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

[Waverunner]

They say that the Norwegian study on Rituximab in ME/CFS is the most viewed on PLoS ONE with more than 16.000 views.

 

[Sasha]

They say that the Norwegian study on Rituximab in ME/CFS is the most viewed on PLoS ONE with more than 16.000 views.

What, ever?!

 

[urbantravels]

Um, I think that's just a current figure, i.e. it's at the top of the list currently, not an all-time figure.

These articles [i.e. this list of most-viewed articles] are updated daily, based on usage data from the previous 30 days.

http://www.plosone.org/home.action;jsessionid=D3A12CA8A172A2498CB0D205FA58DFA5.ambra02

 

[Sasha]

Um, I think that's just a current figure, i.e. it's at the top of the list currently, not an all-time figure.

Still, transient popularity is not to be sniffed at!

 

[urbantravels]

Heck, this is the Internet. What else are we here for??

 

[Waverunner]

The more views the Norwegian study has, the better.

 

[taniaaust1]

Very well observed Kauro! The pilot study for Rituximab was published the same year, but whether they knew about it when publishing their own paper is hard to say without dates. It takes some months from sending it to print until it's published.

The wikipedia intro for ACA was really fascinating: "Anti-cardiolipin antibodies (ACA) are antibodies often directed against cardiolipin and found in several diseases including syphilis[1], antiphospholipid syndrome, livedoid vasculitis, vertebrobasilar insufficiency, Behet's syndrome[2], idiopathic spontaneous abortion,[3] and systemic lupus erythematosus(SLE)."

There is a specialised blood lab (Hemex laboratories) which did a CFS study and found that 92% of those with CFS had a variant of antiphospholipid syndrome or a hypercoagulation issue. http://www.hemex.com/pdf/ChronicFatiguehf.pdf .
(Its another area in CFS which more study is really needed)

 

[taniaaust1]

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

As other said the term A.R.T. has been around a very long time (Aggressive Rest Therapy (ART) is mentioned in some books on CFS treatment.

For myself. I have found that therapy helpful. Many have found it is one of only a few things which helps.

 

[oceanblue]

How big an effect? SF36 data

I'm a latecomer to the Rituximab party and don't have the energy to read the 370-odd preceding posts so apologies if this has been covered already

I think the SF36 data in the Fluge paper gives a useful insight on how big an effect Rituximab has:

van der Meer and colleagues criticised the fatigue scale used in the trial both because it was unvalidated and because it focused on change from baseline rather than absolute scores. They also say the effect on fatigue is small, pointing to the best change score of just under 4 (mean score for all particpants at 24-32 weeks), consistent with "slight improvement"

Fluge and colleagues pointed out that patients peaked at different times reducing the mean peak score, and that scores included non-responders as well as responders.

The SF36 physical function data (Table 4) can get round some of these problems. First, it's a widely used and validated (if imperfect scale), and measures total activity not change scores, both of which should keep van der Meer et al happy. Second, the authors reported peak SF36 change, ie is based on the maximum change for each individual (I think) so should be more to Fluge et al's liking.

Baseline SF36 Physical Function score = 34 (Standard Deviation 6) for Rituximab

Maximum change=39% (Rutiximab group vs 11% for control group)
Net maximum change = 28% (ie RXB change less control change)

Mean net maximum change=9.5 points (0-100 scale)

As far as I know, the maximum change is calculated per individual, so an improvement of 15 points is 50% for someone with a baseline score of 30 but only 25% for a patient with a baseline score of 60. However, to get a useable figure here I applied the mean maximum change to the mean baseline score.

For comparison, the PACE trial found a SF36 score change of 7.1 for CBT and 9.4 for GET. However, the enormous difference with PACE is that it was unblinded so the SF36 scores there might be biased by participants in the treatment groups (the 'therapeutic alliance' between patients and therapists was rated 'very high' so patients might unconsciously boost their scores to make their therapist look good). In the Fluge trial all particpants were blinded to which treatment they had.

So, 9.5 is a pretty good improvement, and in most trials that would cause a stir - but it isn't absolutely enormous either.

Of course, the maximum change figure includes non-responders as well as responders so if we pro-rata all the improvement to the responders (9 ex 13 with SF36 data), we get a score of 13.8 for responders, which begins to look pretty good. However, trials generally don't report mean scores for responders and non-responders separately.

