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

[lansbergen]

Improvements after rituximab have been reported earlier in some conditions but one has to be careful because steroids are often given as premedication.

Is there a relation between cortico responders and rituximab responders?

The reason I ask is a very long story with which I won't bother you.

 

[heapsreal]

There seems to be a group of us that arent good at making antibodies. Myself, others and the cfs outbreak in tahoe had some who were igg positive to ebv, several years later these people tested total negative losing there life long igg antibodies. Also i have issues with making antibodies to hep B vaccines? Is this a sign of b-cell dysfunction that ritux would be useful for??

 

[heapsreal]

With nk cell function and ME people having nk cells that work in a different way, how would it be explained that some have increased nk function after treating viral infections with antivirals. I think it is generally said that nk function is low because the immune system is burnt out from the constant attack of viruses?

 

[Esther12]

I just saw this being posted on twitter, and thought it could be of interest here (although perhaps not): http://www.ncbi.nlm.nih.gov/pubmed/23999819

A possible genetic association with chronic fatigue in primary Sjögren's syndrome: a candidate gene study.

Norheim KB, Le Hellard S, Nordmark G, Harboe E, Gøransson L, Brun JG, Wahren-Herlenius M, Jonsson R, Omdal R.
Source

Clinical Immunology Unit, Department of Internal Medicine, Stavanger University Hospital, Pb. 8100 Forus, 4068, Stavanger, Norway, katnorheim@gmail.com.
Abstract

Fatigue is prevalent and disabling in primary Sjögren's syndrome (pSS). Results from studies in chronic fatigue syndrome (CFS) indicate that genetic variation may influence fatigue. The aim of this study was to investigate single nucleotide polymorphism (SNP) variations in pSS patients with high and low fatigue. A panel of 85 SNPs in 12 genes was selected based on previous studies in CFS. A total of 207 pSS patients and 376 healthy controls were genotyped. One-hundred and ninety-three patients and 70 SNPs in 11 genes were available for analysis after quality control. Patients were dichotomized based on fatigue visual analogue scale (VAS) scores, with VAS <50 denominated "low fatigue" (n = 53) and VAS ≥50 denominated "high fatigue" (n = 140). We detected signals of association with pSS for one SNP in SLC25A40 (unadjusted p = 0.007) and two SNPs in PKN1 (both p = 0.03) in our pSS case versus control analysis. The association with SLC25A40 was stronger when only pSS high fatigue patients were analysed versus controls (p = 0.002). One SNP in PKN1 displayed an association in the case-only analysis of pSS high fatigue versus pSS low fatigue (p = 0.005). This candidate gene study in pSS did reveal a trend for associations between genetic variation in candidate genes and fatigue. The results will need to be replicated. More research on genetic associations with fatigue is warranted, and future trials should include larger cohorts and multicentre collaborations with sharing of genetic material to increase the statistical power.

 

[Jenny]

The IL-6 polymorphism link is certainly interesting. I think it would be helpful to repeat the study on homogeneous disease groups like RA or lupus. The effect might turn out to be different for each disease mechanism. Finding such variation in responses in ME is I think a fine detail in comparison to just getting the data confirmed and trying to get an idea who might have B cell related disease and who might not. Interesting though.

Hope I'm not going off on too much of a tangent here, but apparently increased IL-6 production is linked to Mannose-Binding Lectin deficiency. Some of us on this board have MBL deficiency (I have none as I'm homozygous) and we've discussed how it might be fruitful to look more systemically at the role of MBL in ME.

Professor Edwards - are there any plans to look at MBL deficiency in the ME patients in your forthcoming trial?

 

[Jill]

Sorry to butt in here, I just wanted to pass on this film/podcast from the University of Otago - in it Prof Tate discusses his research project and his daughters life with this illness. It may or may not be of interest to you Prof Edwards. I know also that he would be more than happy to correspond with you further about any technicalities (this is aimed at patients) and you can find his details on the Otago Uni website. He has the unique position of having been a first hand experiencer of the illness (a father who is a scientist) and being head of Biochemistry. THe other 2 speakers may not be of interest - except if you are a keen rugby league player! Our NZ ambassador/or face for the illness is an ex league player. He speaks last.

http://www.otago.ac.nz/prodcons/groups/public/@otagopodcast/documents/audio_video/otago052726.mp4

 

[Jonathan Edwards]

Is there a relation between cortico responders and rituximab responders?

