My Rituximab experience for ME

[Jonathan Edwards]

@Jonathan Edwards
Hi Professor, I understand that most chemotherapy, found it hard to cross the blood brain barrier ... It seems that only a small percentage of heavy and complex molecules of chemo would be able to pass this barrier .. So I ask myself the question: what about for Rituximab especially ? Would you please tell us , in your opinion, how many percent of Rituximab is able to pass the blood-brain barrier to work where it is headquarters of our chronic inflammation? Thanks !

Rituximab does not cross the blood brain barrier very well. But you would not want it to unless you think the B cells are in the brain. The only disease where that seems relevant is MS. Otherwise inflammation in the brain related to antibody production by B cells (and thus treatable with rituximab) will depend on B cells and plasma cells in lymph node and bone marrow. B cells do not occur in inflammation much - they send their antibodies there instead. So I don't think rituximab not getting into brain is likely to be very relevant. In fact it works in MS probably because it kills the B cells outside the brain that are going to be the next lot to get into the brain by mistake. So even there it does not need to get into the brain itself.

 

[Jonathan Edwards]

Limited, oversimplified, and outdated analysis of high IgG titres. The actual analysis says that healthy people can have high IgG titres, particularly within a decade or two of the original infection. In that case, high titres only mean that the individual has developed immunity from a past infection and antibody production has not yet dropped back to normal levels.

Proper analysis says that clinical symptoms should also be considered in the context of high IgG titres. Look it up. If the patient shows symptoms of the infection in question, there is a greater likelihood that the high titre is indicative of a reactivated infection.

Additionally, antibody titres drop over time. That is why older people are advised to get a shingles (chicken pox, VZV, HHV-3) booster. If a patient is decades past the original infection, IgG titres should not be high. Extremely high titres in patients past their 30's are suspicious, particularly in the light of symptoms of the illness, because it is highly unusual to have high CMV or HHV6 titres at that age.

Lastly, high titres are not considered irrelevant if the patient is immune impaired. They are considered a matter of concern in post-transplant patients, HIV patients, and other immune-impaired populations. Since a significant portion of ME/CFS patients are immune impaired, high titres are not irrelevant in ME/CFS and can be indicative of reactivated infections. There's a reason most top ME/CFS specialists use antivirals with a reasonable degree of success.

Broad-based rules of thumb for healthy populations do not necessarily apply to ME/CFS patients. Intelligent professionals use basic principles instead of rules of thumb to analyze complex situations, and know what the limitations of the rules of thumb are when they apply them to simple situations.

Dear SOC, you do not need to teach granny to suck eggs. We were all taught all that as medical students. But nobody said anything about high titres. The point was simply that having IgG to a microbe is not an indication of ongoing infection. Clinical evidence of infection is something different.

 

[funkyqueen]

Rituximab does not cross the blood brain barrier very well. But you would not want it to unless you think the B cells are in the brain. The only disease where that seems relevant is MS. Otherwise inflammation in the brain related to antibody production by B cells (and thus treatable with rituximab) will depend on B cells and plasma cells in lymph node and bone marrow. B cells do not occur in inflammation much - they send their antibodies there instead. So I don't think rituximab not getting into brain is likely to be very relevant. In fact it works in MS probably because it kills the B cells outside the brain that are going to be the next lot to get into the brain by mistake. So even there it does not need to get into the brain itself.

Thank you very much for these interestings informations , @Jonathan Edwards

 

[Eeyore]

@Jonathan Edwards -

How sensitive is CRP for MS? Does it elevate reliably?

 

[Jonathan Edwards]

@Jonathan Edwards -

How sensitive is CRP for MS? Does it elevate reliably?

I have never used it in MS so I really don't know.

 

[deleder2k]

What about anesthesia while on RTX treatment for ME? Is it safe? Or would the risk of infections be a problem? I am talking about general surgery like tonsillectomy, knee surgery, deviated septum reconstruction and so on.

