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

[MsJustice]

No problemo. I Googled is all but I agree it would be good to look at symptom resolution from the patient perspective - as we were talking of before. Sometimes it can get lost in the science

There was the video from Norway - did you see it - one of those responders on Ritux in the initial trial. She was filmed kayaking I believe - though am no expert. Could have been a canoe for all I know

No, I haven't seen that video. Is it on youtube?

 

[Jonathan Edwards]

I'm quite curious myself about a possible role of interferon in ME. As a longtimer I remember over two decades ago it was a prime suspect with quite a number of papers still in the archives I believe suggesting interferon as the cause of most ME symptoms. I'm even more curious now after reading a 2012 paper from researchers in Amsterdam describing an interferon [gene expression] signature used to predict non-responders to rituximab in RA. Are you by any chance familiar with their work and interferon signature and might something like that be helpful in trying to sort out which ME patients may respond to rituximab?

Sorry, I have not read up in detail about this yet. I am aware that interferon is on the agenda. We now know a lot more about alpha interferon, which might be important, but I only know about it in limited contexts.

 

[Bob]

Jonathan Edwards, thanks again for all of your thoughts and information.
This discussion thread is becoming ever more interesting, and intriguing, thanks your's and everybody's contributions.

Your thoughts re thyroid issues are interesting. I fully follow your logic, regarding the relationship between antibodies and various signs/symptoms.

I had my major ME relapse a few months ago, and that's when my (apparent) thyroid symptoms started fluctuating wildly, and the bog-standard test results came back normal very recently. I thought my doctor said she was going to get some anti-body tests done this time, and I haven't yet discussed the results, except that I've been told they are 'normal'. I'll get a copy of the test results this week.

Regarding how long the antibodies last, would we have any idea about this from how long it takes a symptomatic flare-up to recede? After a flare-up, my symptoms tend to start improving very slowly over a period of months, and then there is continued slow improvement over a period of years, if I pace myself very carefully. And when relatively stable, I can increase my activity levels very gradually without major relapse. Do you think (hypothetically) this might suggest that my anti-bodies last for a number of months?

 

[Esther12]

Only untreated thyroid disorders are exclusionary criteria for ME/CFS.

But still, I know a few people who escaped their ME/CFS on account of being diagnosed with an under-active thyroid, even though they still had on-going symptoms with treatment. A lot of people are keen to get rid of a diagnosis of ME/CFS.

edit: Edited to remove someone else's medical tale of woe.

OK, so since I am no longer registered as a medical practitioner and should not be handing out personal advice anyway I will explain my general interest in the thyroid and ME.

Doctors love to have simple explanations.

A desire for a simple explanation has caused a lot of harm to ME/CFS patients imo. Especially as, while patients may prefer simple stories that make their lives easier, those with power over them often prefer simple stories that make patient's lives more difficult. It's not hard to guess which stories end up affecting how patients are treated.

Jonathan Edwards:

Without wanting to ask for individual medical advice, for patients who have underactive thyroids, and have ongoing symptoms with treatment, would they be likely to receive any additional worthwhile treatment through the NHS, if they were to ask for the antibody testing you mentioned?

 

[Jonathan Edwards]

I had a quick look at the paper from Cor Verweij's group on interferon signature. To be honest I am not sure what to make of interferon related gene expression in total peripheral blood cells in relation to RA. I suspect it would not tell us much about another disease like ME. Can't really connect up.

As for TH17 I am not sure that this is a helpful category in humans. IL-17 certainly exists but these TH subgroups look a bit arbitrary to me and people spend far too much time arguing about them when the problem in front of us is a disease with abnormal B cell behaviour (antibodies). IL-17 may well be crucial to one autoimmune disease or other but I haven't seen where yet.

 

[Jonathan Edwards]

Your thoughts on time course sound logical Bob.

And for Esther12, I am not overoptimistic that getting antibody results would change the approach to people with underactive thyroids in NHS endocrinology clinics. If doing more means giving rituximab then we are still at the starting blocks I think.

