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

[Jonathan Edwards]

Nor ageing per se perhaps but leptin secreting white adipose tissue?

Percentage body fat tends to increase with age up to a point. The very old tend to have trouble maintaining weight. Plus of course females tend to naturally have a higher proportion of body fat.

Hmm. ... So why has nobody ever noticed either in clinical practice or rigorous epidemiological studies (like the RA Norfolk register) any association at all between incidence of any autoimmune disease and obesity, as far as I know? Type 2 diabetes does not count here; the maybe autoimmune type 1 cases are mostly thin.

 

[Marco]

Hmm. ... So why has nobody ever noticed either in clinical practice or rigorous epidemiological studies (like the RA Norfolk register) any association at all between incidence of any autoimmune disease and obesity, as far as I know? Type 2 diabetes does not count here; the maybe autoimmune type 1 cases are mostly thin.

Fair enough. I'm clutching at straws here but is there a possibility of latent autoimmune diabetes of adults (LADA) being misdiagnosed as type II diabetes? (noting that the CDC seem to think there's a high prevalence of metabolic syndrome in ME/CFS).

Good old Wiki :

It is estimated that more than 50% of persons diagnosed as having non-obesity-related type 2 diabetes may actually have LADA. Glutamic acid decarboxylase autoantibody (GADA), islet cell autoantibody (ICA), insulinoma-associated (IA-2) autoantibody, and zinc transporter autoantibody (ZnT8) testing should be performed on all adults who are not obese who are diagnosed with diabetes.[4] Not all people having LADA are thin, however—there are overweight individuals with LADA but who are misdiagnosed because of their weight. Moreover, it is now becoming evident that autoimmune diabetes may be highly underdiagnosed in many individuals who have diabetes, and that the body mass index levels may have rather limited use in connections with latent autoimmune diabetes.[5] Also, many physicians or diabetes specialists don't recognize LADA or don't know that Type 1 diabetes frequently occurs in adults, and so LADA is misdiagnosed as or mistaken for Type 2 diabetes very often.

Epidemiological studies do appear to link obesity with dementia but that's another thing altogether (?) :

http://www.nia.nih.gov/alzheimers/features/big-belly-bad-brain-examining-body-fats-ties-dementia

Sorry, been clearing out my potting shed today and rather lost my train of thought but I don't think I was suggesting that leptin levels trigger autoimmune disease but may contribute to sustaining it or to disease activity.

 

[Legendrew]

Thought this may be of interest, the UK government has conceded that the swine flu vaccinations can sometimes be a triggering factor for narcolepsy. Interesting how one vaccine in particular seems to trigger narcolepsy more often than others, I've read similar reports of vaccinations triggering ME such as hepatitis B which is the vaccine in question a third of the time. I have to say it interests me considering my ME seemed to be triggered by vaccinations.

Media coverage http://www.theguardian.com/society/2013/sep/19/swine-flu-vaccine-narcolepsy-uk

Scientific paper http://www.bmj.com/content/346/bmj.f794#aff-3

 

[Jonathan Edwards]

Thought this may be of interest, the UK government has conceded that the swine flu vaccinations can sometimes be a triggering factor for narcolepsy. Interesting how one vaccine in particular seems to trigger narcolepsy more often than others, I've read similar reports of vaccinations triggering ME such as hepatitis B which is the vaccine in question a third of the time. I have to say it interests me considering my ME seemed to be triggered by vaccinations.

Media coverage http://www.theguardian.com/society/2013/sep/19/swine-flu-vaccine-narcolepsy-uk

Scientific paper http://www.bmj.com/content/346/bmj.f794#aff-3

My impression is that the Scandinavian study is much more convincing. The UK study I find quite hard to interpret, since about as many people as got narcolepsy in the study would have been expected to get narcolepsy that year anyway. As they say, there did not seem to be an indication of more narcolepsy that year. Perhaps the mere fact that the study seemed to give a second positive signal made the government feel they could not expect to defend a legal case on the basis of no evidence. My memory of the scandinavian study was that it was pretty convincing as it stood. Nevertheless, I am still unclear whether or not vaccination does more than bring the onset forward a bit in people who will get the disease anyway. Interesting though.

