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

[Dolphin]

The exact same thing has been said about CBT/GET, which is supposed to be effective and safe too. I have spent enough time and energy evaluating the evidence for CBT/GET to know this is questionable, and I have bad life experiences with GET. I have little reason to doubt whatever limited evidence there is for Rituximab so far, but my concern is not just about "severe reactions" but ANY significant decline in health whatsoever which would make life not worth living anymore.

Years ago I had intravenous EDTA chelation therapy, which now I know was quackery but is still supposed to be relatively benign. I have made many cumulative mistakes, but that treatment happened to coincide with the beginning of a rather dark phase for my health, and maybe this is irrational enough to require CBT (hehe), but considering that I cannot even tolerate a daily aspirin anymore without a decline in health, the thought of infusing something like Rituximab scares me.

Doesn't seem irrational to me.

 

[Firestormm]

I think we need to better understand the reason why those who responded to Rituximab did. Our condition has no marker to determine that we all in fact have the same things wrong with us compared to Rheumatoid Arthritis. We don't know if autoimmunity applies in all cases. If this can be established pre-treatment it might prove a means of selection and a better predictor of safety than a diagnosis based on symptoms is by itself. Establishing the why is important in this respect I would suggest.

Jonathan Edwards some of those receiving Rituximab and who share our diagnosis appear to have been patients of Dr Andreas Kogelnik over the US. You might want to contact him perhaps. The OMI-MERIT initiative of which he is Founder and Director - was looking at a Rituximab trial for CFS although I haven't personally heard where they are with it.

 

[OverTheHills]

I certainly understand this viewpoint.

However, I would be very unhappy if trials were blocked for ethical reasons because of a fear of side effects. This illness can lead to long-term complications from immobility, weight gain (while not universal, there is increased risk of it from a decrease in activity levels and, for some people, medication), inflammation, etc, possibly shortening lives. And it certain has a major effect on morbidity.

Current treatments such as exercise programmes are certainly not without their risks either.

So while I don't think anyone should be forced to take the therapy (and I can't see that being an issue in my lifetime), I think the facility should be there to trial the drug.

While I definitely respect Bob's fear of losing further function, I feel very differently about Rituximab trials.

I am approaching my mid-50s with no dependents, I have been sick for 9 years and I have been pretty conservative in trying treatments up till now. My approach to risk is changing because my greatest ambition is to resume being physically active (hiking) after my health improves, so I feel I have an important window or timeslot of the next few years. There are few other prospects for a radical improvement in my health on the medium horizon. So I aspire to become part of a Rituximab trial in a couple of years time (assuming I meet the entry criteria) while I will still be able to gain real benefit if it works. I realise there is a big downside risk. I remember that (phase 1? ) trial at Northwick Park Hospital where previously healthy young people nearly died and probably suffered severe lasting harm.

OTH

 

[Firestormm]

I remember that (phase 1? ) trial at Northwick Park Hospital where previously healthy young people nearly died and probably suffered severe lasting harm.

OTH

Was that trial for Rituximab? Thanks

 

[ukxmrv]

I was thinking of this trial when OTH's mentioned it. Nothing to do with Rituximab

http://en.wikipedia.org/wiki/Northwick_Park_Hospital

((snip))

Healthcare Commission report

On 13 March 2006, six people in a drug trial at the independent Parexel drug trial unit (which is not run by The North West London Hospitals NHS Trust) became severely unwell following administration of TGN1412 and were transferred to the intensive therapy unit at Northwick Park. Affected patients developed multi-organ failure and required intensive medical support by the critical care team at Northwick Park, led by Dr Ganesh Suntharalingam. All the patients subsequently survived and the last one was discharged in June 2006.Victims from this drug trial sought compensation for their multiple injuries with the help of a British law firm. Parexel, the American company responsible for the clinical trial, brought their own lawyers along for the hearings about the TGN1412 drug, billed as a possible wonder cure for arthritis, multiple sclerosis and leukaemia. The compensation money will largely be spent on equipment, adaptations and assistance they will need with their injuries.[2]

 

[Kate_UK]

But Rituximab has been around for years, surely it's nothing like the level of risk as the Northwick Park trial.

 

[Sasha]

I am approaching my mid-50s with no dependents, I have been sick for 9 years and I have been pretty conservative in trying treatments up till now. My approach to risk is changing because my greatest ambition is to resume being physically active (hiking) after my health improves, so I feel I have an important window or timeslot of the next few years. There are few other prospects for a radical improvement in my health on the medium horizon. So I aspire to become part of a Rituximab trial in a couple of years time (assuming I meet the entry criteria) while I will still be able to gain real benefit if it works.

