Dr Bieger and Dr Mikovits discuss treating ME patients with Rituximab

[Countrygirl]

Just a reminder that the pdf of the 2014 article on the concept of innate immune changes in ME and the potential consequent immune suppression can be found here.

https://www.novapublishers.com/catalog/product_info.php?products_id=52282

The concept that chronic microbial infection drives constant

activation of the innate immune system through alterations in the production of innate

immune cells and accompanied by abnormal production of pro-inflammatory cytokines

and chemokines, and that this leads to progressive immune deficiency seen in many CFS

patients has only recently been appreciated. In investigating the distribution of immune

cells in the peripheral blood of a cohort of CFS patients who have an antibody

recognizing the SFFV envelope protein, we discovered profound alterations in the

number and types of cells, particularly in the cells regulating the innate immune system.

These changes included chronic activation of monocytes and dendritic cells, and a

marked increase in NKT cells and decrease in NK cells. The cytokines in plasma from

these CFS patients was assayed in a multiplex platform, and one of us published findings

showing signatures of infection; that is, significantly high levels of many proinflammatory

mediators such as IL-12, MCP-1, IL-8, IP-10, IL-6, TNF-α, and IL-1β

while being low in the critical antiviral cytokine IFN-α. In expanding these results, we

found that subsets of these CFS patients had increased TGF-β and others had increased

IL-9. We will discuss these and other published results that suggest that chronic

stimulation of the innate immune system is a component of the development and

progression of disease in many CFS patients. In chronic diseases the resulting

immunodeficiency allows activation and replication of many secondary pathogens. Thus

CFS patients can share complex pathogenic complications with patients with HIV AIDS

and HTLV-1 associated myelopathy. In many CFS patient populations, the presence of

several concomitant infections, from Borrelia burgdorferi to reactivated exogenous and

endogenous viruses, chronically dysregulating the immune system, is a major risk factor

in the development of pathology. Other risk factors include alterations in microbiota

regulation, mitochondrial toxicity, cognitive dysfunction and impaired methylation

pathways. These factors can also increase the risk of others diseases, including cancer, in

some CFS patients. These results have important implications for the management of

many people with this diagnosis. We will review in this chapter the use of antiinflammatories,

anti-virals and other therapies, as well as discussing how repurposing

drugs holds promise in the treatment of patients displaying the immune abnormalities

identified in these CFS patients.

Also, as an aside, I hope the previous misunderstandings regarding the video that is the subject of this thread have been settled as explained elsewhere.

When Dr Beiger made reference to an 'oral' form of rituximab I understand he meant 'sublingual'. As has also been posted elsewhere, low doses of rituximab, I understand, are given in RA. http://www.ncbi.nlm.nih.gov/pubmed/23983134

According to the information I have gleaned, 500mg (maximum dose 1000mg) is also the dosage used in the ME trial here https://clinicaltrials.gov/ct2/show/NCT02229942. From my understanding, this is the 'low' dosage referred to the video.

I hope what appear to be misunderstandings do not continue to detract from the value of the video.

 

[Gijs]

With all due respect, Jonathan Edwards, it is YOU who are talking about "well standardised tests of immune function". I am looking at other metrics that may have merit; metrics that perhaps deserve further research.

Why look for immune issues? What's that old adage: Where there's smoke, there's fire?

Where is the fire when it is extinguished? The symptoms of ME doesn't fit with the immunesystem. They fit perfectly with the brain and (autonomic) nervoussytem. The immunesystem is red herring Mikovits talks about HIV AIDS and says that ME is the 'same', i think she is overreacting, AIDS is much, much more worse then ME. I know ME patiënts who had NK cel 'disfunction' later on the function was normal and they felt bad anyway.

 

[heapsreal]

All I can gather from the research community about the NK results is that a recent attempt to reproduce the results failed.

http://www.translational-medicine.com/content/pdf/1479-5876-9-81.pdf
This study was quite a large study replicating the result of a previous smaller study conducted.