I don't claim this is mathematically rigorous but I think the numbers give probably give a reasonable feel for the effects of the study, using different data. The results appear to be good if not awesome.

Maybe I should add that I think the Fluge study is tremendously exciting. I don't know if rituximab will prove to be a magic bullet for CFS, even if they tweak the dosage, but I do think the study provides striking evidence of an immune system role in the illness. As the authors say:

the presented findings may have a major impact on the direction of biomedical research in CFS.

 

[Esther12]

Thanks for that OB. 34 to 44 is kind of great... but it certainly isn't a cure!

I'm hopeful about this study... but I think it's possible that we're just seeing a placebo response from an active drug - admittedly, a more impressive placebo response than there was with CBT/GET... but PACE has left me with a lasting cynicism about claims of treating CFS. If it was a real affect then there's a great hope that this would lead on to more real understanding and effective treatments for CFS, even if Rituximab itself is of only limited worth.

 

[Vitalic]

Just adding my post from the Research forum here in case anyone can help:

Has anyone thought about how the autoimmune aspect might be reconciled with the gene expression alterations detected by Light et al?

?-2A Increase Subgroup (34/48 CFS subjects): This group exhibited
large gene expression increases after exercise in the following genes:
P2X4, P2X5, TRPV1, ?-2A, ?-1, ?-2, COMT and IL10. "Interestingly, the
genes found to be dysregulated in the present study represent most of
the pathways hypothesized by others to be altered in CFS.

At first glance I can't see an obvious way that the two could fit together, ACA autoantibodies attacking mitochondria can explain a portion of the symptomatology but not all, and I struggle to see how pain/fatigue receptors would be upgregulated as a result of these autoantibodies. That said, my knowledge of autoimmune diseases is very limited so I'd love it if someone could enlighten me.

Also something I noticed regarding LDN:

Another thing I just realised, if this is indeed getting close to the central pathological mechanism of the illness, then Low Dose Naltrexone surely becomes a must-try treatment for anyone that believes they may fit within that subgroup:

Endorphins effect the immune system by enhancing natural killer cell response and reducing B-cell (antibody) activity and LDN's effectiveness is being tested in several autoimmune diseases.

LDN appears to effect the functioning of the regulatory immune cells in the central nervous system called microglial cells. Upon activation by infection or cell damage micoglial cells produce pro-inflammatory cytokines, reactive oxygen species (free radicals) and nitric oxide. Microglial cells may be a key component of the 'sickness response' that produces fatigue, fluey feelings, pain, etc. when we come down with an infection. Some researchers believe that microglial cells are chronically turned on in ME/CFS and fibromyalgia. LDN appears to block a receptor on the microglial cells thus inhibiting their activation.

LDN might be having the same effects as Rituximab but obviously in a less drastic way.

 

[kurt]

Mean net maximum change=9.5 points (0-100 scale)
For comparison, the PACE trial found a SF36 score change of 7.1 for CBT and 9.4 for GET. However, the enormous difference with PACE is that it was unblinded so the SF36 scores there might be biased by participants in the treatment groups (the 'therapeutic alliance' between patients and therapists was rated 'very high' so patients might unconsciously boost their scores to make their therapist look good). In the Fluge trial all particpants were blinded to which treatment they had.

So, 9.5 is a pretty good improvement, and in most trials that would cause a stir - but it isn't absolutely enormous either.

Yes, Oceanblue, very good point. To put this in perspective, I personally have experienced about a 25 point improvement, on a 100 point scale, starting at about 10 (10% functional, housebound and mostly bedridden). That improvement came from treating gut, mold, methylation, chronic infection, dehydration/OI and personal stress issues, mostly using natural therapies.

But then, having half of the improvement I experienced, simply from administering two doses of a single biologic is pretty impressive. My improvement spanned about 5 years and took a lot of trial and error, including moving to a different climate. Of course, if someone is helped through this type of functional/integrated approach, improvement would probably only take 1-2 years. And there is more help now.

So now I am wondering whether all the self-treatments that work are acting on the same mechanism Mella & Fluge have discovered. If dysbiosis and exotoxins (such as mold or Lyme) are triggering an autoimmune response for example, and a partial methylation cycle block is creating the 'vicious circle,' the self-treatments I used and others here use might be partially addressing the autoimmunity problem already.

