Astounding Norwegian research breakthrough with Rituximab can solve CFS mystery!!!

[perrier]

for Kati

Kati writes:


There is a lot of money for cancer. There is money for spinal cord injury. There is money for trauma. There is still lots of money for MS research. Lots of money for HIV/AIDS. Diabetes. What about ME? We do have the right to health care, crumbling system or not. So Helene, if you want to same the health care system, you can stay home. It is in my opinion that I am entitled to health care in Canada. I will see one specialist after the next until I get what I need.

The Rituximab story is a good one to argue to our government because it is already administered to many different diseases. Who prescribes it? Oncologists and Rheumatologists do.

Do we, patient with ME have the right to health care? Yes, just the same as cancer patients and AIDS patients, and the rest of them. That is my opinion, and you are certainly entitled to yours.[/QUOTE]

Helene responds: I was not trying to distress any of the Canadians here, not at all. I was just stating some facts, which have been highlighted by CBC shows. Of course, I agree that ME needs the same attention as AIDS etc., and I have spoken out on this whenever I have had an opportunity. I was just stating that at the moment,despite the use of the Canadian definition for this illness, there are very few physicians knowledgeable in this illness and a great number of patients go abroad for help, for this illness and for other complicated illnesses. Cancer is handled pretty well in Canada. Tax dollars pay for the medicare system and ME patients deserve the same level of care. How could I think differently. Cheers, Helene

 

[Sasha]

Take a look at this interview with Dr Bell on Norwegian TV on YouTube! It only lasts a minute or so but you'll feel great - he says, "I've not seen results like this in any medical study in the 25 years that I've been in this field. So that these are extraordinary results."

Dr Shepherd of the ME Association says in the New Scientist article, "It's the most encouraging drug result so far in the history of this disease [...] Although it's a small trial, it's produced dramatic results." I don't think I've ever heard him get very excited about research findings so this is something!

The MEA say that they want to fund Rituximab research:

Further research into the use of this drug clearly needs to be carried out and I have already raised the issue of rituximab at a meeting at the MHRA earlier this week.

The MEA Ramsay Research Fund would be very willing to consider helping to fund a UK clinical trial if anyone in a reputable clinical unit wants to apply.​

 

[Sasha]

CFS Patient Advocate has posted about Rituximab in his blog here and refers to an "excellent article" that Cort did last December about Rituximab here. I'm off to read it!

 

[perrier]

for Boomer

What is happening with the BC clinic for me/cfs that was supposed to open up in Vancouver this fall? Has that dropped off? Thanks.

Hi Boomer:
I would love to know what the status of this project is. Haven't been able to learn anything. Cheers, Helene

 

[perrier]

thanks for posting link

Take a look at this interview with Dr Bell on Norwegian TV on YouTube! It only lasts a minute or so but you'll feel great - he says, "I've not seen results like this in any medical study in the 25 years that I've been in this field. So that these are extraordinary results."

Dr Shepherd of the ME Association says in the New Scientist article, "It's the most encouraging drug result so far in the history of this disease [...] Although it's a small trial, it's produced dramatic results." I don't think I've ever heard him get very excited about research findings so this is something!

The MEA say that they want to fund Rituximab research:

Further research into the use of this drug clearly needs to be carried out and I have already raised the issue of rituximab at a meeting at the MHRA earlier this week.

The MEA Ramsay Research Fund would be very willing to consider helping to fund a UK clinical trial if anyone in a reputable clinical unit wants to apply.​

Like everyone I am also very excited. I hung onto Bell's every word. I heard him say, however, that he believes that a recovery is possible for those ill up to five years. Did I hear correctly?

What about the rest of us?

 

[currer]

http://www.hemispherx.net/content/investor/default.asp?goto=663 (courtesy of the other forum)

Can anyone understand this?

It mentions ampligen, immunotherapy, rituximab, and cancer.

 

[biophile]

This is what they defined as a 'major' (positive) response

First, here are the main results of the study again ... "Major or moderate overall response, defined as lasting improvements in self-reported Fatigue score during follow-up, was seen in 10 out of 15 patients (67%) in the Rituximab group and in two out of 15 patients (13%) in the Placebo group (p = 0.003)." Looking at Table 3, what surprised me is that in the Rituximab drug group, a "major" positive response was much more common (60%) than a moderate positive response (7%). In response to caution on this thread from multiple posters regarding the definition of "major" without knowing more about it, I looked into this further and I hope the following will be useful.

