My Rituximab experience for ME

[Jonathan Edwards]

I always find your answers very interesting, Prof, Edwards, but they always make me want to ask more questions...how can autoantibodies cause disease in some cases but not in others? You said in the other thread that there is not a direct correlation to the level of antibodies, so is it a binding thing?

One starts off as a medical student with the simple idea that any antibody to self will cause harm. But then you have to think of the effector mechanism. And it turns out there about a dozen major pathways. And it also turns out that none of them will necessarily get engaged, or even if they do, cause any trouble. Just an antibody sticking to something is just an antibody stuck to something. To cause trouble there would need to be cytokine triggering or complement cascade activation or blocking of function or apoptosis or whatever. The autoantibodies I know most about are rheumatoid factors and when I realised I did not really know what to expect them to do I built CADCAM (computer assisted 3D printing) models from crystal structures and started joining them up. It became clear that it all depended on where the antibody bound to its antigen, how many binding sites were available, where complement might engage, where Fc receptors might engage, and on to more questions than one could hope to answer. And you cannot even just answer for one antibody because effects are likely to be dependent on different complementary antibodies binding to different parts of the same antigen. The immune system makes a lot of use of rules about how many sites you need to bind to activate pathways. This is probably a way of stopping individual rogue antibodies causing havoc.

So the simple idea that any antibody that binds to self will cause disease is way off target.

 

[msf]

Well, I haven´t even started on my medical career yet, so you´ll have to forgive me.

 

[Eeyore]

@msf - I'm finally at a point where I do understand the cause of my ME on a molecular level. It is not infectious for me. It is genetic and it is autoimmune/autoinflammatory/immune dysregulatory. In my case, I can now explain all my symptoms with lab and genetic testing and I understand the mechanisms of my own disease.

Mine started with a nasty virus, like so many other people's ME. It looks the same as for everyone else with it. I have the common exercise abnormalities of low VO2 Max and low AT and I have the same exercise intolerance as everyone else. I have the autonomic symptoms and signs, POTS, sleep disorders, etc. I'm hypothyroid. I even ran a fever for 2 yrs after getting sick - and spent much of my earlier years with the illness believing there was an infection to be found, since I felt fine, then got sick, then never felt fine again. However, after really looking hard, there is no infection. It was a red herring - a wild goose chase.

I can't say everyone is the same as I am, but I have very good reason to suspect that a substantial subset shares the basic pathology that I have.

 

[msf]

Me too, and I´m 95% sure that mine has an infectious component. So either we have two very different diseases, or one of us is wrong.

 

[msf]

Oh, and how do you know it was a virus?

 

[Eeyore]

@msf - I developed obvious clinical signs of infection, including prolonged high fever. Blood work the night I got sick in the ER showed lymphocytosis, a hallmark of viral infection. A number of other symptoms were consistent with viral etiology. I do not know what virus. It was not EBV or CMV though, as I tested negative then (and do now) for both of those. It was summer, so it was likely an enterovirus. The symptoms were consistent. I was sent home and told to follow up with my doc.

I am skeptical of anyone who says that the cause is an ongoing infection. I believe that the vast majority of us had an infectious trigger. I doubt that any particular infection is central to ME, or that a substantial number of patients actually have ongoing, active infection.

There are diseases that are triggered by infection, such as reactive arthritis and guillain-barre syndrome that are not infectious. ME is more like these. Also, an infectious etiology is entirely incompatible with the efficacy the Norwegians are getting right now with rituximab - so at least in the majority of patients, infection is not the key problem. Infection would get worse with rituximab, not better (and you'd see patients getting very ill as you immunosuppressed them while they fought infection). We don't observe this. Even the patients who don't respond are not showing severe severe complications. They aren't dying of infections because of the immunosuppression.

In contrast, if you were dealing with a chronic infection, immunosuppression would be the last thing you'd want to do - e.g. HIV, HCV, HBV, HTLV-1/2, active EBV/CMV/HHV6/VZV, etc. Patients would get much worse and possibly die.

