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

[Firestormm]

Thanks Firestormm, I haven't seen those discussions. It sounds like quite a complicated drug. We definitely need these trials to happen.

I think ME is a complicated (little understood) and heterogeneous condition, Kate. Bottom line is that we might all share similar problems biologically - but I think we need to establish what they are and how they might be helped with this treatment first. And maybe as good a place to start as any is with those who have been treated and responded poorly. I wouldn't really know how to go about it - but I do appreciate people returning to share their experiences good or bad. It really helps

 

[Sasha]

I think ME is a complicated (little understood) and heterogeneous condition, Kate. Bottom line is that we might all share similar problems biologically - but I think we need to establish what they are and how they might be helped with this treatment first. And maybe as good a place to start as any is with those who have been treated and responded poorly. I wouldn't really know how to go about it - but I do appreciate people returning to share their experiences good or bad. It really helps

What's interesting about Rituximab is that 67% of the treated group in the Haukeland study improved vs 15% of controls, and there is some question (if memory serves, which it doesn't always) over whether those two control patients (the 15%) had ME proper - I think they only fulfilled the weaker CFS criteria used in the study, which used two (CCC & Fukuda?).

So, regardless of our heterogeneity, two thirds of PWME selected according to the Haukeland method got benefit. I don't know if there was some built-in extra filter - perhaps in how patients in Norway are assessed for ME and therefore filtered before they even got to being considered for the study - but this doesn't seem to be some drug that only works for some tiny subset of us. Two-thirds odds of improvement are good enough for me.

 

[Firestormm]

Two-thirds odds of improvement are good enough for me.

You are right in what you say, Sasha about the Trial itself; but these off-label treatments and responses need to be considered as well. And discovering why those 2/3rd's responded is really important to me at least.

As for the sentence above - this is what is making people get off-label treatment and believing it might be applicable in the real world or at least worth a punt. It was a 15 patient small Trial. I really cannot wait for the next announcement, and the one after that with more patients and bigger numbers generally.

I really do hope the fraction stays true and is repeated in the UK smaller Trial. If the drug is approved for use in the UK based on these initial findings say, then at this point I would not be willing to try it; but with more results that endorse the initial ones together with a better understanding about why this drug appears to work for those it does and for those it doesn't - I would.

Supporting this UK attempt at a Trial is the right thing to do in my opinion and for what it is worth - but the pre-trial findings are just as if not more important to me

 

[Sasha]

Hi Firestormm - we have a different approach to risk at this point (not surprising - we all will, depending on our circumstances and history and stage of life) - but we agree that the important thing now is to get this trial funded, fast.

 

[Firestormm]

Sasha you are probably right I think Norway has offered us perhaps the first real opportunity to try and better understand what is or might be ME. This is what is very important to me. If we can understand 'why' it will mean so much even if the attempts at replication do not lead to approval. To have a large cohort of patients defined using the very criteria we have had concerns with - but are all by and large diagnosed by - to have something discovered that they all have in common that responds to this drug: well, frankly, I would cry

 

[Sasha]

Sasha you are probably right I think Norway has offered us perhaps the first real opportunity to try and better understand what is or might be ME. This is what is very important to me. If we can understand 'why' it will mean so much even if the attempts at replication do not lead to approval. To have a large cohort of patients defined using the very criteria we have had concerns with - but are all by and large diagnosed by - to have something discovered that they all have in common that responds to this drug: well, frankly, I would cry

I think it's the CCC that are looking good, though, since those were the Haukeland criteria for all but two of the patients (again, if memory serves). I think most of us are reasonably happy with the CCC (but if we're not, let's please not hijack this thread with a discussion of diagnostic criteria! ). Most of us in the UK aren't diagnosed via the CCC, more's the pity.

