan Edwards has any thoughts about any of this at all, if it makes any sense?

 

[lansbergen]

I'm out of my depth here, scientifically, but I can't help feeling that it's more complex than an auto-antibody at play, and that we have a more complex immune dysfunction.

Hypothetically, again, perhaps there is some sort of destructive biological loop at play, and an auto-antibody is targeted at a part of the immune system. So that when an auto-immune response is provoked or triggered, by exertion, the auto-antibody attacks a part of the immune system which makes the immune system dysfunctional. And perhaps this immune dysfunction causes, or allows, the auto-immune response to take place in the first place. So it's a destructive feedback loop.

I'm sure I'm talking absolute nonsense, in terms of actual science, but I'm just trying to get my head around the possibilities.

I do not know it is autoimmune but I have no doubt in my case there is an immune reaction when overdoing and it hurts like hell. The immunemodulator I use, helped a lot. It gradually became less severe and at less places.