CFS symptom scoring was based on a visual analogue scale 110 (1: no symptom; 5: moderate symptom; 10: very severe symptom). There were 29 recorded symptoms including fatigue, with 4 categories. During multiple follow-up points, the patients recorded overall change in each symptom the preceding two weeks as compared to baseline. This was also based on a visual analogue scale (range: 06; 0: Major worsening; 1: Moderate worsening; 2: Slight worsening; 3: No change; 4: Slight improvement; 5: Moderate improvement; 6: Major improvement), similar to a Clinical Global Impression Scale (CGI). A Norwegian translation of the SF-36 health survey was also used, including the eight subdimensions. There is also something about physician-reported measures to complement the patient-reported measures.

They plotted scores over the course of the trial on graphs, but back to the definition of major response: "From the self-reported symptoms recorded every second week (Figure S2, scale 06), a Fatigue score was calculated as the mean of the four symptoms: Fatigue, Post-exertional exhaustion, Need for rest, Daily functioning. [...] A major response was defined as a Fatigue score ?4.5 for at least six consecutive weeks, also demanding recordings of some fatigue symptoms as major improvement (value 6) during the response period". There are equivalents for other symptom categories but these aren't included in the definition of "major" so I didn't include them here. Also note that, "A moderate response was recorded as Fatigue score ?4.5 for at least six consecutive weeks, but without recordings of fatigue symptoms as major improvement during the response period."

So for example, a patient could be classed as having a "major" positive response if all 4 fatigue symptoms were at least equal to or better than halfway between "slight improvement" and "moderate improvement" for at least six consecutive weeks. Alternatively, the threshold average score of ?4.5 could also be reached if 2 out of 4 symptoms had "major improvement", which is the maximum on the improvement scale. They also state that "some" symptom recordings had to be "major improvement", but I haven't found clarification on that yet. Note again that the 4 symptoms in the "Fatigue score" category are: fatigue, post-exertional exhaustion, need for rest, daily functioning.

How does this compare to the PACE Trial? Difficult to say exactly, but here are the details ...

When using bimodal scoring on the Chalder fatigue questionnaire which has a range of 0-11, 3 or less is considered to be normal for healthy people. Participants in the PACE Trial had to score 6 or more out of 11 for entry at baseline. In the original published protocol, a "positive outcome" for fatigue was defined as a 50% reduction in score, or a score of 3 or less out of 11. This was later dropped as an outcome goalpost, and so was their stricter criteria for "recovery".

In the Lancet paper, after switching to Likert scoring (range=0-33) a mere decrease of 2 points out of 33 was deemed an "improvement" in fatigue. I won't go into the definition of patients returning to "normal" because it weds thresholds in both fatigue and physical function, based on being within 1 standard deviation of the mean score from questionable population samples.

PACE also presented a simplified version of the CGI scores which collapsed the "much better" and "very much better" answers into one ie "positive change" at 52 weeks.

CGI equivalent in PACE: SMC (defacto control group) = 25% | APT = 31% | CBT = 41% | GET = 41%.

CGI equivalent in Rituximab trial: saline control group ~7% major + ~7% moderate = ~13% | active drug group = ~60% major + ~7% moderate = ~67%.

The above doesn't take in account the possible differences in cohort characteristics. Despite being recruited from secondary care, it seems unlikely to me that the obvious majority of PACE Trial participants would have met Canadian criteria, where 100% met Oxford criteria (Sharpe et al 1991), ~67% met CDC criteria (Reeves et al 2003), and ~51% met London ME (version 2?) criteria. In the Rituximab trial, 13/15 or ~87% of the control group met Canadian criteria but I don't see proportions mentioned for the active drug group. Another clue comes from recent epidemiological research conducted in the UK which suggests that only about half of those meeting CDC criteria (Fukuda et al 1994) also meet Canadian criteria. Note that Reeves et al 2003 is basically Fukuda et al 1994 with some additional recommendations.

 

[Sasha]

Like everyone I am also very excited. I hung onto Bell's every word. I heard him say, however, that he believes that a recovery is possible for those ill up to five years. Did I hear correctly?

What about the rest of us?

Yes, that's what he said but he may have been going by the longest time of being ill (5 years) among the three patients who had had long-term responses and were back at work with no sign of relapse. The other in the Rituximab group had been ill 1 year and the placebo big responder had been ill 0.7 years (i.e. about 8 months). Or he may not have been going by that! He didn't explain.

As for the rest of us (25 years here), even if total recovery wasn't available I'd be thrilled to even get 20% up the scale at this point! But I'd hope for more. A lot of things open up in life opportunties even a point or two up a ten-point fatigue scale.

 

[SpecialK82]

Very exciting study - great to see!

I would think Rituximab manufacturer, Genentech would be pushing to get trials done for us.

