RME Conferences in Stockholm and Malmö, October 2017.

[ivorin]

Jo Cambridge - Uni College London

Prof of Immunology. Works with Jonathan Edwards

Co-operates with Norwegian team

What B cells are doing in ME/CFS. Results of Norway. Big results should be out in next few weeks

How to possibly identify patients who could benefit from Rituximab treatment?

ME is being recognized as a physical disease now, people in my department in the UK will not agree with me but at least we are here

Virtually ever patient we have studied relates to a viral or inoculation onset

Signalling pathway in stress

Need something that perpetuates the chronic disease. Need something that is hard wired and keeps come back.

3 steps
Any kind of insult will cause a damage / danger signal
When the infection takes hold the immune system steps in
Memory immune response - B cells make antibodies

Innate immune system - killing of virus infected cells - NK cells - initial response in ME/CFS could be where things start to go wrong

NK cells results published in ME - could be antibody or soluble factors

Cytokines profiles - can tell you what the stimulus is and what the effects will be in lots of tissues

In ME/CFS different cohorts - some cytokines up and down. Decent control cohorts - look at PWME after EBV. Disease duration. Adolescent patients

B cells - inconsistent data. Some say more /less etc.

What did strike us when we reviewed the data was the B-cell viruses were involved in onset for many patients. Onset of B-cell Lymphoma.

Some of the Cytokines reported raised in ME/CFS are related to B-cells

Rituximab used for 20 years in RA and 10 years in Lymphoma. Brave Norwegians she calls them. Rituximab used in 8/10 different diseases in her unit?

Ethical approval could be hard to get as it is a IV infusion - has been said to her. In her own patients not much in the way of problems with reactions. They currently do a test to see if B cells are killed.

Peripheral B cells come out of bone marrow. New naive B cells, most die but some are selected and turn into memory cells or plasma cells. Rituximab doesn't kill stem cells and pro-B cells. Rituximab using immune system to kill B cells. They coat cells and the macrophages kills them.

In tissues B cells are resistant to being killed.

Rituximab is given in large quantities 1-2 grams and coats the B cells in the bone marrow and stops them coming out plus kills the peripheral cells.

Summary of data so far (running through existing research)

£2000 pounds a go for Rituximab in the UK. The blood levels of Rituximab in the Norway studies was huge. She thinks they used a lot of the drug.

She talks about RA in the UK - there are seropositive and seronegative patients. They only use seropositive patients. Showed a slide of all the different condition they treat and the antibody tested

IResponse to Ritaximab epends on how quickly the autoantibody cells regenrate - precusors of autoantibdies

A lot of patients are being treated off label and they haven't responded but it takes a while. She thinks it is a soluble factor or something subtle rather than just the B cells themselves.

Maybe stopping the B cells interacting with other immune cells that could be happening.

If Rituximab works we need to look at B cells.

When the B cells comes back they come back from the naive and the interesting things is that when they B cells relapse is it bad B cells or the number? It's the quality and not the number

Graph of patient in Norway - during period of getting better there were no B cells in the blood. When B cells removed get rid of all the ones turning into memory cells. When they come back (maturing) the ME symptoms came back.

This helps them to work out how to give a dose to stop patients relapsing

Some B cells trigger a relaspe when they come back but some Norway patients are still fine. That suggests that the B cells need to do soemthing to activate again.

Metabolism - B cells sensitive to metabolic activity. How they interact with other cells / pro-inflammatory etc. T cells boring.

B cells can maybe give us indication of what could be happening in our cells. 2 years ago with Fane looked at extended phenotype analysis. 20/30 patients.

No differences in subsets with controls. Then looked at something else - major differences. Subtle. Overlapping populations of B cells. CD24 higher in ME B cells and more molecules per cell. Importnat molecule in B cell maturation. 2 difference in EBV response. AMPK is a key producer. ATP levels. This is related to CD24 and they don't know if the pathway is functioning in ME patients.

Talks about IGM antibodies to EBV

EBV response may be disturbed

B cells have different energy requirements depending on stimulus.

Graph on products between T and non-T dependent responses - lactic acid higher on one

Question - do any of these ME patients have IGM rheumatoid factor or CCP antibodies ?

Answer - in Norway a few IGM but low titres and UK no CCP antibodies

So the Ritux results may be out in the next few weeks? Is this just for the trial patients themselves? Sorry to be bothersome, but it's a huge thing for us.

 

[Demepivo]

Part 1 of the streaming

 

[Demepivo]

Part 2

 

[Jo Best]

So the Ritux results may be out in the next few weeks? Is this just for the trial patients themselves? Sorry to be bothersome, but it's a huge thing for us.

Yes the Phase 3 RituxME results will be known by the researchers this month when the codes are broken (as it was double-blind trial) and participants will be informed which group they were in, but then the analysis of the data needs to be done and the researchers have said that they won't make the results public until published in 2018.