 

[Bob]

I have seen this comment on the forumhttp://forums.phoenixrising.me/index.php?threads/final-rituxan-blog.23367/#post-357591

My main complaint is PAIN... and I will do damn near anything to reduce it....but to my dismay my PAIN has INCREASED and my pain med intake has DOUBLED since starting on the Rituxan.... ;( ;( ;(...........................................................................................................................................................................................................................................Oh and PS to those of you who are considering Rituxan...if you fall into the PAIN syndrome category my opinion is DON'T do RITUXAN!!! I asked my doc if I was the only one responding with an inflammitory BOMB response...and his reply was "No that those who have the pain syndromes are experiencing this".... Wish I would have known that before throwing 7K out the window! Guess I get to be rich in my next life.... ;(

I hadn't seen that discussion, but it's interesting about the issue of pain because I noticed that, in the results of the Norway study, in 3 of the patients, the outcome for pain seems to be independent of the outcomes for all the other symptoms (i.e. pain sometimes responds atypically to treatment compared to the other symptoms), as per this table, unless I'm misinterpreting it (See patients C,H & J):
http://www.plosone.org/article/info:doi/10.1371/journal.pone.0026358.g003/largerimage

 

[Dolphin]

Maybe I didn't make it clear what I was disagreeing with. It was specifically this that Dolphin said:

For people who are ill longer, the best hope I think is with drug therapy, which will sometimes involve drug companies who have patents.

I don't think drugs are necessarily the best hope for anyone, including those who have been ill for a long time, unless they have already tried the safer alternatives. I would not want to discourage anyone from trying a licensed treatment as long as they had a very full understanding of the possible adverse effects, and believe strongly that it is usually better to try safer options first. I absolutely agree that all potentially-beneficial options should be available. Drugs might turn out to be the best option for some after other things have been tried.

How I wish that I had known 18 years ago about pacing and the leaky gut diet and supplements. I might have had my life back long ago and avoided some of the worst effects of this illness on my health and circumstances.

The previous sentence of mine was:

Some people who haven't been ill/diagnosed too long may think they can avoid drugs to get better (and some people indeed do seem to get better fairly quickly after some infections like Epstein Barr Virus).

I later went on to clarify

when I said "get better", I meant to full or near full functioning e.g. able to work full-time.

I haven't come across published evidence large numbers of long-term patients getting back to full functioning or near full functioning with specific non-drug therapies. Perhaps the leaky gut approach will help but I don't know of any published evidence that it has a good record of returning high percentages of people with long-term ME/CFS to full or near functioning.

There are all sorts of theories in other fields how conditions, such as Cancer, could be treated "naturally". But many people would think for many Cancers, drug treatment or surgery, both of which can carry risks, is better on average.

What I see is, in long-term patients, the recovery rate is lower. I see lots of people living reduced lives. Some people may have some sort of life, once they are not working, but I don't class that as recovered. I think drug options need to be explored more.

 

[MeSci]

I haven't come across published evidence large numbers of long-term patients getting back to full functioning or near full functioning with specific non-drug therapies. Perhaps the leaky gut approach will help but I don't know of any published evidence that it has a good record of returning high percentages of people with long-term ME/CFS to full or near functioning.

I don't think large, long-term studies have been done yet on leaky-gut treatment, and of course it will rely a lot on how well people stick to it, and whether they also pace and rest optimally. But I expect it to take a year or several. If the phenomena referred to in the paper 'Tight Junctions, Intestinal Permeability, and Autoimmunity Celiac Disease and Type 1 Diabetes Paradigms' here:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2886850/

are relevant to ME, then a cure will depend on the cessation of production of autoantibodies, which will not occur as soon as the triggers are removed, just as vaccine-derived immunity does not decline immediately after a vaccine has conferred the immunity. The immune system will gradually learn that it doesn't appear to need the antibodies in question, and in the vaccine situation a booster will be needed. The analogous pathological situation to boosters would be causing the gut mucosa to become hyper-permeable again due to consumption of foods that are not tolerated, and/or an unhealthy balance of gut flora and/or an unhealthy gut pH, which will start to allow the triggering substances to start entering the bloodstream again.