Although, I think the most important element of the study is not necessarity the drug itself, but that we learned of a way to stop ME/CFS problems, we took a giant leap forward and open new avenues of research. From this knowledge, it would seem possible to develop safer and more targeted ways to control CFS upstream. In otherwords, to do a "surgical strike" instead of dropping a nuclear bomb.

Also thanks Rich for your analysis!

 

[richvank]

Hi Rich, i have just finished watching the three hours of your swedish talk (thank you) and then went straight on to the presentation of the Rituximab trial at the Invest in ME conference, which i have to say was very exciting and inspiring.
You note that one of the patients was completely well a year later biut had only recieved the placebo, the researchers noted in the talk that this patient did not meet the Canadian diagnostic Criteria and was the only patient in the trial who did not, they presented this as a possible explanation for the result.

If as you point out low Glutathione is the major problem in M.E (i simplify so that my brain can function) then surely this could be rpoven by giving IV infusions of Glutathione. I realise this would not lift the block but surely would prove what would happen once you did lift the block. Is this possible?

Hi, justy.

Thanks for hanging in there for my whole talk! I appreciate knowing what the researches said about the patient on placebo who recovered. All of us suffer from lack of an agreed-upon, solid case definition that is tight enough to give a very homogeneous cohort. It is hard to believe that a person who is seriously ill from ME/CFS could be cured by salt water!

With regard to IV infusion of glutathione, this has been done and is being done by quite a few practitioners. The general experience is that in most cases it brings temporary relief of symptoms (for about a day or two), but in a subset it actually makes the symptom picture worse. When glutathione is given by I.V., about 80% is taken out of the blood by the kidneys. It is initially broken down, and then some is reformed. Some cysteine is put back into the blood. About 10% is taken by the lungs. The rest goes to a variety of tissues. The problem with I.V. application is that it is apparently not able to raise the glutathione level inside the cells very much, in general. Probably the intracellular levels are raised more by use of liposomal glutathione, or possibly the acetylglutathione that is now being offered. But I think it is still likely that the vicious circle mechanism will prevail unless glutathione comes up a lot, on a sustained basis, and lifting the partial methylation cycle block is the only way I have found that will do that on a more permanent basis. But perhaps in the two patients in this study who recovered after Rituximab treatment, just lowering the inflammation was enough to break the vicious cycle, so that glutathione came up enough to restore the B12 function to normal and lift the partial methylation cycle block.

As you know, the methylation treatment alone has not brought total recovery to very many PWMEs/PWCs, though it brings significant improvement to most. One of the possible reasons why it has not brought complete recovery in many of the cases may be that there is some condition in the body that is still placing a big demand on glutathione, and just lifting the partial methylation cycle block is not able to overcome it. Inflammation-related oxidative stress seems like one good possibility. If Rituximab lowers the oxidative stress, at least temporarily, this might be enough to help break the vicious circle. Perhaps the methylation treatment combined with one course of rituximab would push more people into recovery. This is just speculation at this point. It does seem to be true that the few people who have recovered apparently completely after the methylation treatment was given had had other types of treatment before that, some of them directed at knocking down infectious diseases, and hence, inflammation. Maybe that's how all of this fits together. Note also that there were some people in the Rituximab study who were not helped by the treatment. Perhaps the dominant glutathione demand in these people was due to toxins rather than to infections. If this was the case, knocking out the B cells would not have lowered the demand on glutathione, and that could explain why there was no improvement. There are many factors that can place demands on glutathione, and not everyone with ME/CFS shares the same ones.

I'm hopeful that as time goes on more researchers will begin to believe that glutathione is an important actor in this drama, and will begin measuring it in an accurate way. I think that could help to pull all of this together.

Thanks for your comments.

Best regards,

Rich

 

[Sasha]

In response to caution on this thread from multiple posters regarding the definition of "major" without knowing more about it, I looked into this further and I hope the following will be useful.

Hi biophile - thanks for that useful summary.

I've read the paper now and the take-home on fatigue that I got from it was that participants started with an average fatigue rating of 3 on a 10-point scale and improved to a mean of 4 at six months-ish before declining a bit (Fig. 2, both patient-reported and self-assessed). That's not a huge average improvement but then treatment wasn't continued for long and I'd say it's a big improvement in six months. Also, some patients had much, much bigger responses and some appear to have gone into long-term remission so that average figure is hiding some good stuff.

Clearly much better results than PACE and unlike PACE, the authors appear to be being very transparent about what analyses were specified in the protocol and where they did additional analyses in the light of their results.

Very much looking forward to seeing more Rituximab stuff getting going. Hope Cort or someone can produce a list of what's now in the pipeline and what those studies are looking at in terms of biomarkers, polymorphisms, etc.