 

[Snow Leopard]

I'm not certain that it's a large subset. I thought it was quite a small subset, but slightly larger than the general population. Do you happen to have any stats? (I can't find any, but I have come across them before.).

You're right, I don't know why I phrased it like that, I guess I was being quite liberal. Heh.
How about a' small but notable subset'?

 

[MeSci]

So the story for autoimmune hypothyroidism is that you make autoantibodies to thyroid proteins, these interfere with thyroxine production and you feel lousy because you are hypothyroid (low thyroxine). But hang on a minute, for some odd reason it is well known that it takes many weeks for a lot of people to get better on replacement thyroxine and some never seem to feel much better (they are regarded as being a bit unhelpful by the doctor). Thyroxine acts within hours. Maybe some of its actions would require clearing away accumulations of 'myxoedema' over weeks but most patients d not have much myxoedema these days. And I have seen at least one case where the patient felt lousy before the thyroxine levels went down. Also the books say that the condition often starts with a flu-like illness - which does not make sense in thyroxine terms at all.

If you look at the other form of autoimmune thyroiditis it becomes clear that it is seriously oversimplifying to blame thyroxine for all the symptoms. Thyroxine makes people jittery and hot but what about the eyes being pushed forward by swollen fatty tissue in the orbit, or lumps on the shins or fat ends to the fingers? These do not occur if you just give people too much thyroxine; they are something to do with other aspects of what the autoantibodies are doing.

So about fifteen years ago I came to the conclusion that the 'flu'ish feeling that people with autoimmune hypothyroidism often complain of may well have nothing to do with low thyroxine. After all, if you have active inflammation in your thyroid you might expect to feel a bit crummy. It may be hard to separate the 'flu'ish aspects from the sleepiness due to low thyroxine but if things are complicated then we need to think complicated.

So my thought would be that anyone with anti-thyroid antibodies with a normal thyroxine level who feels ill may well feel ill because of the direct effects of the antibodies. In this case the antibodies may not be stopping thyroxine production but they may still be having an effect. If autoantibody production is a cycle that involves interference with B cell regulation then presumably antibodies to thyroid proteins have some sort of knock-on effect on immune regulation - and maybe that is what is causing the symptoms, through upsetting cytokine levels, in a way that does not depend on actual thyroxine levels. This is speculation but it is the sort of speculation that got us somewhere last time.

The problem now is that all doctors assume that you do not need to know about the antibodies because all that matters is the thyroxine level. The antibodies can be tested for in any standard general hospital immunology service but I suspect most GPs would not bother. This is partly because a small proportion of perfectly healthy people have these autoantibodies - may be in this case the loop does not trouble either the thyroid or the cytokines because the antibodies are binding in a slightly different way (as I said before antibodies can mimic more or less any patterns of function you like). This means that someone with thyroid antibodies does not necessarily need any medical treatment. However, if I had thyroid antibodies I would want my thyroxine levels checked every now and again because we know that the antibodies can change their effects - from down to up or up to down - over time (clonal drift again it would seem). And if I felt fatigued and virusish I would suspect the antibodies might have something to do with it. It is probably safe to say that the symptoms associated with antithyroid antibodies and low or normal thyroxine levels are mostly not very severe, but maybe in a few cases they are very severe and because nobody sees the connection the conclusion is that the person has 'ME' unrelated to the antibodies. Maybe this is an important subset of ME (because it is not in fact hypothyroidism). It might respond well to rituximab if it was but if the antibodies are long lasting bone marrow ones it might not. So there is a lot to think about.

Interestingly, the only time an endocrinology colleague came to ask me about maybe treating thyroid patients with rituximab it was to try to deal with the thyroxine-unrelated eye problems. Dealing with the thyroxine is easy, but not the other aspects of Grave's disease.

Could a lack of response to administered thyroxine be because of a lack of, or inefficient, thyroid hormone receptors?