This is in fact relevant to treatments such as rituximab, I think, as it usually requires repeat treatments, and one needs to think about why this is. Why do the B cells go out of balance again?

An analogy for leaky-gut treatment and rituximab might be:

You are hitting yourself on the head with a hammer.
It gives you a headache.
Do you stop hitting yourself over the head, or do you carry on doing it, and take painkillers?

Maybe people taking rituximab need to address the cause of the B cell imbalance as well as correcting it, and try to stop it going wrong again.

And maybe this is already being looked at.

 

[Dolphin]

I don't think large, long-term studies have been done yet on leaky-gut treatment, and of course it will rely a lot on how well people stick to it, and whether they also pace and rest optimally. But I expect it to take a year or several. If the phenomena referred to in the paper 'Tight Junctions, Intestinal Permeability, and Autoimmunity Celiac Disease and Type 1 Diabetes Paradigms' here:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2886850/

are relevant to ME, then a cure will depend on the cessation of production of autoantibodies, which will not occur as soon as the triggers are removed, just as vaccine-derived immunity does not decline immediately after a vaccine has conferred the immunity. The immune system will gradually learn that it doesn't appear to need the antibodies in question, and in the vaccine situation a booster will be needed. The analogous pathological situation to boosters would be causing the gut mucosa to become hyper-permeable again due to consumption of foods that are not tolerated, and/or an unhealthy balance of gut flora and/or an unhealthy gut pH, which will start to allow the triggering substances to start entering the bloodstream again.

I have come across lots of therapies that sound plausible in theory, and tried a few myself.

However, these days, I am less interested in reading about plausible theories and more interested in seeing positive results.

I'm not saying the theory is right or wrong.

But my stance is different to yours:

I maintain hope that improvement will continue, and I have no wish to take a drug, least of all a dangerous one.

At this stage, I'm quite willing to take a drug if it has good results. This, of course, means being more cautious with some drugs than others, but I don't have an ideological stance about not taking them.

 

[Firestormm]

I hadn't seen that discussion, but it's interesting about the pain because I noticed, in the results of the Norway study, that the outcome for pain seems to be independent of the outcomes for all the other symptoms (i.e. pain responds atypically to treatment compared to other symptoms) in 3 of the participants, as per this table, unless I'm misinterpreting it (See patients C,H & J):
http://www.plosone.org/article/info:doi/10.1371/journal.pone.0026358.g003/largerimage

Mon ami

Thanks for this. I don't understand it, but thanks. I do see where you are coming from but would need to go back to the paper myself. Which I may well need to do if this excellent thread and discussion (in several places) continues which I very much hope it will

 

[MeSci]

I don't have an ideological stance about not taking them.

Nor do I! My stance is based on science.

 

[Dolphin]

I don't have an ideological stance about not taking them.

Nor do I! My stance is based on science.

Well, I find:

I maintain hope that improvement will continue, and I have no wish to take a drug, least of all a dangerous one.

an ideological stance about not taking them [drugs].

I want to take what works, whether it's a drug or not.

 

[Bob]

How I wish that I had known 18 years ago about pacing and the leaky gut diet and supplements. I might have had my life back long ago and avoided some of the worst effects of this illness on my health and circumstances.

For myself, I swear by pacing. I believe that pacing transformed my experience of my illness, and I believe it created a beneficial biological environment for my symptoms to stabilise and improve over the long-term. After learning pacing, it led me to a stable period of my illness that was not intensely distressing (which was an enormous relief). But, that didn't stop me accidentally over-doing my activities one day, and experiencing a long-term crash from hell. So it is in no way a cure, but it helps me manage my symptoms, and experience stability and gradual improvement.