Status, RituxME
All patient treatment and follow-up has been completed according to schedule in September 2017. The placebo and rituximab groups will be revealed to the scientists in October, and all participants will receive a letter informing them of which treatment group they were allocated to. We will then start working on the analysis of results, and expect to publish the results of the study in a medical journal during the first half of 2018.
https://helse-bergen.no/seksjon-engelsk/seksjon/Cancer Treatment and Medical Physics/Sider/RituxME.aspx

The Bergen team plan to visit Norwich again by the end of 2017 to discuss the UK trial.
This working collaboration and the work performed at UCL was credited as enormously valuable to the Norwegian rituimab trial work by one of the specialists there. http://www.investinme.org/ce-news-1708-01.shtml

 

[Cam Newton]

What about the CycloME trial? From what I’ve heard the Norwegians say during lectures, cyclo may have even better results than Rtx.

Also, can someone ask Jo Cambridge about her thoughts on Mark Davis’ findings on t-cells?

 

[Murph]

Here's a few of the interestng slides Jonas Blomberg put up. I couldn't nderstand what he said but the sldies were in Englsh!

 

[Murph]

and 2 more

 

[Murph]

What does physiologic dysfunction refer to?

Hanson used that term when talking about this patient, who was unable to raise their vo2 max on day 2 of the cpet and had a big differnece in their anaerobic threshold (not shown)

This patient is said to have an anaerobic problem

and finally one with autonomic dysfunction: a big fall in vo2, but because blood pressure never rose.

 

[Jo Best]

What about the CycloME trial? From what I’ve heard the Norwegians say during lectures, cyclo may have even better results than Rtx.

I believe they plan to publish results of CycloME Part A in the same time frame as RituxME.

Status, CycloME part A

The treatment and follow-up phases were completed in August 2017.

Analyses of the overall results indicate that there is reason to pursue further testing of cyclophosphamide treatment in ME/CFS. We have therefore decided to move on with an amended protocol for part B of the study.

We expect to publish the results from part A of the CycloME trial during the first half of 2018.
https://helse-bergen.no/seksjon-eng...atment and Medical Physics/Sider/CycloME.aspx

Part B of the CycloME trial includes patients with severe to very severe CFS/ME.

Based on an analysis of the preliminary response and toxicity data from CycloME, part A, we concluded that in order to extend the trial to include patients with severe to very severe ME, we needed to adjust the protocol and plan the intervention and follow-up of each patient with great care. In order to gain more experience with this highly vulnerable group of patients, we have now received approval from the Regional Ethics’ committee and the Norwegian Medicines Agency to conduct a pilot study involving three to five participants. If the pilot patients tolerate the treatment well, we may include a total of up to 20 participants. https://helse-bergen.no/seksjon-eng...and Medical Physics/Sider/CycloME-part-B.aspx

 

[ukxmrv]

There was one new thing in Hanson's talk I think. Her as yet unpublished Study of the gut virome found more bacteriophages (viruses that attack bacteria) than in controls. A similar effect has been seen in chrons and colitis. She hypothesised that the phages could be killing off gut bacteria contributing to the well documented lack of diversity and dysbiosis.

I've always thought there needs to be somethign upstream of simply hvaing the wrong bacteria in your guts. Why is it so hard to change them? After all, even if FMT works it seems to reverse after a while. A chronic oversupply of bacteriophages could be locking in dysbiosis.

Here's a link that IiME put on their Facebook page to an interesting talk

https://quadram.ac.uk/events/professor-martha-clokie/

Good short description of her work on B'phages and disease


Bacteriophages are extremely abundant in most environments including the human microbiome where they outnumber their hosts in a ratio of about 10:1.

They shape and manipulate the ecology of the environment in which they are found. both by encoding specific genes that express proteins which change the physiology of their host bacteria, and by shaping population dynamics by selectively killing specific populations of bacteria. Classical 16S barcoding of bacteria associated with disease clearly doesn’t detect bacteriophages and yet phages may have important roles in exacerbating disease symptoms and persistence.

To address this lack of knowledge, my lab has developed methods to characterize bacteriophages associated with human diseases. In this talk I will review the roles of bacteriophages associated with gut and respiratory diseases with a focus on the research in my laboratory on Clostridium difficile and on COPD (Chronic Obstructive Pulmonary Disease).

Further information: https://www2.le.ac.uk/departments/iii/people/dr-martha-clokie

 

[Jo Best]

Here's a link that IiME put on their Facebook page to an interesting talk https://quadram.ac.uk/events/professor-martha-clokie/

Host: Simon Carding

Simon Carding leads the gut microbiota in ME/CFS research at Quadram Institute, hub of the Invest in ME Research Centre of Excellence for ME. https://quadram.ac.uk/targets/me-cfs/

With partners at UCL, we are looking at the nature of autoimmune reaction in patients with ME.

An important aspect of our research into links between the microbiota and ME/CFS is to better understand the role played by viruses in the microbiota. Much research has focused on the bacterial populations, but the microbiota contains many other organisms, including fungi and viruses, as well as bacteriophages (viruses that infect bacteria). Viruses in particular are of interest in the study of ME/CFS as there has been evidence suggesting a viral role in triggering ME/CFS without being able to identify specific causes. Working with colleagues at UEA, we are looking to fully study the viral component of the microbiome, the virome, and its relevance to ME/CFS.

https://quadram.ac.uk/targets/me-cfs/

 

[pattismith]

Here's a few of the interestng slides Jonas Blomberg put up. I couldn't nderstand what he said but the sldies were in Englsh!

Thank you!