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

[ixchelkali]

Interesting video from Norway in case it hasn't been seen. (click cc button for English subtitles).

http://www.youtube.com/watch?v=ZBCXKIRBQ-s

(all the funding in place for continuing research).

Thanks! I had watched that clip earlier and all I could understand was Dr Bell's comments. I didn't know the cc feature gave English subtitles.

I can see why Dr Bell was excited. Pretty amazing to see someone who was that severely ill for 9 years get well.

 

[ixchelkali]

One point that keeps nagging my brain is the common trigger of EBV for ME/CFS. Nearly everyone has EBV, but most people manage the virus. We often don't, and often also have CMV (the other HGV - Herpes Gama Virus). I've posted previously the NK cell connection, the NK cells help keep EBV from converting B cells. So whatever causes the low NK cytotoxicity, might that be our ultimate core pathology? If the NK can not keep EBV controlled and B cells get converted, there is higher risk of an autoimmune response, which creates oxidative stress. When this happens in a person with weak methylation, we get the MB-GD situation, mitochondria melt-down, etc. If this is our etiology, then killing off the B cells might not be the ultimate therapy, restoring NK cytotoxicity would be higher up in the chain of events that leads to the eventual MB-GD/mitochondria problem... sorry this is a bit cryptic, still thinking this through. Anyway this model resonates well with the fact that we now have three different therapies that significantly alter the course of ME/CFS, anti-virals (particularly those targeting EBV/CMV), methylation support, and now B cell depletion. IF the model of

NK=>EBV=>B-cell=>Autoantibody=>Oxidative Stress=>MB-GD=>Mito

is correct, then the divergent therapy success is explainable, each works on different areas of the etiology. Or not. Will be interesting to see who 'cracks' the ME/CFS model first, seems like we have our Rosetta stone now, thanks to the works of many (now incl. Mella/Fluge).

That's an interesting scenario and it seems plausible. The autoimmune theory is a possibility, but on the surface seems a little simplistic. There are several possible explanations for this new finding, and in my opinion, they have yet to advance convincing arguments why autoimmunity is a better explanation than other possibilities.

But at the very least, the response to Rituximab adds another piece to the puzzle. Another big question: WHY do some patients feel better when you knock out their B-cells? And why is there a long delay between the treatment and their improvement?

I think that any theory needs to account for all the peculiarities of ME/CFS, including PEM/PENE, abnormal exercise response, altered immune system profile, and the higher-than-normal infection rate with pathogens such as EBV, CMV, HHV6, and enteroviruses. I'm not prepared to accept the autoimmune theory until those issues are addressed, but I'm interested to hear how the researchers may account for those things.

 

[ixchelkali]

aggressive resting

I love this! Best oxymoron EVER! I am going to borrow this, mellster, and use not only as a practice but as my answer when people ask me "And what do you do?"

I call it A.R.T.: aggressive rest therapy

 

[Andrew]

Here's a movie with captions (but not interview with David Bell). To turn on the capture, click on the CC at the bottom of the interface. Sometimes I have to click more than once.

http://www.youtube.com/watch?v=ZBCXKIRBQ-s

 

[ixchelkali]

something that might interest you to know --

A.R.T. ( Agressive Rest Therapy ) was actually used somewhat and often talked about as treatment back in the 80s. Obviously it did not make anyone better, just kept them from getting worse. (mostly)

Awwwww, I thought I thunk up that term myself. Well, I did, but I thought I was the first.

 

[valentinelynx]

So what auto-immune disease follows infectious outbreaks? None are acknowledged as yet. Rheumatoid arthritis, Lupus etc dont come in infective outbreaks.

Someone may have said this already, but I don't think I can get through the rest of this thread tonight...

"Reactive arthritis (Reiter's Syndrome or Reiter's arthritis), is classified as an autoimmune condition that develops in response to an infection in another part of the body. Coming into contact with bacteria and developing an infection can trigger the disease.[1] Reiter's syndrome has symptoms similar to various other conditions collectively known as "arthritis". By the time the patient presents with symptoms, often time the "trigger" infection has been cured or is in remission in chronic cases, thus making determination of the initial cause difficult."

...