 

[currer]

Dear Esther,

I am sorry but this is nonsense.

I was present when the Norwegian researchers presented their study results.

The improvement was dramatic and was felt to be such by the patients involved.

I accept that it is difficult to interpret the paper so if anyone has any doubts about the findings please get the DVD from Invest in ME. the researchers own discussion of their study is much clearer. It is good value for money.
http://www.investinme.org/IiME Conference 2011/IiME International ME Conference 2011 DVD Orders.htm

Thanks for that OB. 34 to 44 is kind of great... but it certainly isn't a cure!

I'm hopeful about this study... but I think it's possible that we're just seeing a placebo response from an active drug - admittedly, a more impressive placebo response than there was with CBT/GET... but PACE has left me with a lasting cynicism about claims of treating CFS. If it was a real affect then there's a great hope that this would lead on to more real understanding and effective treatments for CFS, even if Rituximab itself is of only limited worth.

 

[kurt]

Just adding my post from the Research forum here in case anyone can help:

Has anyone thought about how the autoimmune aspect might be reconciled with the gene expression alterations detected by Light et al?

At first glance I can't see an obvious way that the two could fit together, ACA autoantibodies attacking mitochondria can explain a portion of the symptomatology but not all, and I struggle to see how pain/fatigue receptors would be upgregulated as a result of these autoantibodies. That said, my knowledge of autoimmune diseases is very limited so I'd love it if someone could enlighten me.

Actually I suspect the Lights' studies may add some confirmation to the autoimmunity hypothesis eventually. The details are obviously not worked out yet, but if our autoantibody is in fact the one in the Hawaiian study (anti-mitochondria), then there is already some evidence of linkage between mitochondria function and pain receptors. Here is a study showing a mito-pain mechanism that works through the amygdala (now that is interesting!):

J Neurosci. 2011 Jan 19;31(3):1114-27.
Mitochondrial reactive oxygen species are activated by mGluR5 through IP3 and activate ERK and PKA to increase excitability of amygdala neurons and pain behavior.
Li Z, Ji G, Neugebauer V.
Source
Department of Neuroscience and Cell Biology, University of Texas Medical Branch, Galveston, Texas 77555-1069, USA.
Abstract
Reactive oxygen species (ROS) such as superoxide are emerging as important signaling molecules in physiological plasticity but also in peripheral and spinal cord pain pathology. Underlying mechanisms and pain-related ROS signaling in the brain remain to be determined. Neuroplasticity in the amygdala plays a key role in emotional-affective pain responses and depends on group I metabotropic glutamate receptors (mGluRs) and protein kinases. Using patch-clamp, live-cell imaging, and behavioral assays, we tested the hypothesis that mitochondrial ROS links group I mGluRs to protein kinase activation to increase neuronal excitability and pain behavior. Agonists for mGluR1/5 (DHPG) or mGluR5 (CHPG) increased neuronal excitability of neurons in the laterocapsular division of the central nucleus of the amygdala (CeLC). DHPG effects were inhibited by an mGluR5 antagonist (MTEP), IP(3) receptor blocker (xestospongin C), or ROS scavengers (PBN, tempol), but not by an mGluR1 antagonist (LY367385) or NO synthase inhibitor (l-NAME). Tempol inhibited the effects of IP(3) but not those of a PKC activator, indicating that ROS activation was IP(3) mediated. Live-cell imaging in CeLC-containing brain slices directly showed DHPG-induced and synaptically evoked mitochondrial superoxide production. DHPG also increased pain-related vocalizations and spinal reflexes through a mechanism that required mGluR5, IP(3), and ROS. Combined application of inhibitors of ERK (U0126) and PKA (KT5720) was necessary to block completely the excitatory effects of a ROS donor (tBOOH). A PKC inhibitor (GF109203X) had no effect. Antagonists and inhibitors alone did not affect neuronal excitability. The results suggest an important role for the novel mGluR5- IP(3)-ROS-ERK/PKA signaling pathway in amygdala pain mechanisms.