 

[tatt]

a few questions/comments that I don't think have been covered, apologies if they are idiot questions but excessive activity recently has affected my brain and I'm not clear what else rituximab may do besides kill B cells.

I'm one of the people who had significant remission on a gluten free diet. I've read that gluten sensitivity problems involve gliaden recognising B cells. Is part of the benefit from rituximab that it kills these cells?

I'm quite interested in why some people respond to treatments and others don't. Magnesium levels are often low in ME and the effect of hydrocortisone on magnesium levels may have something to do with why some people feel worse on hydrocrtisone supplements. Is there any reason why rituxmab might change magnesium levels?

Anecdotally people with ME report improvement on holidays to warmer climates. Dr Stasha Gominak (american neurologist) has linked vitamin D deficiency to sleep quality and disrupted sleep is common in ME. Her website doesn't seem to be loading for me and unfortunately she hasn't carried out clinical trials yet. Discussion here

Do you think vitamin D deficiency could have any effect on why some people respond to rituximab and other don't?

 

[Jonathan Edwards]

I'm not clear what else rituximab may do besides kill B cells.

I've read that gluten sensitivity problems involve gliaden recognising B cells. Is part of the benefit from rituximab that it kills these cells?

Is there any reason why rituxmab might change magnesium levels?

Do you think vitamin D deficiency could have any effect on why some people respond to rituximab and other don't?

RItuximab only kills B cells. That is the advantage of this type of custom made protein molecule - it only does one thing, unlike most traditional drugs that interfere with all sorts of things.

In coeliac disease there are T cells recognising gliadin, but not B cells. The B cells recognise a self molecule called tissue transglutaminase. The T cells reacting to gliadin may not in themselves be a problem, since gliadin is not part of self but the role of the antibodies is not fully understood. I do not think we know whether rituximab has useful effects in coeliac disease. One problem might be that recovery of the gut is so slow that you would need to deplete B cells for a long period before you knew the answer.

Rituximab would not change magnesium levels. I don't think vitamin D levels would affect the action of rituximab as such. I vitamin if D deficiency significantly contributed to cases of ME then those might not respond to rituximab but I see that as vanishingly unlikely. Vitamin D replacement is very easy and if it really made a major difference in ME everyone would know about it, I think.

 

[August59]

My impression is that the Scandinavian study is much more convincing. The UK study I find quite hard to interpret, since about as many people as got narcolepsy in the study would have been expected to get narcolepsy that year anyway. As they say, there did not seem to be an indication of more narcolepsy that year. Perhaps the mere fact that the study seemed to give a second positive signal made the government feel they could not expect to defend a legal case on the basis of no evidence. My memory of the scandinavian study was that it was pretty convincing as it stood. Nevertheless, I am still unclear whether or not vaccination does more than bring the onset forward a bit in people who will get the disease anyway. Interesting though.

I have never had a flu shot and I got narcolepsy 3 years ago!

 

[lansbergen]

RItuximab only kills B cells. That is the advantage of this type of custom made protein molecule - it only does one thing, unlike most traditional drugs that interfere with all sorts of things.

How can one be sure it does not bind to simular epitopes on other molecules? How was crossreactivity ruled out?

 

[MeSci]

I'm one of the people who had significant remission on a gluten free diet. I've read that gluten sensitivity problems involve gliaden recognising B cells.

You may be interested in this review paper which is one of several describing non-coeliac gluten sensitivity.

I'd ignore the animal studies, as animal 'models' are very poor proxies for humans.

 

[Jonathan Edwards]

How can one be sure it does not bind to simular epitopes on other molecules? How was crossreactivity ruled out?