The reason I ask is a very long story with which I won't bother you.

I don't think there is a useful answer to that. Most inflammatory features of autoimmune diseases respond to steroids and so do some others, like low platelets, but many non-inflammatory features do not. I doubt anybody has looked for correlations and I think they would be all over the place in different situations.

 

[Jonathan Edwards]

There seems to be a group of us that arent good at making antibodies. Myself, others and the cfs outbreak in tahoe had some who were igg positive to ebv, several years later these people tested total negative losing there life long igg antibodies. Also i have issues with making antibodies to hep B vaccines? Is this a sign of b-cell dysfunction that ritux would be useful for??

There are lots of variations like this in antibody production and persistence. A significant proportion of normal people do not make antibodies to Hep B very easily. I doubt they mean very much to be honest.

 

[Jonathan Edwards]

With nk cell function and ME people having nk cells that work in a different way, how would it be explained that some have increased nk function after treating viral infections with antivirals. I think it is generally said that nk function is low because the immune system is burnt out from the constant attack of viruses?

I can't say why NK results should go up and down but a lot of immune assays do. I can't see any reason why they should change because a virus has been cleared, if it has. I am not aware of any scientific basis for the idea of the immune system being 'burnt out'. Bone marrow should produce new NK cells every day from stem cells, which never burn out except in rare situations like myelofibrosis. I think the problem is that attempts to give simple explanations for what goes on in the immune system are often a bit half baked. One has to stick to the detail of what actually happens.

 

[Jonathan Edwards]

Hope I'm not going off on too much of a tangent here, but apparently increased IL-6 production is linked to Mannose-Binding Lectin deficiency. Some of us on this board have MBL deficiency (I have none as I'm homozygous) and we've discussed how it might be fruitful to look more systemically at the role of MBL in ME.

Professor Edwards - are there any plans to look at MBL deficiency in the ME patients in your forthcoming trial?

MBL deficiency is quite common and although it can predispose to things like troublesome skin infections it is not clear to me that it would fit in with a story for ME. It is involved in a particular pathway for antibody binding and inflammation that is relevant to bacteria more than viruses. I think we are getting in to small print here a bit! It is one of a hundred things that could be looked at and we have limited resources!

 

[heapsreal]

I can't say why NK results should go up and down but a lot of immune assays do. I can't see any reason why they should change because a virus has been cleared, if it has. I am not aware of any scientific basis for the idea of the immune system being 'burnt out'. Bone marrow should produce new NK cells every day from stem cells, which never burn out except in rare situations like myelofibrosis. I think the problem is that attempts to give simple explanations for what goes on in the immune system are often a bit half baked. One has to stick to the detail of what actually happens.

Maybe my wording isnt correct but dr peterson and dr klimas who both treat with antivirals and also test nk function have mentioned improvement of nk cell function once antivirals have cleared the infection/s. im not sure if it can be explained away by essays fluctuating, i say this because many test with extremly low nk function pre treatment and while during treatment and it isnt until the long course( as in months to years) of treatment has cleared the infections, that nk function returns to within normal ranges.

I suppose im picking your brain or arguing the point that i think many do have ongoing chronic infections and this is backed up by improvements in patients conditions with treatment and some deterioration when treatment is stopped. Maybe im a glass half empty kind of guy when it comes to ritux, as a person i know who was treated with this medication for her cfs had several herpes viruses break outs, severe urinary tract infections and a severe worsening of symptoms that took several months to recover from and no improvement past their pre ritux treatment.

Im concerned that chronic infections are easily explained away. My experience and many others here with cfs/me are that chronic infections do exist and i think is the reason for my friends negative results with ritux. I dont know why and i cant explain it but many cfs/me people react very differently to medication the way other non cfs/me people react.

I hope im wrong as it would be alot easier to get a couple of infusions a year then to live of valcyte which i have had good improvement from. Im just hesitant about ritux and knocking a part of the immune system down when one could have active infections??

cheers!!!

