Invest in ME/Prof Jonathan Edwards statement on UK Rituximab trial, 30 July

[Isabelle]

@MeSci and @maryb

In regards to the bisphosphonates, I did ask about OP treatments. I think it is important to weigh up the costs and benefits of any medical treatment or procedure (Rituximab included). I was told that the safety and efficacy studies were done on menopausal or post-menopausal woman, and therefore didn’t really apply to me. It wasn’t so much that the costs outweighed the benefits, as that the costs were largely unknown.

 

[maryb]

@Isabelle
'The doctor also said not to go horse riding or play golf'

I wasn't going to post again off topic but this just made me smile.......I mean I can't even walk 100yds WTH

 

[greeneagledown]

@Jonathan Edwards

Many cancer patients who receive Rituximab multiple times end up developing resistance to the drug, rendering it ineffective. If it turns out that Rituximab is an effective but transient treatment for ME/CFS, is it possible, even probable, that many CFS patients would also develop resistance to Rituximab after repeated use? Does that sometimes happen in the non-cancerous diseases for which Rituximab is used, like RA? I don't know enough science to even know whether this is a dumb question or not.

Forgive me if you've already addressed this issue elsewhere on this site.

 

[Jonathan Edwards]

Dear Greeneagledown,
Nope, we haven't addressed it. And no, it isn't a dumb question.

The two situations are different in an important respect. The B cells to be got rid of in cancer are malignant B cells. Malignant cells usually have multiple errors in their DNA that make them able to grow without being regulated. Very often these errors include an error in DNA error repair - which allows the other errors accumulate. As a result, although all the cancer cells come from the same original cancer cell you end up with a range of cells with different errors. For almost all anti-cancer drugs the drug will often only affect some of these cells, which is partly why the drugs are often given in combinations. The problem is that the cells that survive and then continue to grow are going to be ones the drug does not get rid of. So next time you try the drug nothing much happens - you have resistance.

In autoimmunity things are quite different. All the B cells involved in the disease have quite normal growth regulation. It is just that they are being stimulated when they should not be. So with repeated rituximab treatments there is no reason why you should 'select for' certain resistant disease-related cells. Whether or not cells are killed is probably more to do with which part of the lymph node they are hiding in. And, as described way back in this thread, the situation is more complicated because there are signal loops between plasma cells and B cells and relapse of disease is largely due to 'education' of new B cells by antibodies from plasma cells to take over the role of ones that have been killed. On the other hand, if various signal loops are competing with each other it might still be true that repeated treatment with rituximab will favour the dominance of loops you don't want at the expense of normal B cells.

So what do we actually find in autoimmunity? Over the 12 years I gave repeated treatments I do not remember ever getting true resistance once we had a good response. We had a different problem with a few people - their antibody stores got so low that we had to switch away from rituximab to other drugs - that is definitely an issue for maybe 2-5% of people treated. It will be different for different diseases I suspect but it does seem that the theory works out in practice - resistance following initial response is not a major issue in autoimmunity.

What I think is much more encouraging is the fact that in some autoimmune diseases repeated treatments seem to lead to long term remission without further treatment. There is a suggestion that ME may be one of those from the Norwegian experience.

 

[Sasha]

What I think is much more encouraging is the fact that in some autoimmune diseases repeated treatments seem to lead to long term remission without further treatment. There is a suggestion that ME may be one of those from the Norwegian experience.

That is enormously encouraging!

 

[Firestormm]

Just noticed a response from Invest in ME on their Facebook page in relation to the total sum raised thus far of £338,000. I wonder if anyone can throw any light on any details with regard to the following:

https://www.facebook.com/groups/5804522506/permalink/10152186333597507/
Iime Charity
Em - the first phase is the preliminary B-cell study which is now underway at UCL. Once that is completed then the clinical trial would begin. So there is still some time before the that happens.
13 hours ago · Like

I think the last I had heard/seen was that ethical approval had been obtained for this pre-trial study, but I had not seen/heard of any further details - such as protocol and cost.

