Dr Bieger and Dr Mikovits discuss treating ME patients with Rituximab

[Undisclosed]

Thank you @Jonathan Edwards it's a very interesting dynamic because patients have grown attached to Dr Mikovits because she cared and interacted with a group of patients (she probably still does). (And some will actually bad mouth me because I am saying this) The same patients fund her travels to conferences and meetings.

The very same people are considering boycotting Invest in ME because something bad has been said about JM. That's a very bad state of affair.

My opinion is, if you are a scientist, publish. This is the scientist's language in communicating the science.
We are in great need of good (published) science.

It would be ridiculous to boycott Invest in ME, one of the few UK charities that deal with pure research.

I know what it is like to be bad mouthed by these people @Kati No worries, they are not worth the time or trouble. Robyn Erland the ring leader of defamatory comments has totally lost the plot. It is sad. Follow the science, not people.

 

[DanME]

I feel sorry for all concerned, but my feeling is that the ME community needs to move on to real science. The landscape in view, after chucking almost everything so far in the bin, may look arid and unpromising but it always looks like that at first. And there is a mass of data already gathered that does help - it just needs to be considered in a wider perspective.

I totally agree with Prof Edwards. We need to move on to real science. And the first step to accomplish this, is to be very sceptical about everything, which has been proposed so far. Of course we got used and even attached to some theories over the years. But this alone doesn't mean they are true. At the core of real sience lies true sceptism, the avoiding of biases (and humans are especially good in having biases) and most of all the acceptance of the unknown and the personal limits of your own understanding.

The cause and the pathophysiology of ME are still unknown. We maybe have some hints pointing in some directions, but that's it so far. There is no shame in admitting that. To the contrary. Only, if we (or better the scientist) are able to let go of our biases and favourite theories, we may find the truth.

Science (at least in the natural sciences) is not a debate club, where the most fascinating or the most logical sounding idea wins the debate. It is about proposing good and thought out hypotheses and then testing them rigorously. The testing part is the most important. A lot of theories and ideas, which sounded logical and very intelligent at first, didn't make it in the end. That's why we need good old fashioned evidence and proof for our claims. And until we have that, our claims are nothing more than hypotheses (like psychosomatics seems nothing more than a bunch of hypotheses).

Science is a process and the scientists developed a lot of tools to avoid and circumvent the flaws of the human psyche. We love anectodal evidence, it's emotional relatable, but nearly worthless in a scientific context, we love our own theories and ideas, we love to be proud of our intelligence, but this very fact can be (and often is) directly in the way of finding the right answers, that's why science invented double blinded studies, randomisation and uses complicated math, known as statistics. We are prone to over interpret small studies and results, but in reality larg cohorts and replication are needed to support our theories.

ME is inflammation in the brain? We have a problem with Methylation? ME is caused by EBV? Where are the large studies proving that? I don't know them. Yes, we have some hints, that EBV and Microglia may play a role. But we are far from having the ultimate answers to those questions. Who would have thought, that Rituximab could help some PWME? Fluge and Mella had a theory, that the bettering of some cancer patients may be not a coincidence and then they started to test their theory and are still doing that. Over and over again. With RC trials.

Finally, what Mikovits is telling us in her video isn't fleshed out at all. It's confusing and she is obviously all over the place. A lot of nice ideas, which sound intelligent for the layman at first, but haven't been tested so far. I am extremely sceptical. You cannot state, that ME is at the same time maybe caused by a retrovirus or is a slow burning form of cancer or an immuno deficiency or is caused by autoimmunity and while you are doing that, you don't even get your facts straight. I cannot see her admitting the unknown and her limits of understanding about immunology. I cannot see any proof for her claims. XMRV was dismissed by several indipendent teams. Why a slow burning form of cancer? Where does this come from? If she has evidence for that, she should publish it.

Sorry for the very long post, but the attachment of a lot of ME patients to their favourite theories and scientists is bugging me. We need a blank slate and admit, that we don't know, what's going on. We have to find out. With real science.

 

[thegodofpleasure]

There is no point in accusing people of bad faith here. I am not saying things because I want to do someone down and have not made comments without good reason. If people want to query my account, find a B cell immunologist and show them the video. If they say it makes sense, I will think again.

