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

That was a great question and a good answer. Being a chemo nurse (until I got sick) I have seen patients with cancer litterally come back from the dead with Rituxan. i like the fact that "you can make a monoclonal antibody do whatever you like" and indeed there must be a consensus in regards to cytokines. Personally, my Il6 and 8 and TNF have been much below normal, if not close to 0 for Il6 and 8. The fact that a lot of patients have an up-regulated immune system (I haven't had a single cold or other infection since illness onset 5 years ago) must mean something.

Thankyou Prof Edwards, you are very patient and a natural teacher!
You have invaluable insights and knowledge into research in general as well which I feel is also helpful to the ME community.
If we focus our efforts into funding key quality research we are more likely to bare fruit. We need to fund the quality shovels for the most likely places in the garden to dig up some hidden gold!
Its very nice to know we are getting closer and closer to having that happen. Most hopeful

Dr. Edwards, this is an addendum to the information stated above in your statement and is intended as information for the ME community.

Most patients on here meet the CCC definition for ME/CFS. We all know what unrefreshing/unrestorative sleep is and the daytime sleepiness or exhaustion yet at night the insomnia and sleep cycle disruptions etc.

In other words the immune system was killing cells that produce hypocretin. Hypocretins (orexins) were discovered by two groups of researchers almost simultaneously, hence the two names "hypocretins" and "orexins". The first group called them "hypocretin-1" and "hypocretin-2" after discovering that the molecules were found only in the hypothalamus and had some weak resemblance with the gut hormone secretin. Only 10,000-20,000 cells in the entire human brain (out of many billions) secrete these specific hypocretin molecules. Following specific influenza flu infections, the immune system confuses a portion of the flu virus with hypocretin related proteins, destroying the 70,000 neurons in the brain that produce hypocretin.
https://en.wikipedia.org/wiki/Orexin

HLA stands for " Human Leukocyte Antigens". HLA antigens are molecules produced by the HLA genes. HLA molecules are expressed on the surface of white blood cells to coordinate the immune response. DR and DQ are two different types of HLA molecules. HLA genes are very important systems to keep the immune system in check. The HLA molecules are very particular in that different individuals generally carry different HLA "subtypes" (for example DR1, DR2, subtypes of HLA-DR; DQ1, DQB1*0602, subtypes of HLA-DQ). The fact HLA molecules are slightly different from one individual to another makes our immune system slightly different from each other. The immune system uses HLAs to differentiate between “self” cells and foreign cells (and attacks those presented as foreign), and most autoimmune diseases are associated with variants of HLA. In recent studies, more than 90 percent of sleep disorder patients were shown to carry one such variant. https://med.stanford.edu/news_releases/2009/may/narcolepsy.html


The team found that a specific variation of a gene belonging to T cells—specialized immune cells that play a role in all immune responses—was present in narcolepsy.

Furthermore, some Northern Europe countries used a particular flu vaccination against the H1N1 2009 strain called Pandemrix which triggered a sleep disorder in some children (1/16,000 vaccinations in Finland, a 5-13 fold increase risk). http://www.nbcnews.com/id/50742731/ns/health-cold_and_flu/

Following specific influenza flu infections, the immune system confuses a portion of the flu virus with hypocretin related proteins, destroying the 70,000 neurons in the brain that produce hypocretin. Can there only be a partial depletion? research is out on this.

HLA-DR; DQ1, DQB1*0602, subtypes of HLA-DQ
Genetic predisposition can cause narcolespy or depletion in hypocretins


Please Note: All narcolepsy patients have a genetic mutation in HLA-DR DQB1*0602 but all people who have this genetic composition do not acquire narcolepsy via vaccination or its adjuvant

The fact HLA molecules are slightly different from one individual to another makes our immune system slightly different from each other. The immune system uses HLAs to differentiate between “self” cells and foreign cells (and attacks those presented as foreign), and most autoimmune diseases are associated with variants of HLA

Hypocretin Hcrt-1 Hcrt-2 OX-1 Ox-2

1. Autoimmune Disease
2. Complete reversal of circadian rythyms. Sleepiness during the day, wakefulness during the night
3. Tachycardia arrhythmia
4. Orexin is also essential in physiological responses to stress, panic-anxiety syndrome
5. Modulation of breathing and autonomic function
6. Regulation of sympathetic activity, including effects on blood pressure and thermoregulation.
7. Neurocognitive issue, bain fog, short term memory lost,speech language centers
8. Energy homeostasis
9. Metabolic rate and locomotive activity

For Further Research Check:

The autoimmune basis of narcolepsy.