Abstract Background: Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME) is characterised by severe prolonged fatigue, and decreases in cognition and other physiological functions, resulting in severe loss of quality of life, difficult clinical management and high costs to the health care system. To date there is no proven pathomechanism to satisfactorily explain this disorder. Studies have identified abnormalities in immune function but these data are inconsistent. We investigated the profile of markers of immune function (including novel markers) in CFS/ME patients. Methods: We included 95 CFS/ME patients and 50 healthy controls. All participants were assessed on natural killer (NK) and CD8+ T cell cytotoxic activities, Th1 and Th2 cytokine profile of CD4+ T cells, expression of vasoactive intestinal peptide receptor 2 (VPACR2), levels of NK phenotypes (CD56bright and CD56dim) and regulatory T cells expressing FoxP3 transcription factor. Results: Compared to healthy individuals, CFS/ME patients displayed significant increases in IL-10, IFN-g, TNF-a, CD4+ CD25+ T cells, FoxP3 and VPACR2 expression. Cytotoxic activity of NK and CD8+ T cells and NK phenotypes, in particular the CD56bright NK cells were significantly decreased in CFS/ME patients. Additionally granzyme A and granzyme K expression were reduced while expression levels of perforin were significantly increased in the CFS/ME population relative to the control population. These data suggest significant dysregulation of the immune system in CFS/ME patients. Conclusions: Our study found immunological abnormalities which may serve as biomarkers in CFS/ME patients with potential for an application as a diagnostic tool.

Some more clarity on nk function research and testing not done by a commercial lab but by a government funded university study.

 

[heapsreal]

Where is the fire when it is extinguished? The symptoms of ME doesn't fit with the immunesystem. They fit perfectly with the brain and (autonomic) nervoussytem. The immunesystem is red herring Mikovits talks about HIV AIDS and says that ME is the 'same', i think she is overreacting, AIDS is much, much more worse then ME. I know ME patiënts who had NK cel 'disfunction' later on the function was normal and they felt bad anyway.

Maybe look up what a natural killer cell does.

 

[Jonathan Edwards]

I am sorry to say Countrygirl, that this problem is not going to go away. What Dr Mikovits says in this video gives repeated indication that she does not have a grasp of many basic facts about B cell biology or rituximab. I do not think a non-clinical scientist with no grasp of the field should be making recommendations to clinicians about treatment with a potentially dangerous drug. I think it is important that the ME/CFS community are aware of this problem.

The use of rituximab in ME derives in part from my own proof of concept work in autoimmunity and as a result I feel ethically responsible for what happens in this field. When I developed the use of rituximab it was clear to me that if used wisely by people with a detailed understanding of immunology it could be very beneficial. I was also aware, however, that if used by people who did not understand immunology it could do a lot of harm. It is therefore particularly important to me to try to ensure that it is not being promoted by people who have no understanding of the field. That may sound harsh but I am afraid one has to be honest when people's health is at stake.

 

[Countrygirl]

The symptoms of ME doesn't fit with the immunesystem.

In my case: swollen glands; chronic low grade fever; chronic sore throat; persistent infections; repeated, prolonged bouts of pneumonia......................continuously over a period of years following a severe infection that resulted in encephalitis and marked asphasia. After some years, an apparently compromised immunity then takes flight and either kills all infections at 50 paces and there are no more apparent immune responses or could it be that the immune system burns out? What else can this be but immune system involvement?

They fit perfectly with the brain and (autonomic) nervoussytem.

Yes, in my experience, when the disease really became severe, triggered by a hefty chronic dose of organochlorines (it caused others to become chronically ill and my cousin died as a result of the exposure) the neurological symptoms became dominant, tortuous and disabling and far more distressing and unpleasant than the immune problems.

Both the immune and central nervous systems are heavily involved in my experience.

 

[Gijs]

In my case: swollen glands; chronic low grade fever; chronic sore throat; persistent infections; repeated, prolonged bouts of pneumonia......................continuously over a period of years following a severe infection that resulted in encephalitis and marked asphasia. After some years, an apparently compromised immunity then takes flight and either kills all infections at 50 paces and there are no more apparent immune responses or could it be that the immune system burns out? What else can this be but immune system involvement?