However, anecdotal evidence of benefit is not the same as proper research trials. Some patients swear by the Lightning Process and Nickel Therapy etc. Some find magnesium and B12 helpful. Some find diet changes helpful. And some, like me, swear by pacing. But that doesn't mean that those interventions are actually helpful for ME/CFS. It just means that some patients believe that they have found benefit from those interventions (which they might have done.) Some people find benefit from homeopathy, but it has been proved that homeopathy has no medical benefit. So we cannot know if a treatment actually works for a range of patients until it has been rigorously tested in a carefully controlled environment, otherwise known as a clinical trial. That's not to say that people shouldn't engage in activities that work for them, if they find something helpful, that isn't harmful and doesn't drain them of money.

A theory about leaky gut is just a theory until there is good evidence behind it. I don't personally believe that the answer to my illness is in the gut. Actually I strongly believe that we will not find the answer there. But that's just my opinion partly based on my personal experience, and I wouldn't want to hold back any research that was looking into enteroviruses etc.

I would not want to discourage anyone from trying a licensed treatment as long as they had a very full understanding of the possible adverse effects, and believe strongly that it is usually better to try safer options first.

Yes, I totally agree. We've got to work out the exact risk of harm, and the exact potential benefits of Rituximab. Then patients and clinicians can make informed decisions about it. We've got to have access to all the information, and the risks of harm have got to be transparent. We'll only get this info from clinical trials.

Many ME/CFS patients have incredibly distressing and restricting symptoms over a very long period of time, and I think it might be very difficult to convince many such patients to avoid a medication that promised a 50% chance of improvement, even if there is a small risk of harm.

 

[Bob]

Mon ami

Thanks for this. I don't understand it, but thanks. I do see where you are coming from but would need to go back to the paper myself. Which I may well need to do if this excellent thread and discussion (in several places) continues which I very much hope it will

I don't think we can read much into it, but I think it's an interesting observation.

 

[MeSci]

Well, I find:

I maintain hope that improvement will continue, and I have no wish to take a drug, least of all a dangerous one.

an ideological stance about not taking them [drugs].

Sorry for any lack of clarity - that was probably a combination of my ME-brain and being in a rush to get on with my work - I meant a drug for ME, in the context that I am already seeing improvement with a safe natural treatment. I am not opposed to drugs per se, and I do take them for other purposes. I was talking to a friend today who is trying an experimental drug for leukaemia, as her previous regime of rituximab and a chemo drug had stopped working, and it is her last chance. The alternative is death within about a year. It seems to be working, and I am full of positivity for her.

I am not trying to discourage anyone from trying rituximab - just wanting them to be aware of dangers and alternatives. I know how desperation can lead to throwing caution to the wind, and sometimes going from the frying pan into the fire. I know of people who have done this with GET, and left one forum partly because it was so exhausting and distressing to see so many people doing this and not heeding warnings.

I want everyone to get well, and not worse.

 

[user9876]

Yes, I totally agree. We've got to work out the exact risk of harm, and the exact potential benefits of Rituximab. Then patients and clinicians can make informed decisions about it. We've got to have access to all the information, and the risks of harm have got to be transparent. We'll only get this info from clinical trials.

Risks, particularly for low probability events are very hard to quantify.

I think Jonathan Edwards makes an interesting point:

One simple factor is that we got reactions with the drug until we learned to look for early signs and to be very careful with the infusion delivery.

Which suggests that those experienced in giving the drug can start to recognise reactions early and deal with them. Hence safety may also become a feature of experience or eventually how well a detailed protocol and testing can be defined. I assume safety isn't just about the drug delivery but around prechecks and post drug monitoring particularly where a course of drugs is taken. I'm assuming that experiance with patients with various autoimmune diseases will help but ME might lead to different problems. To my mind it does seem to suggest even after trials establish the effectiveness of the treatment there needs to be care in the roll out. Groups delivering treatments need to share best practice, experience and safety information.