Same here - approaching mid-50s and I've been mostly bedridden/housebound for 27 years. If I don't get some health back in the next 15 years I'll be pushing 70 and declining anyway in health due to old age. Like you, I want this window to be spent in good health or I will basically have had very little adult life.

Jonathan Edwards - isn't Rituximab/shouldn't it be available on the NHS off-license or on compassionate grounds (particularly for the kind of patients featured in Voices from the Shadows)? For many of us, waiting five years for trial results to come out, a NICE review and all the rest of it before it's standard NHS practice, will be too late. They're our bodies; we're grown-ups; can't we take an informed risk?

 

[Jonathan Edwards]

The Northwick Park Trial was an example of just how stupid and irresponsible people can get when profit is the motive. Most immunologists would have expected TGN1412 to make people ill and they gave it to six people all at once! Rituximab has been around for twenty years. It can still cause problems if used irresponsibly but there is no comparison. We still want to be as careful as possible, even so.

As Firestormm says we desperately need to find out who rituximab would be good for and who maybe it would be bad for. There were as many unknowns for rheumatoid arthritis at the time but of a different sort. The absence of biomarkers for ME is a big problem but at least the Norwegian study gives us a lead as to where people might look.

 

[Firestormm]

As Firestormm says we desperately need to find out who rituximab would be good for and who maybe it would be bad for. There were as many unknowns for rheumatoid arthritis at the time but of a different sort. The absence of biomarkers for ME is a big problem but at least the Norwegian study gives us a lead as to where people might look.

Morning

Would this part comprise a pre-Trial study? Am unsure how it all works in the world of research; but something that might better ensure outcome in the drug trial? I understand you are off to Norway to meet with the researchers there and I dare say it is something that will be discussed. Am really looking forward to this aspect of your involvement. Discovering something that is in common with those who have responded so well would be game-changing I suspect.

I never did get to say thank you for joining in with our conversations. Very much appreciated.

 

[OverTheHills]

Was that trial for Rituximab? Thanks

Oops sorry Firestormm and Kate I wasn't trying to suggest Rituximab was involved in the Northwick Park Trial or suggest that it is anything like as risky.

I was just trying (badly) to point out that I'm not unaware of or ignoring the fact that all trials involve a level of risk.Time for bed before I write anything else stupid

And like Firestormm I am enormously grateful to Prof Edwards for joining us in our conversations here.
OTH

PS That trial is particularly memorable to me because Northwick Park is only about 5 miles from where I grew up.

 

[Jonathan Edwards]

Sasha - In 1998 all I had to do to set up a trial 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'. I could treat off label and carefully built up enough experience to do a formal trial. (I did get peer review and ethical approval.) What helped, ironically, was that I had to do all this myself without the drug company interfering, because it was not until I had got a result that they were even interested. 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. I am now hoping to prove myself wrong.

Whereas once we could scrape together money to treat people off label, now there isn't even enough money to run a proper service and there are rules everywhere that prevent off label usage. That may protect people from cowboy doctors but it also means that virtually no innovative clinical research is getting done. What seems for sure is that the government no longer sees itself as taking any responsibility for our health.

But life was always full of obstacles. Where there is a will there is a way. On the other hand I actually think there are some difficult decisions to make about treating more patients until we have some way of addressing biomarkers. The real problem with ME is that it is so hard to pin down. For that reason I would not recommend off label treatment except within the confines of a trial with a specific scientific objective.

 

[user9876]

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.

This suggests that trials should be carried out by groups with experiance of using Rituximab so its very good you and UCL are getting involved.

This sounds odd but this is a drug with a complicated action. A more important factor is that reactions may depend on what disease is being treated. I note that someone with CFS and a positive antinuclear antibody developed rituximab pneumonitis (can present as BOOP or ARDS). Pneumonitis is not properly documented with rituximab but it is the reaction that most concerns me. We saw more of it early on, for reasons I do not fully understand. It may be a particular risk in conditions with anti-nuclear antibodies - that is just a thought from some cases. If reactions are more frequent in ME/CFS then we need to think carefully about that.

Do you look at people's lungs prior to treatment?

Also I was wondering if you recommend anything to deal with the loss of immunity. For example, do patients go on a clean diet, get told to avoid crowded places?