Yes, in my experience, when the disease really became severe, triggered by a hefty chronic dose of organochlorines (it caused others to become chronically ill and my cousin died as a result of the exposure) the neurological symptoms became dominant, tortuous and disabling and far more distressing and unpleasant than the immune problems.

Both the immune and central nervous systems are heavily involved in my experience.

The immunsystem in the brain is the real problem (microgla). I have also immuneproblems like you said still it can be due to sympathetic overdrive it is just the other way around.

 

[Gijs]

Maybe look up what a natural killer cell does.

O i know what they do

 

[duncan]

Gijs, I would not disagree with what you have said about the immune system in the brain being a problem.

It is one problem. But only one. Which is what an individual would expect from a systemic, disinterested and random disease.

It is those qualities that almost mandate we explore multiple avenues when trying to better characterize and understand the disease, including immune dysfunction, and CNS involvement, and neuro-components like encepholapathies and brain lesons and atrophies, and other manifestations that might be captured via imaging technologies like PET or fMRI's. Also cognitive variables that might be glimpsed thru neurocognitive tests administered clinically or in research settings. I haven't even touched upon the accrued impact on different organs over the years.

I think these are all puzzle pieces. None should be ignored. They each potentially represent footprints of a possible pathogen, or a misfiring immune system. Indeed, if it's not a pathogen behind this, then doesn't that raise the likelihood that it is an autoimmune disorder? One that should be measurable via some kind of immune metric? Doesn't the same hold true if an active, yet to be identified pathogen is at play?

Turning our backs on any single major component could be a serious mistake.

 

[Gijs]

I agree with you Ducan but i would like see more focus on the brain, nervoussystem, spinal fluid and post mortem brain studies.

My problem with the immunesystem is as follows: ''The immune system has daily cycles and is sensitive to stress''.
I think the autonomic nervoussystem is stuck and influence the immunesystem by burning it out. There is a sort of (abnormal) stress reaction constantly (not due to mental problems!)in ME patiënts, why? That is the one million dollar guestion for me...

I always thought that the parasympathetic system is broken even before Michael van Elzakker claimt it.

 

[Countrygirl]

I am sorry to say Countrygirl, that this problem is not going to go away. What Dr Mikovits says in this video gives repeated indication that she does not have a grasp of many basic facts about B cell biology or rituximab. I do not think a non-clinical scientist with no grasp of the field should be making recommendations to clinicians about treatment with a potentially dangerous drug. I think it is important that the ME/CFS community are aware of this problem.

I appreciate that you want to protect us from scientists who you think do not comprehend immunology. In this case, of course, as you will be aware, that also includes Dr Frank Ruscetti.

I hope you don't mind me making a suggestion, but I do think it would be advantageous to all parties if you discussed this with Dr Mikovits personally, so any potential misunderstanding is rectified for her sake and for that of the patients. It is hardly fair if a scientist is publically criticised on here when they have no chance of redress. Her e-mail is freely available and I am sure she would be delighted to discuss this with you as she is so generous with her time and knowledge.

 

[Undisclosed]

Low dose Rituxan - what dose was Mikovits referring to, I didn't hear her say a dose but I could have missed it.

@Jonathan Edwards -- what low dose were you referring to as a low dose.

It seems the usual crew have decided to comment on what you have said here, on another forum. Can you clear this up please and thank you.

In fact Edwards is an advisor for the Invest in ME Rituxan clinical trial and he has no clue they are using both the low dose and high dose of 1000mg and 500mg. see Here: https://clinicaltrials.gov/ct2/show/NCT01156922?term=rituximab me/cfs&rank=2

B-lymphocyte Depletion Using Rituximab in Chronic Fatigue Syndrome/ Myalgic Encephalopathy (CFS/ME). A Randomized Phase-III Study. (RituxME)

Drug: Rituximab (My note: 500mg is LOW DOSE)

Induction with two infusions two weeks apart, rituximab 500 mg/m2 (max 1000 mg).