 

[Dolphin]

Sorry for any lack of clarity - that was probably a combination of my ME-brain and being in a rush to get on with my work - I meant a drug for ME, in the context that I am already seeing improvement with a safe natural treatment. I am not opposed to drugs per se, and I do take them for other purposes. I was talking to a friend today who is trying an experimental drug for leukaemia, as her previous regime of rituximab and a chemo drug had stopped working, and it is her last chance. The alternative is death within about a year. It seems to be working, and I am full of positivity for her.

I am not trying to discourage anyone from trying rituximab - just wanting them to be aware of dangers and alternatives. I know how desperation can lead to throwing caution to the wind, and sometimes going from the frying pan into the fire. I know of people who have done this with GET, and left one forum partly because it was so exhausting and distressing to see so many people doing this and not heeding warnings.

I want everyone to get well, and not worse.

Ok. But unfortunately with medicine, there are few guarantees. Surgery can occasionally have serious side effects but still in many scenarios can be justified. Similarly drugs in other situations. Just because an intervention can have risks doesn't mean it should be excluded esp. when there aren't proven alternatives (including in conditions with ME where there is not an impending death).

But best of luck with your own regime: I wasn't criticising it: you responded to me first (in case anyone missed the context). I accept your right to try non-drug therapy. I just don't want the option of drugs denied to me in the absence of proven alternatives.

 

[alex3619]

One of the issues with leaky gut theories leading to autoimmunity, or indeed any autoimmune theory, is that there is some evidence that we don't fit the model. We don't seem to have one autoantibody to one target, but many autoantibodies to many targets. It is likely there is something fundamentally wrong with our B cells.

Now I do think gut detox is failing at the very least, allowing increased absorption of toxins including lipopolysaccharides.

One of the things I am interested in is combined protocols. What happens if you treat leaky gut first then take Rituximab? Or combine Rituximab with antivirals? Or antioxidants? Kogelnik seems to want to do this with antivirals and Rituximab. I also suspect that antibiotics and Rituximab might have some small extra benefit, but this is much less likely.

Until we understand mechanisms there will be a lot of serious questions about all these things, and no treatment has guarantees. Its still very much the Lemon Rule: most treatments are lemons but until you try them you won't know if they are sour. Different individuals will respond differently.

The response rate appears to be over 70% now though, but on such a tiny sample it could all be a fluke. Thats why the bigger studies are so important. Its also critical, as many have said, that we identify response biomarkers: who will benefit, and who will be harmed? Its far safer to run a test before treatment than to treat and hope nothing bad happens.

The really big question though is: why do some appear to go into long term remission, and most only temporary remission? That is a really important question.

 

[SOC]

I would think it would be smart to use the same diagnostic criteria Mella and Fluge used -- the CCC, iirc. That would provide at least some level of comparability between the trials.

I wonder if valuable information about safe selection could be gained by talking to doctors who have done extensive immune testing on their patients. Dr Klimas, in particular, is an immunologist and ME/CFS specialist and may have important insight into immune subsets, or which immune tests should be run to screen out patients who might be at greater risk for immune-based side effects.

Jonathan Edwards -- are you aware that many ME/CFS patients have immune abnormalities, including ones that make them susceptible to intracellular pathogens? NK cell dysfunction has been found -- more in NK cell function than number. Another dysfunction showing up is low CD8+ cell number.

Many of us have chronic infections of intracellular pathogens -- EBV, HHV-6, CMV, chlamydophila pneumonia, enteroviruses, etc, which also suggests T-cell deficiencies.

One concern I have in using UK patients in a Rituximab trial is that very few of them have had immune testing to identify immune dysfunctions seen in ME/CFS, nor have many UK patients received drug treatment for the common chronic infections. I would think risk potential would be much higher in patients with untreated chronic herpesvirus infections.

I think consults with Dr Klimas, Dr Petersen, and Dr Kogelnik, in particular, could greatly improve patient selection and pre-trial testing for potential risk factors.