"Reiter's syndrome is an RF-seronegative, HLA-B27-linked spondyloarthropathy[4] (autoimmune damage to the cartilages of joints) often precipitated by genitourinary or gastrointestinal infections. The most common triggers are sexually transmitted Chlamydial infections and perhaps, less commonly, Neisseria gonorrhea; and Salmonella, Shigella, or Campylobacter intestinal infections."

above quotes from Wikipedia

I'm not in any way implying that Reiter's syndrome or the bacteria associated with it have anything to do with ME/CFS. Just that Reiter's Syndrome is a known phenomenon of autoimmunity following infection. Rheumatic fever is another case, where the body attacks parts of itself (heart valves most characteristically) after Strep infection. Juvenile diabetes is thought to be caused by cross reactivity with some infection (don't recall the details if there are any...)

While these are not "outbreaks" it is not inconceivable that an infection that occurs in outbreaks could cause an automimmune reaction through cross reactivity.

 

[sensing progress]

More on the Rituxan (Rituximab) patent: "Roche has claimed patent protection for the drug until at least 2015 and possibly 2018 in the USA and 2013 elsewhere"

Source: http://www.pharmatimes.com/article/11-01-06/Spectrum_plans_to_develop_biosimilar_Rituxan.aspx

 

[em.ge]

UN CONVENTION ON THE RIGHTS OF PEOPLE WITH DISABILITIES

And then, with our new found energy, stamina and pain free we'll drag Wessely in front of the International Human Rights Tribunal for crimes against humanity.


I like your vision of the future - very much - (as an activist)


:victory: GO NORWAY :victory:

Hi,
This is em.ge and I'm new to this forum.
But I've long awaited the day [19yrs] when PwCFS can claim their [enshrined!] human and health rights.
Count me in.
Smiles,
em

 

[ixchelkali]

So what auto-immune disease follows infectious outbreaks? None are acknowledged as yet. Rheumatoid arthritis, Lupus etc dont come in infective outbreaks.

Acute motor neuropathy occurs in seasonal outbreaks in China, caused by campylobacter jejuni. It's a form of Guillain-Barre.

There are several autoimmune diseases where they suspect a viral trigger, including MS and type 1 diabetes. Presumeably if you had an outbreak or epidemic of the triggering virus, you would see a cluster of cases of the autoimmune disease among those who have other predisposing factors (genetics, another virus, or whatever?).

 

[SilverbladeTE]

And with ME, the "diagnosis" of ME itself usually follows a year or more AFTER the event for many folks, so tracing it back to a specific outbreak, and thus specific pathogen's not going to happen :/

As said, for myself, there was a very nasty flu-like bug of long duration in my region (upt o 2 months or more instead of usual 2 or 3 weeks withthe actual 'Flu), from what GP told me, lot of folk came down with ME after that event.

 

[Waverunner]

I'm very happy about the Rituximab study. Does anyone know what the consequences of a temporary B-cell depletion are? I always thought that they were necessary for antigen production. How does the body fight of viruses if the immune system has no antigens? Would this be a problem when PWCs suffer from co-infections?

 

[alex3619]

I'm very happy about the Rituximab study. Does anyone know what the consequences of B-cell depletion are? I always thought that they were necessary for antigen production. How does the body fight of viruses if the immune system has no antigens? Would this be a problem when a PWCs suffers from co-infections?

In the short term the consequence is likely to be that any sustained infection will become a longer and more severe infection. Its probably the biggest risk with depleting B cells.

In the long term the only problem is likely to be a loss of memory B cells, I think. I haven't checked to see they have the CD20 marker. If so, you will lose most or all of the resistance you had to diseases that you have had, including the benefits of vaccination. No vaccination can be considered to be effective in the long run if you take drugs that destroy the cells that remember how to fight an antigen.

I do wonder what effect it will have on allergies though - B cells are only peripheral, but as the Th balance shifts from 2 to 1, which it should do if the theory of Rituximab is right and our understanding of the immunology is right, then allergic responses should decline.

bye
Alex

 

[urbantravels]

I think a somewhat more basic fact is important to understand: following B cell depletion via Rituximab therapy, new B cells eventually come in. The B cell depletion is not permanent. I believe the correct terminology for these new cells is that they are "naive" B cells. So it's not as if you're walking around for the rest of your life with no B cells. One of the many burning questions is whether the "reset" that may be accomplished via B cell depletion is permanent, or whether you would eventually have to repeat the depletion.*

I did not define the term "reset" above - we don't have enough information yet to know what the B cell depletion may be accomplishing in MECFS patients. Although the actual published paper is careful in not making any claims about what the observed results might mean, in talking to the press the authors seem to feel that the results better support an autoimmune theory of the disease, because the improvement was not seen immediately upon the B cell depletion, but was a delayed reaction. They seemed to feel this was consistent with a theory that auto-antibodies were present, but took a while to be cleared from the system - longer than it took to kill off the B cells that produced them. Still unanswered is any question about whether the new B cells might eventually start producing autoantibodies and the cycle might repeat.