Maintenance with rituximab infusions (500 mg fixed dose) at 3, 6, 9 and 12 months.


Edwards has no clue that they are using both low and high dose in the study he should know about.

... .

It is hardly fair if a scientist is publically criticised on here when they have no chance of redress.

Mikovits is free to join the forums and members here are free to discuss researchers and research.

 

[nandixon]

Low dose Rituxan - what dose was Mikovits referring to, I didn't hear her say a dose but I could have missed it.

@Jonathan Edwards -- what low dose were you referring to as a low dose.

It seems the usual crew have decided to comment on what you have said here, on another forum. Can you clear this up please and thank you.

Mikovits is free to join the forums and members here are free to discuss researchers and research.

Professor Edwards can correct this if wrong, but a standard rituximab dose in cancer treatment appears to be in the 375-500mg range.(?) Looks like for rheumatoid arthritis it might be higher at 1000mg.(?)

Mikovits repeatedly said in the video that the dose she was talking about was "low, low" and "much lower than used in cancer," or words to those effect.

So obviously she was implying a dose much lower than the 500mg low end used in the ME/CFS rituximab phase 3 trial.

In other words, the person(s) commenting on the other forum is the one who has "no clue."

 

[Bob]

For clarity:
@ 6.27
Mikovits: "...they should only get it at a low dose, because the dose for a cancer is way too much."
www.youtube.com/watch?v=q_5mQmO4MWU

 

[Undisclosed]

For clarity:
@ 6.27
Mikovits: "...they should only get it at a low dose, because the dose for a cancer is way too much."
www.youtube.com/watch?v=q_5mQmO4MWU

I got that she repeatedly said 'low dose' but did she ever say what that dose is?

 

[Bob]

I got that she repeatedly said 'low dose' but did she ever say what that dose is?

Yes, she repeatedly said "low dose", and said "very low dose" once (@ 8.20) but they never specified the dose.

 

[Isamu]

This is Ron Davis's son. Not so red herring and looks alot like another aquired immune deficiency syndrome. I would say it looks pretty serious. This is from his sister's public page. https://www.facebook.com/photo.php?fbid=10153935106159625&set=p.10153935106159625&type=1&theater

 

[Jonathan Edwards]

Low dose Rituxan - what dose was Mikovits referring to, I didn't hear her say a dose but I could have missed it.

@Jonathan Edwards -- what low dose were you referring to as a low dose.

It seems the usual crew have decided to comment on what you have said here, on another forum. Can you clear this up please and thank you.

Mikovits is free to join the forums and members here are free to discuss researchers and research.

What a muddle!
Dr Mikovits suggested using a low dose, with the implication of somehow being more gentle or something - but I don't think she actually had a dose in mind and I am not quite sure what she thought a smaller dose would achieve. I posted earlier to indicate that deliberately giving a 'gentle' dose by cutting it back - presumably to below a full depleting dose - could actually be harmful and end up making the patient allergic to the drug. As Deleder pointed out, and I had mentioned on the forum long ago, we do not actually know what a subdepleting dose is, so nobody knows how to give a 'low dose'. Basically I am saying you do not fool around with the dosage of a drug with as complicated a mode of action as this.

I think people are getting confused between dose in mg given and dose in mg per metre squared - as I tried to point out. There is also a confusion between induction dose and maintenance dose.

Most people are a bit more than 1.5 metres squared (if I remember rightly from the days I made up the doses) so 500mg per metre squared tends to be about 800-1000mg. Oncologists are used to giving by metre squared. When we started using rituximab in RA we decided to standardise the dose for convenience reasons but it does not make much difference. Haukeland have been using 2 x 500/m2 or about 2 x 800-1000mg for induction just as we use 2 x 1000mg for induction in RA. These are not low doses. There is a study of a lower dose of 2 x 500mg in RA but it is probably not much different in depleting effect so presumably not what Dr Mikovits was talking about.