I'm not just 95% sure. I have objective medical testing now that shows exactly what is wrong with me. I'm not sure that we have the same thing of course - but my point is that I too was quite convinced I had an infection for many years, and I was wrong. It's not hard to see how ME patients get to that conclusion - but I think it's generally incorrect, although I cannot say with certainty that it is true for all of them, I believe the rituximab trials, unless they are a statistical fluke, almost completely rule out any chance that the disease is primarily infectious in nature in the majority of ME patients.

 

[msf]

Prof. Edwards will disagree, but Reactive Arthritis is now seen by many as being caused in some way by the persistence of the triggering organism. The etiology of Gullain-Barre syndrome is not known.

I have also had objective medical testing.

http://pediatriceducation.org/2013/06/24/what-causes-lymphocytosis/

Quite a lot of non-viruses on that list.

 

[Valentijn]

I have objective medical testing now that shows exactly what is wrong with me.

Can you tell us what the problem is in your case? Or maybe I just missed it

 

[msf]

Anyway, I feel we are unlikely to convince each other, so let´s just wait and see, there is a lot of research coming out at the moment!

 

[Eeyore]

@msf - The signs and symptoms of acute viral infection and acute bacterial infections are different, and doctors can generally distinguish them. It's not just about the lymphocytosis.

I have to agree with Dr. Edwards on this one. The evidence is overwhelming that reactive arthritis is autoinflammatory and genetic, not infectious. It's a combination of genetic factors and exposure to certain pathogens. It can even follow vaccination in some cases (for example, BCG, which is not a live vaccine and has no potential to cause active infection).

The etiology of GBS is rather well understood; there is a lot of information on it out there, and we have a pretty good idea what is going on. There are 2 pathogens that tend to trigger it - campylobacter jejuni and CMV. It's a rare case where we have conclusively demonstrated that molecular mimicry is at the root of the disease, as c. jejuni actually displays gangliosides on its surface that are identical to those on human neurons. GBS presents a few weeks after the infection is fully cleared (in the case of c. jejuni) and cultures are uniformly negative for the bacterium. Over time, the antibodies disappear in most patients, and they do not follow a chronic course - most recover fully or nearly so and do not have relapses - without exposure to the antigen, they do not continue to make the antibodies that cause the nerve cell damage that we see in GBS.

Ultimately, msf, you are free to believe what you like. I just hope that you will be openminded to the possibility that there is no infection in your case, and that something else is wrong. No one doubts you are ill on these boards - we're in the same boat. I just know I wasted a long time looking for an infection that was not there. I hope you won't do the same.

 

[Eeyore]

@Valentijn - I'm trying to figure out how to do that. I had some pieces of the puzzle, but only got the last few very recently (within the week). I'm not sure how to proceed at this point. I think it should be investigated in other patients.

I am going to be talking to a non-ME doc about trying rituximab soon - I'll let you know how that goes.

 

[msf]

If doctors can distinguish them, why do they need tests (like they have in the UK) to tell bacterial and viral infections apart?

I think Prof. Edwards will also disagree with you then, I don´t think he believes in molecular mimicry. Negative cultures are not proof that the triggering organism has gone.

http://www.mayoclinic.org/diseases-conditions/guillain-barre-syndrome/basics/causes/con-20025832

You should write to the Mayo clinic and tell them to update their page.

 

[msf]

Oh, and there is a chronic version, it just has a different name: http://www.ninds.nih.gov/disorders/cidp/cidp.htm

 

[Valentijn]

You should write to the Mayo clinic and tell them to update their page.

Mayo is not a reliable authority on medical issues, unfortunately, as is evidenced by the tragic state of their pages regarding CFS.

 

[Eeyore]

@msf - You can believe what you like.

I suppose there is a small chance that it was a bacterial infection, but the symptoms really do not fit. I did have medical testing done that night. The conclusion of the doctors, and I agree with it, was that I had a viral infection, but the exact virus was not determined.

Yes, there is a chronic version of GBS, CIDP, as well as multiple acute forms of GBS (e.g. AIDP, AMAN, AMSAN, etc.) There are reasons that that occurs, and we know at least some of them. It is partly genetic in cause, and partly based on the strain of pathogen.