Cross reactivity is a common problem in laboratory assays and because of this becoming evident in the 1950s it was suggested that cross reactivity might be a factor in diseases like rheumatic fever. In fact the evidence for cross reactivity ever being a problem in vivo is very hard to pin down. Nobody ever found cross reactive antibodies in rheumatic fever. 'Molecular mimicry' seems to be largely a myth, even if, like most medical myths, it has hung around for half a century. There probably are a few examples (Guillain Barre syndrome) but we walk around with antibodies to thousands of things without any evidence of cross reactivity. To function in vivo an antibody has to have a very high affinity in comparison to what can be measured in the lab. There is theoretical possibility of rituximab binding to something else, yes, but nobody has seen any sign of it and rituximab only has a beneficial effect on diseases associated with B cell problems. No side effects have been identified that suggest a cross reactivity. In fact we now have a bout ten therapeutic molecules of this sort for use in rheumatic disease and none of them have shown signs of cross reactivity problems so I think it is pretty unlikely.

 

[user9876]

I don't think vitamin D levels would affect the action of rituximab as such. I vitamin if D deficiency significantly contributed to cases of ME then those might not respond to rituximab but I see that as vanishingly unlikely. Vitamin D replacement is very easy and if it really made a major difference in ME everyone would know about it, I think.

I've assumed that Vit D deficiency and other vitamin deficiencies can add additional symptoms and can be quite common in ME as people can't get out or find it hard to get good quality foods. Hence solving these problems can reduce some additional symptoms and appear to help a little rather than dealing with the actual problems.

 

[chronix]

I've assumed that Vit D deficiency and other vitamin deficiencies can add additional symptoms and can be quite common in ME as people can't get out or find it hard to get good quality foods. Hence solving these problems can reduce some additional symptoms and appear to help a little rather than dealing with the actual problems.

Vitamin D, which isn't really a mineral but a steroid, plays a role in the immune system. The low levels seen in CFS is probably not due to a deficiency but rather downregulation since we usually have high levels of 1,25 dihydroxy, the active form of vit D.

 

[tatt]

I vitamin if D deficiency significantly contributed to cases of ME then those might not respond to rituximab but I see that as vanishingly unlikely. Vitamin D replacement is very easy and if it really made a major difference in ME everyone would know about it, I think.

Sadly nothing with ME is that simple. If vitamin D supplementation had an impact on ME the effect would probably be gradual. Although supplying vitamin D would be cheap there are no drug companies to push for trials and to the best of my knowledge the impact of supplementation has not been studied. I believe it's acknowledged now that vitamin D may have effects beyond bone density (and in particular on autoimmunity) but there are few studies of supplementation. Dr Gominak has suggested that it may be necessary to stay within a certain range - so that excessive supplementation may also be damaging. That would mean more care in planning any trial. She was talking of trying to arrange trials for neurological problems, although not specifically for ME.


Thank you for your comments and thanks to MeSci for the research paper. Personally I don't have high levels of 1,25 dihydroxy and deficiency is quite common in Britain, although probably not as much this year as last.

 

[Legendrew]

Sadly nothing with ME is that simple. If vitamin D supplementation had an impact on ME the effect would probably be gradual. Although supplying vitamin D would be cheap there are no drug companies to push for trials and to the best of my knowledge the impact of supplementation has not been studied. I believe it's acknowledged now that vitamin D may have effects beyond bone density (and in particular on autoimmunity) but there are few studies of supplementation. Dr Gominak has suggested that it may be necessary to stay within a certain range - so that excessive supplementation may also be damaging. That would mean more care in planning any trial. She was talking of trying to arrange trials for neurological problems, although not specifically for ME.


Thank you for your comments and thanks to MeSci for the research paper. Personally I don't have high levels of 1,25 dihydroxy and deficiency is quite common in Britain, although probably not as much this year as last.