 

[Firestormm]

heapsreal have Peterson or Klimas published any studies that would support the claims you are making, out of interest? Just wondering if it isn't a case of doctors finding patients improve on X drug, think it has something to do with XX; and are making conclusions without proper scientific scrutiny? Not saying it is - not saying it isn't. But life in a surgery is often different to life under a microscope or clinical trial

Edit:

I found this review from Klimas in 2007. Of course I have no way of knowing what she (or Dr Peterson) and indeed others specifically look for in their tests, or upon which they base any specific treatments; anyway in relation to NK cells:

Natural killer cell and cytotoxic T-cell dysfunction: interferon β use

Natural killer cells are versatile lymphocytes, which—in healthy individuals—can destroy infected cells. Patients with CFS often have reduced natural killer cell cytotoxic activity [27,28,29•]. Maher et al. [4•] found that the natural killer cells of patients with CFS had abnormally low levels of perforin, which natural killer cells use to penetrate infected cells and inject cytotoxic granzymes.

Perforin plays a critical role in immune surveillance and immunomodulation; therefore, a decrease in perforin levels may play a role in the pathogenesis of CFS. This study was the first to examine cytotoxic T cells in CFS. The authors describe a decrease in perforin and granzyme content of the cytotoxic T cells equal to that seen in natural killer cells. The clinical implications are consistent with an immune system that may allow viral reactivation and raises a concern for tumor surveillance as well.

Some researchers have proposed that natural killer cell activity (NKCA) could be used as an immunological subgroup marker in CFS. Siegel et al. [29•] found that relative to CFS patients with normal NKCA, patients with low NKCA levels reported more cognitive dysfunction, more daytime impairment, and less vigor. These patients also scored lower on objective measures of cognitive function relative to patients with normal NKCA levels. Immunomodulatory therapies that target natural killer cell and cytotoxic T-cell function would seem reasonable, using
functional and quantitative flow to identify the appropriate subgroup [30•].

I also have no idea if the theory expressed above is still something that is behind treatment with specific drugs in their clinics today. I suspect the studies above have never been replicated, but as science 'surges' forward perhaps we will see these smaller studies replaced with larger ones - and some of these theories replaced also - or at least confirmed.

Appreciate any more recent publications from Klimas and/or Peterson supporting any theory they may have about NK cells and specific drug treatment - as well as the theory behind it. Do you happen to know if any drug trials are planned on the back of any of their theories?

Thanks

 

[voner]

........... I do not personally have a patient set. I am going by the literature.

Prof. Edwards,

You may not personally have a patient set, but you are serving as an advisor to a group that is going to select a patient set. Many of us would like to know how that patients that is going to be selected, and I'm guessing that you may have some advice on that, or maybe you may not?

So maybe I'll rephrase my question,

Have you formulated any thoughts about the Criteria for the patients set, Or is that not in your realm of advice/thought?

 

[Legendrew]

Prof. Edwards,

You may not personally have a patient set, but you are serving as an advisor to a group that is going to select a patient set. Many of us would like to know how that patients that is going to be selected, and I'm guessing that you may have some advice on that, or maybe you may not?

So maybe I'll rephrase my question,

Have you formulated any thoughts about the Criteria for the patients set, Or is that not in your realm of advice/thought?

I'd have thought using the same criteria as Fluge and Mella would be the most logical way to go.

 

[Firestormm]

voner personally I would want any patient who is diagnosed by the NICE criteria to be in the Trial along with controls as a minimum.

It is NICE in this country by which many patients are diagnosed and to exclude this criteria would be 'nuts' in my opine.

Once you got 'em of course further bio-analysis would be very important on entry and exit

Methinks Prof. Edwards talked about this previously in the thread; but I forget. It's all gotten rather nicely long now hasn't it?

 

[Bob]

I hope that the Canadian Consensus Criteria (CCC) will be used, alongside NICE or Fukuda to select patients.
Unlike Fukuda and NICE, CCC patients do at least require post-exertional malaise, that many of us would consider an essential feature of ME.

 

[Marco]

Thanks for posting this Esther12

A possible genetic association with chronic fatigue in primary Sjögren's syndrome: a candidate gene study.

Fatigue is prevalent and disabling in primary Sjögren's syndrome (pSS). Results from studies in chronic fatigue syndrome (CFS) indicate that genetic variation may influence fatigue.

The association with SLC25A40 was stronger when only pSS high fatigue patients were analysed versus controls (p = 0.002).

http://www.ncbi.nlm.nih.gov/pubmed/23999819


This is interesting to me from the perspective of neuroinflammation. Even from just the discussions in this thread it does seem that fatigue is highly prevalent in a range of autoimmune diseases as are other neurological symptoms similar to those seen in ME/CFS :

Involvement of nervous system pathways in primary Sjögren's syndrome.