Alternatively, if the B cells are harboring a persistent infection, such as herpesvirus infection, and the depletion is benefiting the patients because it's killing off enough of the cells to get the infection under control, you might expect that the B cell depletion would improve the patients' symptoms more quickly. But there is clearly a whole lot we don't know about the exact mechanisms causing all our symptoms.

I'm sorry, I've been reading past posts rather quickly, but to whoever said the 'autoimmune disease' hypothesis seemed 'too simple' - whew! There is nothing simple about autoimmune diseases, and they most certainly can and do cause multi-systemic problems. Auto-antibodies can attack anything in any system of the body, including the nervous system and the cardiovascular system.

And yes, autoimmune processes can be triggered by an initial infectious event; this is seen in multiple autoimmune diseases, and hypothesized (but as yet unproven) in many more.


* When do we get to say we're 'cured'? Well, cancer patients don't really get to say that either. The benchmarks are whether you are cancer free at a certain time horizon - (x) number of years - and this varies tremendously across different kinds of cancer. With some cancers, if they have not recurred after X years, the probabilities say you are most likely "cured" and that particular cancer will not come back - but it is still a probability (albeit a very strong one) and never an absolute guarantee. Of course, we don't live forever, so eventually the threat of return goes away, one way or another...

 

[urbantravels]

Someone posted above wanting to know whether Rituximab will ever be available as a generic. At the moment, there are NO drugs in the mAb class that are available as "generic". This is not due to the evil nefariousness of pharmaceutical companies, but due to the technical problems in establishing whether you can ever make a 'copy' of a cellular product that is exact or "close enough" to be the equivalent of the original product. These are drugs that are way, way, WAY more complex than most existing drugs, where you can usually say with some confidence whether or not a generic product is a comparable molecule to the original product.

More, much more, about mAbs than you probably wanted to know:

http://www.landesbioscience.com/journals/mabs/about/#background

 

[Waverunner]

Thanks Alex for clearing this up.

If auto-antibodies are the problem in CFS (at least this is what the study points towards) why is it not possible to identify these auto-antibodies and maybe tailor treatment towards these auto-antibodies only instead of wiping out all B cells? It would be very important to know who falls into the category of PWCs who will be helped by B-cell depletion. Do you think that new diagnostic CFS markers could be developed as a result of this study?

 

[alex3619]

Hi Waverunner, speculating here. I don't see how they can target the antibodies directly unless they are very clever, and follow that up with lots of expensive research. We can design fake targets for the antibodies to soak them up, but the side effects of that are unknown. Attacking the antibodies is difficult as they are many different kinds that could be made to target any specific target. There is also the risk that such a treatment will knock out all antibodies, and if we have to keep taking it because it doesn't fix the problem, it will reduce B cell immunity permanently - for as long as you are on the drug. One clever option is to use the antibodies to flag/identify the B cells making them and use a targeted drug to kill them - but again this runs the risk of knocking out all B cells, atlhough this should not be any worse than Rituximab.

As for biomarkers, if they can find a pattern of chemistry inducing the immune chemicals or autoantibodies, then it might lead to a diagnostic tests. That is still years away though. I am concerned that Rituximab as a treatment might not be available until about 2017. The extended Phase 2 clinical trials wont finish till 2013, I don't think we can see the Phase 3 to finish till at least 2015, and then add two years for dithering around, publication delay, doctor and government resistance etc.

Anticardiolipin antibodies while prevalent at 95% are not diagnostic in themselves as so many diseases have this from HIV to rheumatoid arthritis. We need to know more.

I know that e. coli has cardiolipin in its bacterial membrane. I wonder if bacterial product translocation might not induce anticardiolipin antibodies, which then go on to attack our own mitochondria. I have still to research this properly though.