PMID: 21248136 [PubMed - indexed for MEDLINE] PMCID: PMC3073477 Free PMC Article

also, this study shows that interfering with mitochondria function alters the pain response:

J Neurosci. 2011 Sep 7;31(36):12982-91.
Mitochondrial Ca(2+) uptake is essential for synaptic plasticity in pain.
Kim HY, Lee KY, Lu Y, Wang J, Cui L, Kim SJ, Chung JM, Chung K.
Source
Department of Neuroscience and Cell Biology, University of Texas Medical Branch, Galveston, Texas 77555-1069, USA.
Abstract
The increase of cytosolic free Ca(2+) ([Ca(2+)](c)) due to NMDA receptor activation is a key step for spinal cord synaptic plasticity by altering cellular signal transduction pathways. We focus on this plasticity as a cause of persistent pain. To provide a mechanism for these classic findings, we report that [Ca(2+)](c) does not trigger synaptic plasticity directly but must first enter into mitochondria. Interfering with mitochondrial Ca(2+) uptake during a [Ca(2+)](c) increase blocks induction of behavioral hyperalgesia and accompanying downstream cell signaling, with reduction of spinal long-term potentiation (LTP). Furthermore, reducing the accompanying mitochondrial superoxide levels lessens hyperalgesia and LTP induction. These results indicate that [Ca(2+)](c) requires downstream mitochondrial Ca(2+) uptake with consequent production of reactive oxygen species (ROS) for synaptic plasticity underlying chronic pain. These results suggest modifying mitochondrial Ca(2+) uptake and thus ROS as a type of chronic pain therapy that should also have broader biologic significance.

PMID: 21900577 [PubMed - indexed for MEDLINE] PMCID: PMC3179262 [Available on 2012/3/7]

I find the second study particularly interesting given the known problems in ME/CFS with magnesium/calcium ratios.

 

[Esther12]

Dear Esther,

I am sorry but this is nonsense.

I was present when the Norwegian researchers presented their study results.

The improvement was dramatic and was felt to be such by the patients involved.

I accept that it is difficult to interpret the paper so if anyone has any doubts about the findings please get the

The trouble is... I'm also sceptical of reports from patients and unpublished claims from researchers too! Someone who was semi-recovered was wheeled out to promote the PACE findings and CBT/GET. XMRV and PACE have both left me feeling deeply sceptical of any claim about treating CFS. To me, the results from the Rituximab paper look hopeful for indicating a mechanism for CFS and future research (although it could be a false lead), but less exciting as a treatment than the press reports seemed to indicate. That the level of improvement is difficult to really judge from the paper is somewhat worrying, but I'm still hopeful. There are other reasons to think that autoimmune factors could play a role in CFS, so hopefully we will get some more good research in this direction soon.

I'm just pouring cold water all over the place these day, aren't I?

 

[kurt]

Thanks for that OB. 34 to 44 is kind of great... but it certainly isn't a cure!

I'm hopeful about this study... but I think it's possible that we're just seeing a placebo response from an active drug - admittedly, a more impressive placebo response than there was with CBT/GET... but PACE has left me with a lasting cynicism about claims of treating CFS. If it was a real affect then there's a great hope that this would lead on to more real understanding and effective treatments for CFS, even if Rituximab itself is of only limited worth.

Just want to point out that placebo studies generally fail with ME/CFS. So if the patients were real ME/CFS, they probably had no placebo effect.

Esther, have you watched the Norwegian TV video yet? They show one of the responders, a young lady who was very sick for many years and now is an outdoors person with a lot of energy. Very impressive and definitely not something we see from placebo. But I think you make a good point that the AVERAGE gain is definitely not cure (I just posted on that as well). So I agree, this is great hope we are getting more understanding, but Rituximab may not be the best therapy, this direction of inquiry is just starting. If you look at other autoimmune disease that may now be close relatives of ME/CFS (Lupus, Celiac, some liver disorders, APS, etc), there ARE alternative therapies that help many people.

 

[Esther12]

Just want to point out that placebo studies generally fail with ME/CFS. So if the patients were real ME/CFS, they probably had no placebo effect.