A relatively high rate of affective and cognitive symptoms, as well as abnormal fatigue and poorly characterized pain, are features of pSS that contribute to diminishing health quality in the pSS population.

http://www.ncbi.nlm.nih.gov/pubmed/18984410


I'm not convinced that these symptoms are due to 'living with a chronic illness' or directly result from ongoing peripheral inflammation.

It appears that the SLC25A40 gene (also known as SLP1) belongs to a family of genes (the mitochondrial solute carrier family 25) that are widely expressed in the central nervous system and transport solutes across the inner mitochondrial membrane (which I assume is basically essential for proper mito function).

The only link to disease (sic) that I can find to this gene is in experimental autoimmune encephalitis (EAE) a rat model of multiple sclerosis; where SLP1 expression was found to be upregulated in EAE rats 100 fold and appears to be protective against neuroinflammation.

Novel role for SLPI in MOG-induced EAE revealed by spinal cord expression analysis.

Expression of SLPI was upregulated more than hundredfold during EAE attack. Using immunohistochemistry, SLPI was identified in macrophages, activated microglia, neuronal cells and astrocytes

CONCLUSION:

We identified novel features of gene expression in the CNS during EAE, in particular the suppression of genes of cholesterol biosynthesis and a strong upregulation of SLPI, a gene which is for the first time associated with autoimmune inflammation. The capacity of SLPI to increase proliferation of adult NSC and of oligodendroglial differentiation suggests a novel role for SLPI in the promotion of tissue repair, beyond its known functions in the prevention of tissue damages by protease inhibition damage and modulation of inflammatory reactions.

http://www.ncbi.nlm.nih.gov/pubmed/18501024


So what 'inflammatory reactions' might it be protecting against?

Fatigue in primary Sjögren's syndrome--a link to sickness behaviour in animals?

Increased levels of IL-1Ra in the CSF are associated with increasing fatigue in PSS patients, indicating that the activated IL-1 system is a possible biological factor associated with fatigue.

http://www.ncbi.nlm.nih.gov/pubmed/19560535

… and in a post hoc analysis (no significant differences were found at the pre-defined primary end-point) this study found that IL1 inhibition resulted in a 50% reduction in fatigue in 6 out of 12 patients :

Interleukin-1 inhibition and fatigue in primary Sjögren's syndrome--a double blind, randomised clinical trial.

http://www.ncbi.nlm.nih.gov/pubmed/22253903

Rituximab has also been shown to reduce fatigue in pSS patients.


So how would a gene involved in mitochondrial function protect against neuroinflammation? It seems that a low energy state (low mitochondrial function) in the brain leaves the brain more susceptible to neuroinflammation. E.g. :

CNF1 Increases Brain Energy Level, Counteracts Neuroinflammatory Markers and Rescues Cognitive Deficits in a Murine Model of Alzheimer's Disease

http://www.plosone.org/article/info:doi/10.1371/journal.pone.0065898


Unfortunately the full paper Esther linked to is behind a paywall and you can't tell from the abstract how the SNP associated with high levels of fatigue in primary Sjogren's affects mitochondrial function. From the above discussion you could speculate that the SNP would result in lower activity and hence reduced mitochondrial function and reduced protection against neuroinflammation and the resulting fatigue and other symptoms.

Sounds plausible to me?

 

[Sasha]

voner personally I would want any patient who is diagnosed by the NICE criteria to be in the Trial along with controls as a minimum.

It is NICE in this country by which many patients are diagnosed and to exclude this criteria would be 'nuts' in my opine.

I have to disagree there - the NICE (Oxford?) criteria are very vague. It makes no sense to run a trial on a group of patients of which only a fraction have 'proper' neuroimmune ME. That would just dilute the effects. I think we need at least CCC, like the Haukeland study.

 

[Jonathan Edwards]

Have you formulated any thoughts about the Criteria for the patients set, Or is that not in your realm of advice/thought?

I will leave that to those who look after people with ME/CFS. I presume they will start with the Fluge and Mella choice but might want to narrow it down a bit further. We can't treat 'controls' in the sense of people without ME/CFS with rituximab - but I suspect that is not quite what Firestormm meant. I don't think NICE is relevant here - they are only really interested in practical health care delivery once the trials have been done.

 

[user9876]

I don't think NICE is relevant here - they are only really interested in practical health care delivery once the trials have been done.

I think that Firestormm was refering to the diagnostic criteria published in the NICE guidelines. They are some of the least strict of the available criteria.