Bye
Alex

 

[urbantravels]

If you haven't read this reply thread on PLOSOne yet, it's worth perusing, both for Tom Kindlon pointing out the many deficiencies of clinical endpoints used in other trials of ME/CFS 'treatments' - hello PACE trial! - but also for the correction issued to VanDerMeer et. al.'s mistaken notion that a 'delayed reaction' isn't found in treatment of other autoimmune diseases by B cell depletion.

http://www.plosone.org/annotation/l...notation/43f3e6a8-cf7d-4438-8b97-b21b9c31bf5c

Van Der Meer:
"It is not so much the finding that a form of immunotherapy may work, but rather the peculiar late response (between 6 10 months). Such a late response has not been seen in other conditions in which RTX works."

Jonathan Edwards:
"The criticism made here contains several errors. There is nothing peculiar about the late response. It is to be expected. I was responsible for both the phase I and the proof of concept phase II (NEJM 2004) studies in rheumatoid disease, which formally established the validity of B cell depletion in autoimmune disorders. From the very outset in 2000 we reported that responses could take many months to develop, in line with autoantibody decline."

It reminded me of Marshall McLuhan appearing on-screen in Annie Hall to correct the blowhard in the movie line who is trying to impress his date with his knowledge of McLuhan: "I heard what you were saying! You know nothing of my work!"

This morning, via a Tweet from @DeBortgjemte, this interesting story about B-cell depletion in RA (Rheumatoid arthritis) and how, yes indeed, at first the medical establishment thought it was a bogus idea and didn't want to hear about it.

http://www.thenational.ae/news/uae-news/science/switch-off-switch-on

Affecting about one in 100 people worldwide, RA can strike anyone literally overnight, their immune system suddenly attacking their joints. The condition is excruciatingly painful, and for years there seemed no hope of a cure. Until recently, the prime culprit was held to be T-cells: white blood cells that play a key role in the disease-fighting immune system. Yet despite intensive study, no one could explain how or why T-cells should produce a lifelong ailment such as RA. Most tellingly of all, therapies targeting T-cells failed to benefit patients.

This prompted Professor Jonathan Edwards and Dr Geraldine Cambridge at UCL to ponder the possibility than B-cells might be to blame. Their idea was based on the fact some B-cells are known to make antibodies which inadvertently seek out and destroy healthy tissue. Normally, these would be destroyed by the B-cells themselves. But what if some of the antibodies by chance possessed the means to evade their own destruction - and go on to attack the joints?

That led Prof Edwards and Dr Cambridge to a radical new approach to treating RA: "rebooting" the immune system by destroying all the B-cells, and then starting over with fresh ones. Fortunately, a compound capable of targeting just B-cells had just become available: rituximab, a so-called monoclonal antibody which homes in on specific targets like a heat-seeking missile. This could destroy all the B-cells, leaving patients to develop a whole new set free of the renegade variety that attack joints.

That at least was the theory, and with the standard T-cell theory not getting anywhere, the team thought it was worth bringing to the attention of other researchers. They soon found that new ideas aren't always welcome in science - even if the old ones aren't working. Their academic papers were rejected by journals as "obviously" wrong - on the grounds that they focused on B-cells, not T-cells.

 

[Waverunner]

It really hurts to hear that we may have to wait till 2017, Alex. I'm still hoping that the whole CFS research speeds up a little bit but on the other side I see a global recession and a financial meltdown in Europe coming up in the next few years so who knows. Kind of depressing.

Urbantravels, it's funny that a moderator already tuned in after some people spoke up against Vandermeer. I didn't find any insulting posts except Vandermeers. To claim that physical ill people have a psychological problem only, is fine of course.

"Active debate is to be welcomed, but please refrain from making personal comments about researchers or their motivations. Some of the comments in this thread are sailing close to the wind.

Please re-read the PLoS ONE commenting guidelines, particularly:
- Discussions should be confined to the demonstrable content of articles and should avoid speculation about the motivations or prejudices of authors (this would extend to commenters too)
- Language that is insulting, inflammatory, or obscene will not be tolerated.

Thank you.

Matt Hodgkinson
Associate Editor
PLoS ONE"

 

[Tristen]

In the short term the consequence is likely to be that any sustained infection will become a longer and more severe infection. Its probably the biggest risk with depleting B cells.

In the long term the only problem is likely to be a loss of memory B cells, I think. I haven't checked to see they have the CD20 marker. If so, you will lose most or all of the resistance you had to diseases that you have had, including the benefits of vaccination. No vaccination can be considered to be effective in the long run if you take drugs that destroy the cells that remember how to fight an antigen.