Edit: Esther12 has very helpfully pointed out that the scale in Fig 2 is not the 10-point symptom severity scale but a scale of improvement where 3 = no change (just typed "no chance" by mistake there, suppose it amounts to the same thing!), and 4 = slight improvement. As the individual patient data in Figs A and C show, however, some patients had "major improvement" (6 on the scale).

 

[richvank]

Hi, Rich, how high is "a little higher than normal"?

thanks,
willow

Hi, Willow.

Sorry, I don't have numbers to give you. The abstracts just say that the titers were low. I think they mean low compared to what happens in a recognized autoimmune disease, such as systemic lupus erythmatosis. I think docs use ANA to help with their differential diagnosis between ME/CFS and lupus sometimes.

Personally, I don't think ME/CFS is an autoimmune disease, though some autoantibodies can be found in it, especially the thyroid ones, if a person has Hashimoto's as part of ME/CFS. Wikland reported that 40% did in his study, and Byron Hyde also finds a lot of Hashimoto's in his ME cases.

It's known that some cells die early in ME/CFS. Dr. Howard finds elevated levels of cell-free DNA due to this. Howard Urnovitz has suggested looking at this DNA to find retroviral DNA in it. This is the socalled "Next Generation Sequencing" that was reported on at the Ottawa conference. I think Judy Mikovits is moving in that direction, too.

Anyway, when cells die at a higher rate, I think that autoantibodies can rise, as the immune system responds to the fragments of these cells before they have been cleaned up by the macrophages. I think this is what accounts for the autoantibodies that have been observed in ME/CFS, except for the thyroid antibodies, and I have invoked Duthoit's mechanism for that, i.e. glutathione depletion causing higher hydrogen peroxide, which damages proteins there and provokes the autoimmune reaction.

Best regards,

Rich

 

[Esther12]

I've read the paper now and the take-home on fatigue that I got from it was that participants started with an average fatigue rating of 3 on a 10-point scale and improved to a mean of 4 at six months-ish before declining a bit (Fig. 2, both patient-reported and self-assessed). That's not a huge average improvement

I've only had a quick look - but the six point thing is based upon improving/getting worse. So a score of 4 means getting better, rather than any absolute level of disability. If someone stayed at 4, they would eventually fully recover. I'm not too sure how to interpret the results myself, or what level of improvement we should expect if these results held up. It's certainly a hopeful study though.

 

[Enid]

Please can we change the title of this thread from "those crazy Norwegians"- not something anyone would want to meet - especially dedicated Docs.

 

[Sasha]

I've only had a quick look - but the six point thing is based upon improving/getting worse. So a score of 4 means getting better, rather than any absolute level of disability. If someone stayed at 4, they would eventually fully recover. I'm not too sure how to interpret the results myself, or what level of improvement we should expect if these results held up. It's certainly a hopeful study though.

Argh, you're right! Thanks, Esther. I'll add an edit my OP.

 

[Enid]

Thanks Rich - it's always good to see your informed thinking.

 

[Kati]

Regarding the clinic in British Columbia, as far as I know it is still in the planning phase, I believe they are aiming at early 2012 for opening (with strong emphasis on infectious disease and research)-no location as of yet. What I also know is at least one of the founder of this clinic (not a ME/CFSspecialist) attended IACFSME- which is great news to me.

 

[Cort]

It could also be hitting EBV activation in B cells; those are after all the cells that EBV hangs out it. If Rituximab is knocking the B cells down it could also be reducing EBV cell activation.

However it works this is huge news; the study appears to be really well done -that drug is already being studied intensively in quite a few disorders -and it will alot of immunologists some second thoughts about whats going on in CFS.

 

[Cort]

Nice. But you know what bugs me? The Answer autoimmun disease. Thats basically another word for we don't know. There so many autoimmun diseases out there and still new stuff appears to be cause by autoimmun diseases. And noone knows whats causing this. Personally I don't see autoimmun disease as a real answer.
Its kinda like saying the bulllet caused the death of a person its not murderer and not trying to find out who pulled the trigger. Giving everyon bullet proof equipment and not worrying about all the people running around shooting.

Its also a word for 'a legitimate disease'; recasting ME/CFS as an autoimmune disorder potentially brings a whole group of researchers to study the disorder that never would have thought to otherwise. If this thing breaks in the research community it means alot more research into the physiological aspects of the disorder.

 

[max]

........and the consensus of those that understand this stuff is what?

What do I say to my partner? Is this a major step?

I do not speak "medical" - I'm an activist (I used to be known as a 'carer' - prefer the new label) and do not pretend to comprehend research papers - although I can get the drift, can anyone summarise the findings for me?



Go Norway.