After an induction dose you can give a smaller dose to maintain depletion if you give it before B cells return - at around 3-4 months. The Haukeland chose to maintain depletion with 1 x 500mg/m2 (not 500mg fixed as far as I can see) at 3 monthly intervals. This is equivalent in effect to the induction dose because the bone marrow is still partially under the effect of the original dose.

Nandixon seems to be fairly spot on:
'In other words, the person(s) commenting on the other forum is the one who has "no clue."'
I try as hard as I can not to get into a yaboo match on these things but I think I am entitled to be a bit disappointed that people take such an aggressive and unhelpful line. I am only trying to keep things safe for PWME. It doesn't actually bother me though because there is so much going on that indicates that a proper biological approach is finally winning out over the false belief merchants.

 

[Undisclosed]

So now Edwards is saying this and he can't remember how doses go because it's been too long, seriously????. And he is advising why? And also why is he trying to put words in another scientists mouth? He can't speak for what he thinks her meaning was.
Here's what he said: "Most people are a bit more than 1.5 metres squared (if I remember rightly from the days I made up the doses) so 500mg per metre squared tends to be about 800-1000mg. Oncologists are used to giving by metre squared. When we started using rituximab in RA we decided to standardise the dose for convenience reasons but it does not make much difference. Haukeland have been using 2 x 500/m2 or about 2 x 800-1000mg for induction just as we use 2 x 1000mg for induction in RA. These are not low doses. There is a study of a lower dose of 2 x 500mg in RA but it is probably not much different in depleting effect so presumably not what Dr Mikovits was talking about."
So here's a reminder for Edwards. This paper below clearly states that 500 mg is considered a low dose as it says LOW VERSUS HIGH-DOSE!!!!:
Low- versus high-dose rituximab for rheumatoid arthritis: a systematic review and meta-analysis.
OBJECTIVE:
The approved dose of rituximab (RTX) for rheumatoid arthritis (RA) is 2 × 1,000 mg infusions given 2 weeks apart. There is contradictory evidence regarding the effectiveness of a lower-dose regimen (2 × 500 mg) of RTX. Our aim was to compare the efficacy and safety of low- and high-dose RTX and to test the noninferiority of the low-dose regimen.
CONCLUSION:
Low-dose RTX has similar effectiveness and met noninferiority criteria for most primary outcomes. Considering the lower cost, it should be the standard RTX regimen for RA. http://www.ncbi.nlm.nih.gov/pubmed/23983134

Would anybody care to address this latest bit of ... .

Thanks.

 

[Bob]

@Kina, do you think it's wise to cross-post this childish tittle-tattle from another forum? I don't use those forums precisely because nonsense like that gets posted. And it's irritating to read it in this thread. If anyone wants a reasonable adult discussion here, then they can have one; Jonathan is usually happy to answer questions. Those posts are just irritating, childish and ill-informed.

Jonathan, please don't take these comments to heart. There are a lot of immature people out there who who only hear what they want to hear, and who like to attack anyone who doesn't conform to their way of thinking, even if they clearly know little about the subject at hand.

The next thing that will happen, is that someone will send Judy an inflammatory email containing half-truths and lies, which she will then respond to, believing that the email was sent in good faith and is a true representation of the facts, giving permission to post her reply here. And it will be an inappropriate response because of the misinformation she's been given. (This is what happened previously in a similar scenario.)

I think Jonathan has already answered the latest stuff. Judy was recommending a partial dose of Rituximab, "very much smaller" than a normal dose for cancer, such that not all the B-cells are wiped out. The partial dose is the significant info here. The B-cells would only be partially wiped out, so she's talking about a very low dose, not a standard low dose. Jonathan has explained clearly why partial doses are inappropriate for various reasons. He should know something about it, seeing as he spent his career researching and administering it. If anyone wants to disagree with him - and anyone is obviously entitled to do so - they should at least get their info straight re what Judy is recommending and what Jonathan has said, or they're just wasting everyone's time, and they make themselves look silly.