It will be interesting to see whether Dr Beiger's patients benefit from the advice that Dr Mikovits has offered.
Time will tell whether that advice is valid, but one way or the other, good science will ultimately prevail.

If anyone thinks that Drs Beiger and Kramer participated in the making of this video because they felt that they needed a basic course in immunology, then they are mistaken. I think that their participation therefore speaks for itself.

These are experienced immunologists who certainly know their B cells from their elbows.

 

[alex3619]

On oral Rituximab it is the case that oral drug therapies have in some cases been supplemented with intravenous Rituximab. I am unaware of any oral Rituximab. Is this being confused with oral Ampligen?

My preliminary interpretation is that there are a lot of hypotheses in this video. Some of them might be right. They need to be coherently developed and then published, then if they withstand scrutiny we need pilot studies.

I found this video confusing. More focused, clear, articulated arguments are needed, backed by clear references that support specific points. All this does though is determine what hypotheses need to be tested, and what should be ignored.

There is no question Rituximab is not for everyone. There is some question though as to whether or not some poor responders might respond on a different dosage schedule. I would hope these are some of the things that are under investigation as part of the phase 3 clinical trial.

Antivirals, Ampligen, Rituximab and now other anti-cancer agents are where we are in therapy, with the addition of antibiotics for those with established bacterial pathogens. In the end we are likely to need an entire toolkit of options for patients before we can get almost everyone better. All of these agents, with the exception of Ampligen, need a lot more testing. However, that testing is ongoing.

Ampligen is a special case in that it has already been heavily tested. I think what it needs is a clear marker differentiating responders and non-responders that can be shown before treatment. I think though that a trial dosage might be enough to differentiate responders, and if I were a responder its for damn sure I would want access to this drug.

Ritixumab in combination with other agents are a very important thing for us. We need that research to continue till we understand exactly what is happening, and if it turns out that its only really suitable for a subgroup then at least that subgroup will have a treatment option.

In the end I think we are going to find that specific therapies will work on specific subgroups. Group by group I hope we can chip away at the non-responders till its a null set.

 

[alex3619]

high levels of reverse transcriptase be a good indicator?

This is an important under researched area. If high reverse transcriptase can be shown even in a subset then it needs to be considered. If any reverse transcriptase is found though we need to understand why it is there. It is not clear though that there is a modern study showing high levels of reverse transcriptase in us. It would seem an obvious thing to check, but then again so much is not done in ME research, or is dabbled in a bit and not taken to a full study.

 

[Kati]

There is no question Rituximab is not for everyone. There is some question though as to whether or not some poor responders might respond on a different dosage schedule. I would hope these are some of the things that are under investigation as part of the phase 3 clinical trial.

Rituximab is a b-cell depletion therapy. It works by depleting the body of its B-cell. A higher dosage is not necessarily more toxic.

As far as I know, only one protocol in oncology used weekly IV Rituximab, for non-hodgkins lymphoma and I haven't seen it used at all over my 10 years of oncology nursing. at this point of the game, the question that we need to answer is, is it an effective therapy for {name of disease here}, and why or why not, and for which subgroups, why or why not? We have not answered these questions yet. As usual more research is needed, and more trials are warranted.

 

[alex3619]

One final point on Rituximab. If most responders and nonresponders can be identified with a trial dosage then after the phase 3 trial I would not only be game, I would be prepared to pay for it myself without insurance. Of course I would hope that as a responder then some way could be found to pay for it, such as government subsidy or whatever.

Sometimes you just have to suck it to see if its a lemon for you. Until we have clear biomarkers we will continue to be in this position. By biomarkers I mean both diagnostic and treatment biomarkers, including prognostic biomarkers.

Let me make a chancy prediction here. I suspect many we think of as ME, CFS or SEID will be in different subgroups than most, or even have a different disease. I also suspect many who we are not diagnosing will be found to have our disease/s once we have diagnostic biomarkers. Misdiagnosis includes false negatives as well as false positives.

 

[alex3619]

A higher dosage is not necessarily more toxic.

Dosage schedules are about more than just dosage. Its also about frequency and contraindications. I think at some point the question was raised as to whether the schedule should be increased to once every two months. I would hope that very soon we have some answers on how to optimize a schedule for a given patient.