I do wonder what effect it will have on allergies though - B cells are only peripheral, but as the Th balance shifts from 2 to 1, which it should do if the theory of Rituximab is right and our understanding of the immunology is right, then allergic responses should decline.

bye
Alex

I suspect we will be looking at combo treatments with Rituximab and antimicrobial(s) tailored to a persons infection profile. One busts open hiding places, and the other kills the exposed bugs. It shouldn't be impossible to treat other known infections simultaneously, minimizing chances of reactivation and increased replication. Of course this is based on the idea that B cells harboring a pathogenic bug is the cause of the dysfunction. If not, and the autoimmunity is secondary to other causes, it seems to me the same idea could apply for treatment without increasing pathogen replication.

 

[Waverunner]

Here are little Interviews with Klimas, Komaroff and Montoya about their thoughts on the Norway study:

http://debortgjemteinternational.wordpress.com/2011/10/30/how-important-is-the-rituximab-study/

Nancy Klimas, professor in immunology at the University of Miami, has worked on the immune system in ME/CFS for 25 years, and she was very excited about the upcoming study results.

- I think theyre doing fabulous work. I first heard about their work when that first report came out a couple of years ago. I was in London, and I was all excited, I couldnt wait for them to do this, Klimas said.

She said she wanted to leap right in and do her own study, but she didnt want to step on the Norwegian researchers toes.

- I decided that I needed to let them do what they did, because they did it right, and they deserve all the credit for all the work that theyre doing its very exciting and very innovative, Klimas said.

But she points out that Rituximab is a big gun.

- Youre wiping out all of the B-cell population. So the question in my head about this is why would it work?

She then presented two possible theories. One is that a big subgroup of ME/CFS-patients has an autoimmune disease that is antibody mediated.

- So this could be, if Rituximab works, an autoimmune disease that is specifically and entirely by an antibody mediated autoantibody. We know that Rituximab is being used in autoimmune diseases like RA, Klimas said.

According to Klimas another possibility is that the B-cell is a reservoir for a virus that really matters. The B-cells are the major reservoir for Epstein Barr Virus, a virus that has been linked to ME/CFS several times in the research literature. It is well established in research that mononucleosis trigger ME/CFS in many cases.

- Let us just pretend its EBV for a moment. When were done with our EBV, when you and I had our mono, we are left with roughly one million latent EBV-infected cells. And our immune system handles that. One of the questions that have never been answered in chronic fatigue syndrome patients is, do they have a bigger reservoir than that? Was their primary infection so intense that they have ten million or a hundred million latently infected cells? Because theres going to be a threshold where a normal immune system cant contain latency and cant maintain that virus under control. () Maybe Rituximab simply knocked down the reservoir so intensely so that we got it down under the threshold, and then the immune system could handle it. And that would make sense to me, Klimas said. She stressed that this is just a hypothetical construct without data to back it up, and then adds that she would love to see some before and after cells and serum plasma be sent off from the Norwegian freezers to EBV-wizards like Ron Glasers group.

- Do you think this is a more likely explanation than autoantibodies?

- We dont know. All we know is that they got better, and its not that many yet. To understand the mechanism of why it works is critical to go forward with that kind of investigation. And remember that the ME/CFS population is not homogenous, theyre not all the same, theres going to be a subgroup this matters for. So Im also hoping in the laboratory that they are looking for a biomarker, or at least storing enough stuff so that someone else can look at the biomarkers to predict who responded. Because we might very well discover that its a viral load phenomena or that its only the autoimmune group that responded. And there are markers for things like that, Klimas said.

- Some people in the ME/CFS research community say all the immune findings in ME/CFS are inconsistent, and by that implies that theyre not so important. What are your comments on that?

- Im so frustrated by that response because its been 25 years. Pull out the study that have very large numbers if you want to get some consistency in the data. Throw out all of the studies that have 20 patients and under, and look at the studies that have 100, 200, 300 patients and they are saying the same thing. Its not hard. I think the immunology is proven. Its not controversial. Its not a hypothesis. Its proven. Theres immune activation, theres cellular dysfunction and there is a significant degree of immune dysfunction, Klimas said.

She says increasingly more research are coming out that are backing up this statement.

- Everything is fitting together, the clinical observations, the biological observations and...