I am greatly appreciative of the opportunity to have discussions with a practising scientist - hope we are leaving you enough time to actually do the science!

Maybe we should chip in to pay you a retainer as a scientific advisor!

 

[Gemini]

Do you mean this one?

http://www.ncbi.nlm.nih.gov/pubmed/22540992
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3446469/

Arthritis Res Ther. 2012 Apr 27;14(2):R95. doi: 10.1186/ar3819.
The interferon type I signature towards prediction of non-response to rituximab in rheumatoid arthritis patients.

Yes, that's the one.

 

[Jonathan Edwards]

Could a lack of response to administered thyroxine be because of a lack of, or inefficient, thyroid hormone receptors?

A lack of, or inefficient, receptors would presumably have to be either genetic or due to something interfering. If it was genetic then the person would seem hypothyroid from birth so it would have to be due to something interfering. In the context that would seem to have to be an antibody. I think that is possible for Grave's disease in which either the thyroid or the pituitary seems to think that there is not enough thyroxine around and overproduces but that is the wrong way up. For autoimmune hypothyroidism it wouldn't seem to make a unified story, but then maybe it's complicated. My impression is that the symptoms that do not settle are not particularly ones we know are due to lack of thyroxine (like slow pulse and sleepiness). But my experience with thyroid problems was largely as a side issue in patients who came to me with joint problems and that may bias the picture.

 

[Gemini]

Yes, that's the one.

Another interesting paper coming out of Amsterdam 2013...could be a significant advance

http://www.ncbi.nlm.nih.gov/pubmed/23434571

The type 1 INF signature as a biomarker of preclinical rheumatoid arthritis

 

[Kate_UK]

It might respond well to rituximab if it was but if the antibodies are long lasting bone marrow ones it might not.

So if the bad antibodies come from the bone marrow, rituximab can't fix that? What can?

 

[Jonathan Edwards]

So if the bad antibodies come from the bone marrow, rituximab can't fix that? What can?

It's a bit more complicated. Going back to the Samurai analogy it looks as if in RA there are long lived plasma cells in the bone marrow that make antibodies that can keep the cycle going, but also short lived plasma cells (we think in spleen) making the antibodies that directly cause most of the inflammation. Repeat rituximab therapy can keep people well even if the long lived plasma cells hang on in the background but the more times rituximab is used the more likely it is that useful antibody levels will drop. So if total antibody levels drop my colleagues tend to switch to another drug.

If we want to get rid of long lived plasma cells it seems we need something that actually kills them, rather than waiting for them to die. Nobody has found a good drug to do this, which is why the plasma cell disease called myeloma is so tough to treat. However, we know that under some circumstances all plasma cells will die. With rare reactions to certain drugs and in fact sometimes after rituximab total antibody levels just hit rock bottom - indicating all plasma cells are dead. This would seem to be just what we need. But we do not know why this happens when it does. We also have the tricky situation (now you can see how complicated rituximab usage is) that we have wiped out all the plasma cells but we also have to wait for six months for any B cells to come back. It may be fine to kill off all the old Samurai masters to get rid of the rogue ones but it seems risky to shut the doors of the School at the same time. We might need a few new cadets to train up quick to deal with some infections. The other thing that is of concern is that occasionally after rituximab B cells do not come back for 5 years. It does not seem to matter if there are still plasma cells but with no plasma cells and no B cells replacement immunoglobulin therapy may be be needed and that is expensive and very hard going for the patient.

So the irony is that there may be ways to get rid of the plasma cells. There are some drug combinations that seem to knock down antibody levels rather routinely. But without knowing that we can hit the plasma cells but keep B cell backup it is hard to justify pushing hard along this line. It might be justified for cancer but this problem does not arise for cancer, only for autoimmunity, so it is up to my rheumatological colleagues to take the risk. The view at the moment is, I think, that we do not have enough information to justify an all out attack on B and plasma cells together. Maybe what we need is to harvest and freeze down precursor cells that we can give back to the patient but this would be complex. We also still have no idea why rituximab removes B cells for 6 months. So there's work to do. Unfortunately, I doubt the pharmaceutical companies are very interested in doing it.