 

[Jonathan Edwards]

Morning

Would this part comprise a pre-Trial study? Am unsure how it all works in the world of research; but something that might better ensure outcome in the drug trial?

The world of research works whichever way you think up to do it - which has the unfortunate downside that you have to think it up in the first place - not always so easy! There is a different best way to address every different problem and nobody tells you what that is in advance. In this case we have the circular situation that we want to find biomarkers that predict good responses to treatment but we need to do the treatment to find out what those biomarkers are. It's a bit like trying to find the free end of the sellotape to unwind the next bit. We just need to find that slightly bumpy bit to get started. What helps a lot is everyone thinking of awkward questions. In the end all we are aiming for is the best way we can reasonably think of, and then someone can get on with it, but the more people have bright ideas the better the best we can think of will be. It will all boil down to common sense, but sometimes common sense isn't immediately obvious.

 

[Jonathan Edwards]

Do you look at people's lungs prior to treatment?

Also I was wondering if you recommend anything to deal with the loss of immunity.

Yes, I have always wanted to make sure that patients do not already have major lung problems before they have rituximab.

Loss of immunity may not be that simple. There are rare diseases in which the immune system is just missing a component, or even two. Most problems with immunity are more a case of skewing in one direction or another and the immune system is unbelievably complicated so it is not really a case of up or down or more or less but just not working right in one way or another. I am personally doubtful that ME has much to do with susceptibility to infections. I think it just seems like that. What I think is more likely and more promising as something we could treat is that the immune system is behaving as if there is a serious infection when there is no more than the usual harmless bugs around - that is more or less what autoimmunity is about, at least in many cases. So at present I have no idea what to advise I am afraid.

 

[user9876]

Yes, I have always wanted to make sure that patients do not already have major lung problems before they have rituximab.

Loss of immunity may not be that simple. There are rare diseases in which the immune system is just missing a component, or even two. Most problems with immunity are more a case of skewing in one direction or another and the immune system is unbelievably complicated so it is not really a case of up or down or more or less but just not working right in one way or another. I am personally doubtful that ME has much to do with susceptibility to infections. I think it just seems like that. What I think is more likely and more promising as something we could treat is that the immune system is behaving as if there is a serious infection when there is no more than the usual harmless bugs around - that is more or less what autoimmunity is about, at least in many cases. So at present I have no idea what to advise I am afraid.

Sorry my question wasn't clear I was wondering about loss of immunity caused by the Rituximab treatment. I was wondering if this is a significant risk and hence do you recommend things like a clean diet?

In terms of your view on ME being where the immune system is acting as if there is an infection that fits with things I have read.

 

[Jonathan Edwards]

Sorry my question wasn't clear I was wondering about loss of immunity caused by the Rituximab treatment. I was wondering if this is a significant risk and hence do you recommend things like a clean diet?

My mistake. Loss of B cell immunity with rituximab causes surprisingly few problems. Shingles may be a bit more likely so we tell people to keep away from chicken pox children. We recommend updating vaccinations before the B cells are depleted, but it is not clear that this is really necessary. We used to worry about people going to strange foreign countries but never had any specific reason for this. If there are other pre-existing immune problems very rare severe infections have been reported, although not in my experience. This is mostly an issue for cancer patients having multiple chemotherapy. After several courses of rituximab antibodies can get low and we tend to give it a rest if so. There are other uncommon situations where one has to be careful but in the usual situation there does not seem to be any need to do anything special.

 

[MeSci]

You could have done that all 18 years ago though , MeSci. Those of us who did that and had no improvement are the ones who will be volunteering for the drug trials. There needs to be options available for all groups.

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.

 

[Kate_UK]

I have seen this comment on the forum http://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.... ;(

Personally I do not really have pain as much of a symptom. I don't feel that I want any painkillers. Pain aside, the ICC is a good description of my illness. If those taking Rituxan currently are self selecting then perhaps they are not the best patients for that drug. I remember Lipkin's description that he found about 70% of CFS patients had the weird B-cells. So even in that study all the patients were not the same.

 

[Firestormm]

Kate_UK I think you will find that it isn't the patients (or that patient) self-selecting. Certain doctors are involved here and we have been discussing how they might be assessing suitability elsewhere on the forum. Until this is known and can be quantified - to me at least it seems risky to treat off label. But that's just me and some are being treated in this way and not reporting similar 'side effects' or connections. Also, this connection to 'pain' may not be the actual reason why Rituximab is not helping them. We really do need to learn more I think.

 

[Kate_UK]

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