Esther, have you watched the Norwegian TV video yet? They show one of the responders, a young lady who was very sick for many years and now is an outdoors person with a lot of energy. Very impressive and definitely not something we see from placebo. But I think you make a good point that the AVERAGE gain is definitely not cure (I just posted on that as well). So I agree, this is great hope we are getting more understanding, but Rituximab may not be the best therapy, this direction of inquiry is just starting. If you look at other autoimmune disease that may now be close relatives of ME/CFS (Lupus, Celiac, some liver disorders, etc), there ARE alternative therapies that help many people.

re placebo - I was referring primarily to patients willingness to report an improvement in symptoms when they think that they are receiving an active treatment, rather than the placebo affect significantly reducing actual disability levels. With a condition like CFS, it's often difficult to accurately measure the impact of a treatment, so we'll have to wait and see with Rituximab.

 

[Vitalic]

Whether or not Rituximab turns out to be an appropriate intervention for the illness, which is at this stage a very long way off, rather pales in significance to the potential re-classification of CFS as an auto-immune disorder in my view. I'm actually more interested to hear about the research that follows on the back of this accidental finding, because that is what could make the breakthrough in terms of discovering the underlying pathology, which in turn would allow more targeted, CFS specific treatments to be developed. Obviously if replication studies show that is an effective treatment that would be huge news, but the main focus should still be on using that knowledge to direct future investigations.

 

[currer]

Do you think this work is likely to happen in the US or UK?

 

[Vitalic]

Do you think this work is likely to happen in the US or UK?

Well certainly not the UK! It sounds like the US based researchers are starting to take very seriously the prospect of autoimmune involvement, and the researchers that carried out the Norwegian study have received a grant to investigate the actual mechanisms involved:

But he (Komaroff) hopes the researchers are trying to find biomarkers that can be monitored, to understand what mechanisms in the body that responds to the medication. The researchers in Norway has just got a substantial grant for exactly this kind of work from a philanthropic organization. Their hypothesis is that theres a central autoimmune component in ME/CFS, and that it might be possible to find a specific autoantibody.

Also a quote from Mella/Fluge about their spin-off studies:

Are you gathering data on any of biological markers that might explain Rituximabs effects on CFS such as B-cell levels, the status of EBV infections, NK cell functioning, CD20, CD40, CD69, HLA DR levels in NK/T-cells or levels of TNF-a or IL-10?

Yes, biological spin-off studies are a major part of our effort and we are analyzing how the biological parameters in the intervention group with rituximab are changing compared with the placebo group. The need to harvest biological material sequentially during the study is a reason for not being able to include patients from other parts of our country or the world at large.

This is what excites me the most, I don't think we should build up this particular drug as some kind of magic bullet because it will be such easy ammunition for the psycho-babblers if it turns out the drug is not effective to a clinical level at larger scales, what is important here is the bio-medical evidence and what is says about the underlying pathology, specifically that this is a condition that works without the assumption of any psychological contribution/involvement. If you compared that particular pre-assumption to the pre-assumption that God created the universe/life, or the "god of the gaps" argument, then this discovery could turn out to be the equivalent of Darwin's theory of evolution by natural selection. Talking therapies become instantly obsolete.

Actually I suspect the Lights' studies may add some confirmation to the autoimmunity hypothesis eventually. The details are obviously not worked out yet, but if our autoantibody is in fact the one in the Hawaiian study (anti-mitochondria), then there is already some evidence of linkage between mitochondria function and pain receptors. Here is a study showing a mito-pain mechanism that works through the amygdala (now that is interesting!):



also, this study shows that interfering with mitochondria function alters the pain response:



I find the second study particularly interesting given the known problems in ME/CFS with magnesium/calcium ratios.

Thanks for that Kurt, it seems that there is a potential link there. IL-10 upregulation still has me scratching my head though, if this is an anti-inflammatory cytokine why would it be up-regulated in CFS, you would expect it to be down-regulated if anything, given the prevalence of inflammation in this condition. I also notice that Rituximab increases IL-10 production:

Macrophages were more effective at killing leukemia cells following Rituximab treatment in one study. Rituximab also appears to increase macrophage production of IL-10, an important anti-inflammatory cytokine that is sometime increased in CFS. The production of tumor necrosis factor alpha (TNF-a), one of the most potent inflammatory cytokines, and one which some researchers think plays a role in CFS, was also reduced in Rituximab treated macrophages.

Perhaps IL-10 up-regulation is not an abnormality but a logical response to the presence of inflammation? I guess the link I'm not understanding is how auto-antibodies themselves would result in upregulation of pro-inflammatory cytokines.