I suspect that these vitamin and nutritional deficiencies are likely a downstream symptom of the condition for some people, which would explain the plethora of different deficiencies observed yet seeming lack of consistency across the wider ME group. Perhaps this is a consequence of dysfunctional gut motility and digestion that some seem to suffer with, if this is a downstream effect however any supplementation may help very slightly but is unlikely to have a broader effect on the disease process - the only way to solve the majority of problems is to continue heading upstream until the undesirable dam can be identified.

One question I do have however it why rituximab is the monoclonal antibody of choice at the moment for ME. Certainly the use of the drug by Fluge and Mella in their trials is the likely reason this drug is being pursued and perhaps its fairly well understood risks and method of action are a helpful factor in further research and trials, but I do wonder whether it would be worthwhile for further trials to use similar monoclonal antibodies, it could be helpful to see what works and what doesn't and would likely help with the formulating of the mechanism at play although given the choice I think sticking with the current line of research is the best bet, perhaps further research with different drugs is a few steps down the line once the mechanism is better understood.

 

[user9876]

One question I do have however it why rituximab is the monoclonal antibody of choice at the moment for ME. Certainly the use of the drug by Fluge and Mella in their trials is the likely reason this drug is being pursued and perhaps its fairly well understood risks and method of action are a helpful factor in further research and trials, but I do wonder whether it would be worthwhile for further trials to use similar monoclonal antibodies, it could be helpful to see what works and what doesn't and would likely help with the formulating of the mechanism at play although given the choice I think sticking with the current line of research is the best bet, perhaps further research with different drugs is a few steps down the line once the mechanism is better understood.

Just to demonstrate my ignorance what do the other monoclonal antibodies do? Do they also take out b-cells by the same of different mechanisms? In which case I don't see how they would tell us much is anything about mechanism.

 

[tatt]

I suspect that these vitamin and nutritional deficiencies are likely a downstream symptom of the condition for some people, which would explain the plethora of different deficiencies observed yet seeming lack of consistency across the wider ME group. .

Possibly. Some problems - lack of restful sleep, magnesium deficiency, low levels of 1,25 dihydroxy - are actually quite common across the ME group. Unlike an earlier poster I have no objection to drug therapies but if rituximab proves effective it isn't likely to be available for years.

 

[Guido den Broeder]

Edwards said ::
I had not seen the Tan paper before. The question is why it was never followed up. Presumably it did not prove repeatable?

If its one thing I know about CFS research is that so many interesting papers have been produced , but no-one follows them up. The reasons are various - mainly funding. It has always saddened me to see this. So please don't presume anything Prof Edwards. Maybe email Tan yourself to find out - that is the only sure fire way of finding things out in a field like this.
The reduced blood volume work of Bell & Streeton was stunning, but it too was never followed up (Streeton died and Bell retired) . Each CFS research group are chewing away at their own part of this elephant, then if funds dry up no one seems to ever pick up the loose ends. Its just the way its been I'm afraid.

Reduced blood volume has been confirmed by cardiologist dr. Frans Visser in Amsterdam, still unpublished though.

 

[Sasha]

Jonathan Edwards - there's an interview from 2010 with Dr Lerner on his treatment of patients with antivirals, including his ideas on how B cells infected with EBV (or fragments? he lost me) are involved. All way over my head, as usual.

http://phoenixrising.me/archives/11860

Dr Kogelnik, of course, wants to do a US Rituximab 2x2 RCT with Valcyte in the other arm. I wonder if this theory of Dr Lerner's is behind that.

 

[Firestormm]

Jonathan Edwards

Good luck with the trip to Norway this week.

I sure hope you'll be able to share your experiences with us when you are able

 

[aimossy]

I just read this whole thread from start to finish. I am completely wiped out. also I have put a like on most of Prof Edwards' posts. I probably clogged his alert box with them! hehe! Exhausting myself was completely worth it and it is all thoroughly informative productive stuff!