 

[Kati]

Dosage schedules are about more than just dosage. Its also about frequency and contraindications. I think at some point the question was raised as to whether the schedule should be increased to once every two months. I would hope that very soon we have some answers on how to optimize a schedule for a given patient.

And then again, is Rituximab the right medication? Could Cyclophosphamide prove just as good, if not better and at the same time be much less cost prohibitive for patients?

 

[Jonathan Edwards]

Issues about dosage schedules for rituximab are not really like any other known drug. One of the reasons why FLuge and Mella chose to use rituximab is that it just has one action and we know what that is and we can measure it. It removes CD20+ B cells. So even if not the ideal way of treating an immune problem studying rituximab can tell us something about the disease - whether it needs B cells.

Once you have removed B cells with rituximab they tend to remain absent for six months - nobody knows why but it is consistent. With smaller doses B cells may come back earlier but over the range of total dose of 500-2000mg there does not seem much difference. To remove B cells in theory you only need one infusion, and I have done that on occasions. The double infusion practice is a hang over from some historical events. When first used in lymphoma it was found that some patients had bad reactions due to 'tumour lysis syndrome'. Because they had very large masses of abnormal B cells that all died at once they got sick from the dying cells. The oncologists were probably wise to the risk beforehand because they divided the infusions up into four quarter doses, given once a week, and in fact recommended the first dose be halved at one stage.

When I first used rituximab in RA things were at this stage of four quarter doses once a week. However, at about that time the oncologists had discovered that if you give the drug slowly at first, for most types of tumour you could give bigger doses at one go. The tricky cases were the B cell leukaemias with huge numbers of cells in the bloodstream. Cell lysis syndrome was not expected to be such a problem in autoimmunity (no extra tumour mass) and early studies indicated that it was not. So together with the people at Genetech and Roche we decided to give two half doses instead of four quarter doses. We also rounded up the dose rather than doing it by body surface area.

By chance, at that time we were using cyclophosphamide as well and IV cyclophosphamide has to be given once a fortnight to allow the bone marrow a rest in between. So we decided to give the two rituximab doses a fortnight apart. There was no other reason to do this and in recent years we have given the two doses a week apart. Since any dose around about this level produces much the same 98% depletion of circulating B cells it seems very unlikely to matter.

The next logical thing would be to give the rituximab as a single dose, and occasionally we have done this with a single dose of 1000mg. However, a 1000mg infusion takes about five hours. A 2000mg infusion would not take much longer because after the first four hours the rate has speeded up a lot but nobody has had the courage to try 2000mg infusions in autoimmunity as far as I know. In fact there are good reasons for thinking that one 1000mg infusion is adequate so we may be wasting a vast amount of money and infusion time.

There is no point in giving rituximab two months after the first dose because there are no B cells to kill. It would simply be pouring drug down the drain. There is probably not much need to give another dose at 3 months but the logic of that is to pre-empt any return of B cells that occasionally happens as early as 4 months. I would have done maintenance shots at 4 months I think, but 3 months may be more reliable. If maintenance shots are only 500mg/M2 then they may need to be repeated 3 monthly.

As far as I know there is no logic in any other variation. Nobody is attempting to kill one lot of B cells and not another. Autoimmune B cells are exactly like normal B cells except in that they recognise self rather than non-self. There is nothing to suggest you can kill one rather than the other as far as I know. The reason why rituximab seems to hit the autoimmune clones harder than the others probably has to do with plasma cell half life.

 

[Jonathan Edwards]

One other point is that the doses for cancer and autoimmuity are basically the same. Some cancer patients have been given bigger doses in the hope of getting better cure rate and because cancer cells do not die so easily. The dosing schedules for cancer are quite different because the cancer cells are not developing from bone marrow but growing in a tumour. So it makes sense to give more rituximab if the tumour is still there even if the normal B cells from bone marrow are non existent.

 

[alex3619]

And then again, is Rituximab the right medication? Could Cyclophosphamide prove just as good, if not better and at the same time be much less cost prohibitive for patients?

Cost is a huge issue. We may indeed be better off with something else, but the Rituximab research may be proof in principle that these kinds of treatments work.

 

[Snow Leopard]

In fact there are good reasons for thinking that one 1000mg infusion is adequate so we may be wasting a vast amount of money and infusion time.

Have you suggested this to Mella & Fluge? I would have thought it would have been something to try in their open label study at least.