What the Mayo Clinic is saying is that the disease is incompletely understood - which is true of EVERY disease. Cancer and heart disease are not completely understood. Even the flu is not. We are always somewhere between knowing nothing and knowing everything. This does not mean we know nothing. It is well accepted that GBS and CIDP are not chronic infectious conditions, as it is well accepted that reactive arthritis and the other spondyloarthropathies are not infectious.

 

[msf]

Very kind of you.

 

[msf]

There is not much data on this at all, so I thought this review was quite interesting: http://www.researchgate.net/publica...vasculitis_in_the_setting_of_severe_infection

As Prof. Edwards has mentioned before, Ritux on its own does not seem to be that dangerous in regard to infections.

 

[Tammy]

The reality is that nobody has in fact gathered any information to link viruses as causes to autoimmunity - with maybe a few exceptions (I am not sure I can think of any convincing ones though

Well....like I said before.......apparently those few exceptions (I think there's more than you realize).......may not be convincing enough to you but to enough scientists/researchers to keep this research going.

Most autoimmune diseases have genetic predispositions but the ret of the causation appears to be chance - like in many cancers. And we have very good explanations from within the immune system for why that should be so. The immune system makes antibodies and T cell receptors at random. So I am not suggesting 'no good reason'

Chance? I don't even know where to begin with that that. Obviously I'm missing something. (for another thread)

am not suggesting there is no cause but the idea that we have to have either a genetic or an environmental cause is just plain wrong - the epidemiology textbooks tell us that.

I wasn't aware that the researchers linking virus to autoimmune were even suggesting that...............at least not in the articles that I read.

 

[Eeyore]

@Tammy - The production of antibodies is entirely random. Both the heavy and light chains are produced randomly. Heavy chains are composed of V-D-J regions, chosen randomly from many possible combinations. Light chains are composed of only V and J regions. V stands for variable, D for diversity, and J for joining. Every immunology class involves a study of the details of this process, and you can look up VDJ recombination on wiki if you want details, but the result is that there is a nearly endless array of possible antibodies that can be produced. Each B-cell clone produces only one kind of antibody, with one heavy and one light chain. The variability is so great that we are able to recognize virtually any antigen, but the particular recombination events in each B-cell are random. Similarly, even though they do not produce antibodies, CD4 and CD8 cell clones also have unique, randomly determined receptors. A specific CD4 cell must recognize and activate a specific B-cell, for example, in order for it to proliferate.

Random events in the causation of disease do not preclude genetic or environmental factors. For example, we know that certain chemicals increase the risk of cancer (e.g. benzene, ethidium bromide - the latter is a chemical we use all the time in labs when running agarose gels as it intercalates between the DNA base pairs which allows for visualization of DNA fragments). We also know there are genetic factors that affect cancer risk - for example, there is a condition called Li-Fraumeni syndrome, which is caused by a genetic defect in the P53 gene. Patients almost invariably experience multiple primary cancers by an early age.

Even though these are seen as causes of cancer, ultimately, cancer is ALWAYS a random event. We all have many cancer cells in our body at any time. Normally, our bodies eliminate them before they become a problem. So in the case of benzene or ethidium bromide, you have more cancer cells being created due to the mutagenic potenial of the chemicals - not hard to imagine for a substance that is used to stick in between DNA base pairs. Most are destroyed - but if you have more created, there are better odds one escapes surveillance and survives to become a clinically relevant cancer. In the case of Li-Fraumeni, you don't have more cancer mutations occurring, but the lack of biallelic functional P53 means that more of the cancer cells will survive to become clinically relevant cancers.

In all these cases though, there is a randomness involved. Genetics and environment are risk factors. There is always a degree of randomness in cancer, and the same is true in autoimmunity. We do not see 100% concordance in identical twins for most diseases. There are some genetic diseases with 100% penetrance that you'd see in anyone affected, and there would be 100% concordance between genotype and phenotype, but that is less common than genetics being risk factors that combine with environment and random events to produce an end result.

 

[Tammy]

I have to agree with Dr. Edwards on this one. The evidence is overwhelming that reactive arthritis is autoinflammatory and genetic, not infectious. It's a combination of genetic factors and exposure to certain pathogens

This sounds contradictory to me. ..............when you say certain pathogens..........are you saying pathogens that aren't infectious in that they cant spread?