Quite possible I missed it - not been compos of late - if so could someone refer me to relevant information please? Many thanks.

 

[Jonathan Edwards]

Just noticed a response from Invest in ME on their Facebook page in relation to the total sum raised thus far of £338,000. I wonder if anyone can throw any light on any details with regard to the following:


I think the last I had heard/seen was that ethical approval had been obtained for this pre-trial study, but I had not seen/heard of any further details - such as protocol and cost.

Quite possible I missed it - not been compos of late - if so could someone refer me to relevant information please? Many thanks.

The pre-trial work is now up and running after a lot of bureaucratic hassle as usual these days. The intention is to repeat and extend B cell profiling as reported by Bradley and Bansal and also Curriu with further analyses relevant to autoimmunity. The hope is to be in the best position possible to stratify patients in a trial.

 

[Firestormm]

Thanks @Jonathan Edwards

@Jonathan Edwards

Do you happen to know how long this pre-trial might take? I presume the results will be published prior to the clinical trial commencing, but I wondered if it will be a factor in the trial taking place or not i.e. will the trial take place irrespective of the outcome of this pre-trial?

Thanks.

p.s. I guess these are the relevant papers you referred to above:

Bradley and Bansal: Altered functional B cell subset populations in patients with chronic fatigue syndrome compared to healthy controls

Curriu: Screening NK-, B- and T-cell phenotype and function in patients suffering from Chronic Fatigue Syndrome

 

[Jonathan Edwards]

Thanks @Jonathan Edwards

Do you happen to know how long this pre-trial might take? I presume the results will be published prior to the clinical trial commencing, but I wondered if it will be a factor in the trial taking place or not i.e. will the trial take place irrespective of the outcome of this pre-trial?

The aim of the pre-trial work was to try to establish the best way of doing a trial, not to decide whether or not to do a trial. A trial remains the objective. Time scales are very difficult to predict with current administrative issues.

 

[Bob]

@Jonathan Edwards

This seems to be exploratory research, and it's only a conference abstract (highlighted on Cort Johnson's blog), but I thought you might be interested in having a quick look at it anyway...


http://ctrin.unlv.edu/usb/abstracts/abstract_barao.html

Presentation format: Oral or Poster
Corresponding author: isilvestre@medicine.nevada.edu

Title: Altered Distribution of Lymphocyte Populations in Chronic Fatigue Syndrome Patients
Authors: Isabel Barao, Ph.D., Daniel Peterson, M.D., Dorothy Hudig, Ph.D
Institutional Affiliations: University of Nevada, Reno, School of Medicine, Simmaron Research, Inc., Sierra Internal Medicine
Key Words: CFS, NK cells, T cells, cytotoxicity, viral infections

Objective: The goal of our research is to define immunologic deficiencies of patients with chronic fatigue syndrome (CFS) and ultimately to improve the health of these patients by increasing their immunity.

Setting: CFS is a debilitating disease of unknown cause(s) defined by the Centers for Disease Control and Prevention (CDC) in Atlanta, GA. Our patient population is the well-known Reno-Lake Tahoe CFS cohort.

Methods: Peripheral blood is the site of traffic of lymphocytes with varying roles in immunity. Lymphocytes are circulating so as to be available to fight infections anywhere in the body or trafficking into secondary lymphoid organs where the lymphocytes will proliferate and differentiate.There are different types of lymphocytes in the blood [including helper T cells, cytotoxic T cells, T cells, B cells, natural killer (NK), and NK-T cells]. Alterations in these populations from healthy individuals are a hallmark of immune stress. To profile these populations, we used flow cytometry with fluorescent antibodies to identify the different populations of lymphocytes in the peripheral blood of CFS patients.

Results: We found unusual increases in a 'hybrid' population of lymphocytes in CFS patients. This population has features of both T cells and NK cells and is normally 1-5% of all lymphocytes but can be as high as 30% in the CFS patients.