 

[Legendrew]

A few more thoughts i've had:
Many patients (myself included) had a very acute onset with symptoms more flu like initially which then develop/change over time into the more chronic type symptoms. Speaking from personal experience, at onset my main symptoms were terrible nausea, vomiting, malaise and fatigue. As this year progressed though my symptoms have changed towards more headaches/migraines, Disupted sleep/insomnia, Internal tremor and the PEK. Is this acute/chronic change something seen in any other autoimmune diseases? I dont think ive heardof it myself. It is of note also that for some the onset is very gradual so perhaps it would be of use to see whether the type of onset has an effect upon response to rituximab.
Another thought ive had is in regard to many people attributing contined exertion after onset to further duration and intensity of symptoms. Could this be explained by further exertion leading to an increased concentration of an autoantibody over time? This could further explain why the PEM effect intensifies with contined overexertion and why after periods of rest people are able to do more as the antibody load is lower as a direct response to the smaller volume of the antibody target being released.
Andrew (sorry if some of this doesnt make sense as im using my phone)

 

[Jonathan Edwards]

Many patients (myself included) had a very acute onset with symptoms more flu like initially which then develop/change over time into more chronic type symptoms. At onset my main symptoms were terrible nausea, vomiting, malaise and fatigue. As this year progressed though my symptoms have changed towards more headaches/migraines, disrupted sleep/insomnia, internal tremor and the PEM. Is this acute/chronic change something seen in any other autoimmune diseases? Perhaps it would be of use to see whether the type of onset has an effect upon response to rituximab.

Good thought. In scleroderma there is what is called an 'early puffy phase' which can be acutely inflamed and painful, whereas the rest of the time the illness is almost non-inflammatory. In thyroiditis it is said that there is sometimes an early flu like phase. Rheumatoid arthritis can present with a very acute phase, and some say the long term outlook is better with a sudden onset. But in general I think the situation is unclear. ME does seem to be more associated with a trigger event, at least in some cases. If the vicious cycle model for autoimmunity is right then the mechanism of the cycle is slightly (or very) different for each case so we probably should not expect to draw conclusions.

Another thought ive had is in regard to many people attributing contined exertion after onset to further duration and intensity of symptoms. Could this be explained by further exertion leading to an increased concentration of an autoantibody over time? This could further explain why the PEM effect intensifies with contined overexertion and why after periods of rest people are able to do more as the antibody load is lower as a direct response to the smaller volume of the antibody target being released.

That makes sense but I do not know of an example where we actually know it happens. There may not be any other autoimmune processes in which the target molecule is something produced from time to time. In most of them the target molecule is plentiful all the time. Maybe that would be important. It's worth pondering over I think.

 

[Legendrew]

That makes sense but I do not know of an example where we actually know it happens. There may not be any other autoimmune processes in which the target molecule is something produced from time to time. In most of them the target molecule is plentiful all the time. Maybe that would be important. It's worth pondering over I think.

If that was the case you could draw similarities with celiac disease where i believe the immune response is targeted against gliadin (amongst a few other things) - interesting the immune response itself doesn't cause the celiac symptoms, the triggered inflammatory reaction however causes damage to the intestinal villi. If something similar is happening in ME/CFS perhaps a similar inflammatory reaction is occurring within an organ or tissue in response to a molecule produced after mental or physical exertion. I believe you mentioned in one of your previous posts the large number of changes occuring following excersise and many of these will occur through the secretion of different chemical signals and hormones any of which could be a potential target, As i've mentioned before I believe the sensory nervous system and specifically vagus nerve are effected so perhaps the inflammation occurs her although it has to be said I don't have anything to support this idea.
This could explain why people feel better when not overexerting themselves but never entirely well as such a chemical is always going to be secreted to some degree whereas the gliadin in celiac is not something produced by the body hence a gluten free diet serves as a good treatment.
Andrew

 

[lansbergen]

Would local fatique fit in your model?