I note that they are still going with the following regime with the new trial:

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.

https://clinicaltrials.gov/ct2/show/NCT02229942

Half the infusion cost would make a lot of insurers/govt very happy!

 

[deleder2k]

The open study is completed and sent in for publishing. Not sure if they are planning to do another open label study for RTX. All patients participating in the double-blinded multi-centre study are guaranteed RTX (or some other drug that is better) when the study is completed in 2017. Maybe they have a chance of adjusting the doses then.

 

[thegodofpleasure]

I was recently quite surprised at the way Consultants at Christie's in Manchester used Rituximab, when they gave it to someone I know well, to treat an active EBV infection, rather than giving him the more usual antiviral treatments.

Having been extensively treated for Non- Hodgkin's Lymphoma over a period of 2 years (they had to go the full 9 yards - although it didn't include using Rtx up to this point) and having received a donor stem cell transplant about a year ago, this young man's EBV count (in blood) became elevated and he was plagued by Graft Vs Host problems - particularly in his gut. The Consultant prescribed Rtx infusions, monthly, for 4 months. (I must find out what the dosing regimen was)

After 2 months the EBV count in blood was sufficiently reduced that the Consultant felt confident enough to call a halt to the Rtx treatment. However, the GvHD persisted and a subsequent gut tissue biopsy revealed active EBV at unacceptable levels. The Rtx treatment was restarted after a break of 2 months and I'm happy to say that 2 months on, this treatment now seems to have done the trick.

Besides this somewhat unusual example, I know that Christie's use Rituximab extensively in the treatment of Lymphomas and therefore wonder whether their experience of using Rtx, could be leveraged to our advantage ?

 

[rebar]

I so wish you Jonathan Edwards were directly involved in these studies and trials.

 

[user9876]

I was recently quite surprised at the way Consultants at Christie's in Manchester used Rituximab, when they gave it to someone I know well, to treat an active EBV infection, rather than giving him the more usual antiviral treatments.

Having been extensively treated for Non- Hodgkin's Lymphoma over a period of 2 years (they had to go the full 9 yards - although it didn't include using Rtx up to this point) and having received a donor stem cell transplant about a year ago, this young man's EBV count (in blood) became elevated and he was plagued by Graft Vs Host problems - particularly in his gut. The Consultant prescribed Rtx infusions, monthly, for 4 months. (I must find out what the dosing regimen was)

After 2 months the EBV count in blood was sufficiently reduced that the Consultant felt confident enough to call a halt to the Rtx treatment. However, the GvHD persisted and a subsequent gut tissue biopsy revealed active EBV at unacceptable levels. The Rtx treatment was restarted after a break of 2 months and I'm happy to say that 2 months on, this treatment now seems to have done the trick.

Besides this somewhat unusual example, I know that Christie's use Rituximab extensively in the treatment of Lymphomas and therefore wonder whether their experience of using Rtx, could be leveraged to our advantage ?

After a bone marrow transplant there is a much higher chance of post transplant lymphoma where EBV increases and so they use Rtx to treat EBV in this very specific case.

 

[Jonathan Edwards]

Have you suggested this to Mella & Fluge? I would have thought it would have been something to try in their open label study at least.

An important rule of trial design is that you do not try to ask too many questions and end up answering none. If they changed the dose and it did not work then it might be that only the original dose works. If you split the patients into two dose groups you may get more information but you may lose out on statistical power. This is why the companies involved should have done proper dose response studies to start with. But that might have made things cheaper so they had no interest. I think the regulatory bodies should have insisted on it. One of the major reasons why US physicians do not like rituximab for RA is that they do not get many infusion fees (they actually told me this at an advisory board). If it was only one infusion every nine months they would be even less keen. Maybe that is why the company tried 2 x 500mg rather than the much more sensible 1 x 1000mg (higher peak level).

 

[Jonathan Edwards]

The EBV situation is another story yet again so the dosing is different again.

 

[Bob]

Just for interest, there's no oral form of rituximab, but there is a new (probably much more expensive) subcutaneous version of rituximab (licensed in Europe in 2014) that can be administered in just 5 minutes (by injection under the skin):
http://www.roche.com/media/store/releases/med-cor-2014-01-24.htm
http://www.roche.com/media/store/releases/med-cor-2014-03-28.htm