Interpretation: The results are consistent with altered immunity in CFS patients, particularly altered immune responses to chronic viral infections. Further characterization, including repeated tests of the same patients, is needed to determine if this unusual population is persistent and to determine if it can mediate cytotoxicity towards virally infected cells.

 

[aimossy]

Does anyone know about these 'hybrid' cells? I wonder if they have used the term to explain the nature of these cells because of how this reads.
Is that the actual technical term for these "normally 1-5%" of all lymphocytes?

 

[N.A.Wright]

Does anyone know about these 'hybrid' cells? I wonder if they have used the term to explain the nature of these cells because of how this reads.
Is that the actual technical term for these "normally 1-5%" of all lymphocytes?

A confusing terminology - it's not 'hybrid cells' which is a recognised term, but "hybrid populations", by which the authors seem to imply that there may be some definable patterns to the relative percentages of T and NK cells in (some ?) ME/CFS patients. Needs independant replication to show if this is a real phenomenon or not.

 

[aimossy]

Thanks @N.A.Wright
I wonder does this mean there is a proper technical name for these cells that are usually 1-5% of lymphocytes? I wonder what they are called usually. I didn't frame my question very well. Its quite interesting, even if it does need more looked into of course.

 

[N.A.Wright]

Thanks @N.A.Wright
I wonder does this mean there is a proper technical name for these cells that are usually 1-5% of lymphocytes? I wonder what they are called usually. I didn't frame my question very well. Its quite interesting, even if it does need more looked into of course.

I don't think the authors are claiming to have found new lymphocytes so the reference is as this table: Typical recognition markers for lymphocytes

The authors therefore are likely talking about NK cells - phenotypes CD16 and CD56 and Gamma delta T cells - TCR and CD 3 phenotypes.

This is an area that other researchers have looked at, and while this type of imbalance matched to reference value (normal) lymphocyte count, is frequent, there's been little in the way of consistent pattern between studies. ME/CFS patients seem to have odd lymphocyte profiles but nothing obviously links one group or individual with another. We also need to be cautious because among the many variables, activity level has been proposed as impacting on lymphocyte count. There's also a notable gender difference that has to be allowed for. This doesn't mean this type of research isn't valuable but any result needs to be consitently replicated in independant studies before anythig definitive can been said.

 

[Jonathan Edwards]

Yes, I can't tell from the abstract, and it is a pity that there are no hard figures here, which there should be in a presented paper, but I think they are talking of cells with an intermediate combination of 'T' and 'NK' markers. Amongst the lymphocytes, B cells mature from stem cells very differently from other lymphocytes early on. The T and NK cell populations are not so clearly divided. Differentiation of lymphocytes into different types is measured by the differential expression of a range of gene products, many of which have 'cluster of differentiation' or CD numbers. In simple terms if a cell has CD3 and a T cell receptor it is a 'T' cell. If it is a T killer cell it usually has CD3, TCR, CD8 and CD57. Typical NK cells have no CD3 or TCR but have CD56 and CD16 as part of their killing apparatus. However, over the years it has become clear that you can have cells with intermediate combinations. Some of these have been called NKT cells. The simple story is that cells that kill when they recognise an antigen through TCR with CD8 also have CD3. Cells that kill when they recognise 'missing self' through NK receptors or by binding antigen through CD16 and using 'antibody dependent cytotoxicity' do not have CD3. The reality seems to be a bit more flexible. So I agree with N.A.W. that they are probably talking about something like CD3+ CD56+ cells with either no TCR or a gamma delta set up. The fact that they do not give precise data may mean that they are getting different combinations high in different patients. Again, I agree with N.A.W. that this may be a valuable finding but it is hard to make use of unless someone can show that different populations relate to different disease subtypes, either clinically or on other lab measures so that a consistent correlation can be confirmed in other cohorts.