I know it sounds crazy but I have been monitoring it now for a long time and it happens time after time from the place of activation to the perifere.

Smearing the spot with levamisole or benzydaminehydrochloride cream lessens it.

 

[Kati]

Dr Edwards, many thanks for engaging with patients. Will tickle your scientific bone here by bringing to light this interesting paper from the RA world

http://www.ncbi.nlm.nih.gov/pubmed/20547657


Rheumatology (Oxford). 2010 Oct;49(10):1911-9. doi: 10.1093/rheumatology/keq159. Epub 2010 Jun 14.
Epstein-Barr virus in bone marrow of rheumatoid arthritis patients predicts response to rituximab treatment.
Magnusson M, Brisslert M, Zendjanchi K, Lindh M, Bokarewa MI.
Source
Department of Rheumatology and Inflammation Research, Sahlgrenska University Hospital, Guldhedsgatan 10A, 413 46 Göteborg, Sweden. mattias.magnusson@rheuma.gu.se
Abstract
OBJECTIVES:
Viruses may contribute to RA. This prompted us to monitor viral load and response to anti-CD20 therapy in RA patients.
METHODS:
Blood and bone marrow from 35 RA patients were analysed for CMV, EBV, HSV-1, HSV-2, parvovirus B19 and polyomavirus using real-time PCR before and 3 months after rituximab (RTX) treatment and related to the levels of autoantibodies and B-cell depletion. Clinical response to RTX was defined as decrease in the 28-joint disease activity score (DAS-28) >1.3 at 6 months.
RESULTS:
Before RTX treatment, EBV was identified in 15 out of 35 patients (EBV-positive group), of which 4 expressed parvovirus. Parvovirus was further detected in eight patients (parvo-positive group). Twelve patients were negative for the analysed viruses. Following RTX, EBV was cleared, whereas parvovirus was unaffected. Eighteen patients were responders, of which 12 were EBV positive. The decrease in the DAS-28 was significantly higher in EBV-positive group compared with parvo-positive group (P = 0.002) and virus-negative patients (P = 0.04). Most of EBV-negative patients that responded to RTX (75%) required retreatment within the following 11 months compared with only 8% of responding EBV-positive patients. A decrease of RF, Ig-producing cells and CD19(+) B cells was observed following RTX but did not distinguish between viral infections. However, EBV-infected patients had significantly higher levels of Fas-expressing B cells at baseline as compared with EBV-negative groups.
CONCLUSIONS:
EBV and parvovirus genomes are frequently found in bone marrow of RA patients. The presence of EBV genome was associated with a better clinical response to RTX. Thus, presence of EBV genome may predict clinical response to RTX.

I am curious to hear your perspective as whether Rituximab in ME would have a etter response if there was EBV involvement and whether performing bone marrow biopsies could bring more information to the table in patients with ME, especially in the light of a Rituximab trial.

Also you may know that Lake Tahoe ME expert Dan Peterson performs spinal taps on his ME patients and routinely finds "stuff" that shouldn't be present in spinal fluid, notably viruses. Is that something that has been done on RA patients as well?

 

[Helen]

No, I haven't seen that video. Is it on youtube?

Sorry, only in Norwegian but at the end you will see a girl, now energetic going out in a canoe. She had been mostly bedridden for 9 years.

 

[Sasha]

Jonathan Edwards - following on from Kati's post there, is EBV rather than the other herpes viruses such as CMV and HHV-6 a bit of a suspect in RA and/or other autoimmune diseases? I'm curious because Valcyte and Rituximab are proposed as treatments in a 2x2 RCT in ME planned by Dr Kogelnik, as I'm sure you know, and I thought that was because of the possibility of CMV and HHV-6 involvement in ME, not just EBV (I think the US clinicians favour other antivirals for EBV rather than Valcyte).