Narcolepsy and H1N1 vaccination: a link?

Respiration and autonomic regulation and orexin

Cerebrospinal Fluid Melanin-Concentrating Hormone (MCH) and Hypocretin-1 (HCRT-1, Orexin-A) in Alzheimer’s Disease

Incidence of narcolepsy in Norwegian children and adolescents after vaccination against H1N1 influenza A.

Control of sleep and wakefulness in health and disease.

A patient with both narcolepsy and multiple sclerosis in association with Pandemrix vaccination.
Narcolepsy with cataplexy is caused by a selective loss of hypocretin-producing neurons, but symptomatic narcolepsy can also result from hypothalamic and brainstem lesions caused by multiple sclerosis (MS).

We report a previously healthy man who developed clinical and laboratory verified narcolepsy without having any indication of hypothalamic lesions and MS after vaccination against the influenza H1N1 with Pandemrix. HLA typing showed both DRB1*15:01, associated with MS and DQB1*06:02, associated with narcolepsy. The genetic susceptibility in this patient makes it tempting to speculate upon an immune-mediated mechanism and a common etiology for both diseases in this patient.

Genetic and immunologic aspects of sleep and sleep disorders.

Central Control of Circadian Phase in Arousal-Promoting Neurons
Cells of the dorsomedial/lateral hypothalamus (DMH/LH) that produce hypocretin (HCRT) promote arousal in part by activation of cells of the locus coeruleus (LC) which express tyrosine hydroxylase (TH). The suprachiasmatic nucleus (SCN) drives endogenous daily rhythms, including those of sleep and wakefulness.

Federal US Court rules Hepatitis B vaccine caused Chronic Fatigue Syndrome


Check with a sleep medicine doctor for this condition or for sleep apnea and other associated sleep disorders. You may not have ME/CFS. Unfortunately, the only way to determine is through genetic testing for the specific gene or test result in the CFS.


If you feel that you came down with narcolepsy after receiving a vaccination, you have three years from the date of the vacination to file a claim with the U.S.Federal Court of Claims!

This could only relate to a subset of ME/CFS patients but it is intriguing that if antibodies in the H1N1 vaccine can wipe out the hypocretin in those patients with a genetic predisposition, could the production of the antibodies for those who catch the flu wipe out hypocretins as well for those who have a genetic predispostion. The genetic predispostion is passed down through generations. The other question is what prevented those that have the defective gene from not getting narcolepsy when exposed to the H1N1 flu?

Eco

Disclaimer: The above statements no way implies an Anti-Vax platform but stated scientific inquiry into the facts. I can tell the patient community right here and now that you will receive the disdain of the scientific community by any associating with Wakefield or the Anti-Vax community. You will lose the support of the scientific community. We have enough issues to deal with without adding more.

Ecoclimber you might like to also consider submitting a draft of your comment above for publication as an article on Phoenix perhaps? We're always looking for new things and new authors

The unfolding story of narcolepsy as an autoimmune disease is certainly interesting but I think it is important not to confuse it with ME. It may be a good immunological analogy for ME but the symptoms of narcolepsy are quite different from those of ME. My experience of people with narcolepsy is that they cannot help falling asleep even in the middle of a conversation but they do not necessarily have fatigue or insomnia. They often also have this strange symptom of cataplexy - which is usually suddenly becoming paralysed when laughing. Narcolepsy is very easy to diagnose once you are familiar with it so I think people with it are unlikely to be diagnosed as having ME.

For what it's worth:
[from Action for ME:
http://www.actionforme.org.uk/get-informed/news/daily-press-summary/dailypresssummary25092013 ]

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I did a quick Google search of the Ledbury Reporter site and nothing came up for Rituximab.

Reply to my email:

I think its unlikely that 'resolution' of NHL was responsible solely for the improvement in ME symptoms given that a high proportion of those treated for cancer develop chronic cancer related fatigue either due to the disease or the treatment regime.

Somewhat off at a tangent, but relevant to this thread, the Lights have just published another study comparing mrna gene expression (no exercise challenge used) in prostate cancer patients receiving androgen depletion therapy who experience fatigue and pain and 'CFS' patients (plus healthy controls of course).

They found differences between the two patient groups but in both groups fatigue severity correlated with changed expression of diazepam binding inhibitor (DBI) which modulates GABA -a receptors. Elevated expression of the gene coding for TNF-a was also elevated in CFS patients :

Differing leukocyte gene expression profiles associated with fatigue in patients with prostate cancer versus chronic fatigue syndrome

http://www.sciencedirect.com/science/article/pii/S0306453013002977

Reading this post interested me as I believe ME/CFS relates to peripheral-central sensitisation, glutamate/GABA dysregulation and microglial priming. Did you have a source for the above exerpt?