 

[aimossy]

Thank you N.A.W and Prof for help with this. That makes a lot more sense with your explanations with respect to what these cells actually are and gave me some context

 

[Isabelle]

This may not relate specifically, but given the interest in NK cells in ME/CFS I thought it might be of interest. NK cells may be important in improving the efficacy of chemotherapy and immunotherapy in cancer treatment. Though the evidence is preliminary, pre-treating with chemotherapy seems to improve the response of the immune system to immunotherapy by (I think) normalizing the ratio of T cells (Tregs especially). Something seems to limit the production of anti-tumour (CD 8) T cells though, and NK cells seem a likely candidate. Though given the presence of NKT cells it is probably going to be more complicated. Possibly, the balance of NKT cells may be a key to successful immunotherapy in cancer.

I’ve often thought that if the puzzle of ME/CFS was teased out it was going to have a positive effect on other illnesses – e.g. MS. Perhaps cancer also?
It would almost make the suffering worthwhile. But, personally, I could do without it.

 

[Sasha]

Just read this about autoimmunity on Cort Johnson's blog today:

http://www.cortjohnson.org/blog/201...syndrome-fm-offers-big-move-dr-bateman-talks/

Autoimmune Cause for Postural Orthostatic Tachycardia Syndrome (POTS) Found

[Dr Bateman] reviewed an email she’d just received from a patient whose son is starting to have problems. An athlete, he had started suffering fatigue after his runs. His treadmill test was fine except that his heart rate exceeded 200 bpm and he was feeling so faint they had to stop the test. What did his cardiologist do? He sent him back to his primary care doctor.

Dr. Bateman noted that just this year a paper suggested a cause to the young man’s problem. He clearly had postural orthostatic tachycardia syndrome (POTS) and the cardiologist clearly had no idea what that was. That paper, by the way, was published in the prestigious Journal of the American Heart Association – a journal one might have thought the cardiologist would regularly read.

The paper suggested an autoimmune process was stopping blood vessel constriction and kicking off a furious heart rate that was leaving POTS patients’ brains without adequate blood when they stand. Dr. Bateman noted that hearts beating that rapidly have no time to fill, and therefore they pump out too little blood, and that’s why POTS patients get dizzy when they stand.

Small Fiber Neuropathy Studies Open New Window into Fibromyalgia (and perhaps ME/CFS)

Studies are providing new insights any of which could transform the field Dr. Bateman also cited the small fiber neuropathy (SFN) Fibromyalgia studies, one of which also found evidence of high rates of autoimmunity, as another example of how the field is moving forward. The symptoms of SFN, she noted, are very similar to those of FM, but since neurologists generally do not perform the skin biopsies needed to diagnose SFN, they rarely find anything wrong. (Back to the primary care provider the patient goes).

The findings, which have been validated by several small studies, will, however, change how FM is viewed and treated. They’re blockbuster findings in FM.​

I don't know what POTS/autoimmunity paper this is referring to. Does this tie in with the discussion on this thread about the target of autoimmunity for PWME?

Cort also had a very interesting piece yesterday summarising Dr Bateman's overview of ME research: she's on the IOM committee and attended the IACFS/ME conference and so had had to look at the research in both a more broad and intensive way than she had previously and felt that she was putting the pieces together. I know you've also studied the literature intensively, @Jonathan Edwards (and from a standing start!), coming in with your expertise in autoimmunity and wondered if you see a similar picture. Here's the link:

http://www.cortjohnson.org/blog/201...ng-chronic-fatigue-syndrome-dr-bateman-talks/

 

[Jonathan Edwards]

To be honest, this review is a bit broad brush for me. Bits of evidence like this do not 'add up' to it all being autoimmunity. Each piece of evidence may or may not provide a clue to what is happening for a particular subset of PWME. I think there are strong reasons for suspecting that in a proportion of cases there is autoimmunity involved but I see the key arguments rather differently, as we have debated before. But these are clues worth airing and following up, certainly.

 

[Sasha]

I wish you were on that committee, @Jonathan Edwards!