All a quick search has lead me to is this, which appears to run contrary to what you were suggesting:

http://www.sciencedirect.com/science/article/pii/0165572893900635

Hi

If you're interested in this line of reasoning you might be interested in this series of blogs :

http://www.cortjohnson.org/authors/marco/

PM me if you want to discuss this or I'll PM you with the sources once I've tracked them down (it was a while ago) rather than derail this thread.

Apologies all

Recently someone brought the following paper to my attention, i'm not sure whether it has been posted before:

http://www.hindawi.com/journals/mi/2008/792428/

I have to say it's quite an interesting idea that perhaps, whether directly or indirectly, these vasoactive neuropeptides are down-regulated hence producing a wide range of seemingly disparate symptoms. I also remember when discussing narcolepsy you mentioned the small peptides involved - many of these vasoactive neuropeptides implicated here are too quite small, with Vasoactive intestinal peptide only being made up of 28 amino acid residues.

I'm not sure I like the emphasis this paper in particular places upon the blood brain barrier interaction, however this may be down to me not liking the BBB theories in ME and perhaps not understanding the implications the paper is making. The paper also references the TH1/2 shift which I know you're not a fan of - sorry!

I've just started a new thread about a new FDA warning to clinicians on rituximab.

It's here.

It all seems a bit broad brush to me to be honest!

It's now up at: http://worcsmegroup.weebly.com/news.html

Does anyone know when the Norwegian ME study is going to be published? I want to forward it on to our chief rhematologist who uses Rituxan here in Auckland. I think he may have been involved in the arthritis work Prof Edwards. His name is Peter Gow at Middlemore hospital, Auckland. I also used to go to school with the country manager at Roche NZ, and he is interested to see the paper too . New Zealand is such a small place......

The Norwegian controlled trial of rituxmab in ME was published online in PLOS ONE on October 19, 2011. It will come up on Google under Fluge, Mella, PLOS ONE. They have another open study in progress, as well as more follow up data from the original study. I am not sure when that will be published. The next formal study will start in January and nothing will be published for at least a year and probably two.

New Zealand may be quite small but so is the world. I remember Peter from Guy's Hospital thirty five years ago. Send him my regards. Sounds as if your Roche friend needs to do some homework!

I was talking to Dr Fluge and Dr Mella last week and they continue to see good response rates with rituximab. Their work is progressing well in interesting directions but there is a lot of work to be done to really pin down the mechanisms involved with objective measures.

Jonathan Edwards - I had thought that Fluge & Mella had done a follow-up study giving Rituximab to the placebo patients from their initial trial using a different dosing schedule, which they reported on at the IiME conference (still embargoed, and I've only seen the DVD which doesn't show that presentation). It has been reported on Norwegian TV as being even more successful than the first study. I thought that was being submitted for publication as a stand-alone study. Maybe I've got that wrong.

Jill - the original study is here:

http://www.plosone.org/article/info:doi/10.1371/journal.pone.0026358

(I don't know how to do the @ quote thingy - duh will have to read up I guess)

Sasha:
This is what I had understood also from the Invest in ME conference of May this year. I was under the impression that the results presented were to be published at the end of your summer ie end of our winter - which is about now??

Professor:
I hope to see Peter shortly and will pass on your regards. He is still working (google Middlemore and his name and you'll find him - or let me know and I'll find his email for you) , although is semi retired. He has always had an interest in ME - I think more because people got sent to him - not that he knew much about it. He advocated a lot for arthritis patients when rituxan wasn't approved by our drug buying agency. I think *he * basically got Rituxan approved eventually , he was on the case and in the papers supporting the patient lobby. Hilarious you know him, but I thought you might because wasn't he involved in the worldwide rituxan arthritis trials?

It's easy - all you do is type '@' and then the username of the person you're tagging, with no space between the '@' and the name. Then when you post your message, it magically comes alive as a tag.

Yes, I think the open label study will be ready for publication quite soon. The response rate is a little higher than in the controlled trial but fairly similar. It provides more information about repeated treatments and general safety and tolerability but being an open study will not be seen as moving the key question of proof of efficacy forward. The big multicentre study will be the gold standard for that and hopefully we will have more evidence from a UK study not too far down the line.

Peter may have been involved in rituximab studies in RA after I left that to the company to work up for a license. There was certainly a lot of interest in the Antipodes in the idea of using rituximab even before I got started on it. I was asked to talk about it at the big OZ/NZ meeting in 1998 just before we treated patients.