 

[Eeyore]

@SOC -

Actually, reactivated herpesvirus infections are extremely normal in the general / healthy population. They are generally subclinical and not noticed by the patient. Almost everyone is infected with at least one of the 8 known human herpes viruses (counting 6A and 6B as one - which is debatable). They reactivate all the time. If they did not, titers would drop to nothing in a matter of years and immunity would be lost. Rather, the more modern model is that in all infected people (which is always for life, with all herpesviruses) there is a chronic active infection. They've studied the alpha herpesviruses (mostly VZV I think - i.e. chicken pox because of the high morbidity of shingles as people age) a lot in this respect - they are highly neurotropic - and found that infected cells chronically produce low levels of infectious virus which are continuously suppressed. Sometimes reactivations are worse than others, and if it manages to escape the immune system's suppression, shingles can develop (in the case of VZV).

I'm highly skeptical that herpesviruses play an important role in ME, although I believe they can sometimes trigger it. One piece of evidence that I would be looking for would be a substantially higher rate of shingles. I have never heard of an ME patient even getting shingles - although I'm sure there must be some - yet if their ability to control herpesvirus infections were so impaired as to cause an ongoing illness, one would expect to see it frequently. Also, many of us never had any kind of obvious herpesvirus infection at all other than chicken pox as a kid (my mother and I included). No infectious mono (caused by EBV or CMV - some use the term for both), no cold sores, etc. - and these are all common in the population. I did have roseola as a kid, but almost all kids do - and it was neither unusually severe nor prolonged, and I had a generally healthy childhood.

There are so many things that one would predict would be there if ongoing herpesvirus infections were important in ME that are not. Another really obvious one is that studies looking at titers of herpes virus antibodies in ME patients do not show any significant difference vs controls.

Also - there is huge variation in titers in the population, and in individuals over time. This is partly due to reactivations - so I agree with your point that IgG levels would rise with reactivation. I do not agree that high levels indicate any unusual level of reactivation. I do believe that a change off a person's normal baseline could potentially indicate reactivation (although other causes are possible - cytokines that induce production of antibodies are not specific for a given pathogen, so another infection might increase it by general B-cell stimulation).

If anything my experience has been that ME patients do an unusually good job of suppressing viral infections - more suggestive of excessive immune activation and elevated interferons, yet we haven't really succeeded in showing this either. We have shown (Hornig/Lipkin) that in early ME, interferon gamma and other cytokines are elevated, but we have not shown that in long duration ME patients (the opposite being true).

I get sick far less often than most of the people around me. My sister, who never had ME, gets at least 5-10x the number of colds as other random viruses as I do. My mom, who had something that looked very much like ME when younger, but then recovered mostly with some residual dysfunction, almost never gets sick. I can't remember the last time she had a fever - probably over a decade - and she teaches primary school kids. With me, one could argue it's because I'm a shut in and not exposed much, but not with my mom.

There is clearly some evidence that herpes viruses are sometimes the triggers (but not always). That's all the evidence I see though.

 

[Eeyore]

@deleder2k - Dr. Edwards might know something I don't, but I don't think there is any concern with immunosuppression combined with anesthesia. Anesthesia just blocks nerve impulses generally, through a variety of mechanisms (sodium channels, NMDA receptors, GABA receptors, etc.) I suppose there might be some higher risk of some infections with surgery itself, but not tied to the anesthesia.

 

[Jonathan Edwards]

What about anesthesia while on RTX treatment for ME? Is it safe? Or would the risk of infections be a problem? I am talking about general surgery like tonsillectomy, knee surgery, deviated septum reconstruction and so on.

I do not think we have evidence for any major infection problems with surgery during B cell depletion. There is a theoretical increase in infection risk but new antibody responses are probably unlikely to be very important in resistance to standard perioperative infection problems. Something like knee surgery needs careful thought because infection can be a major long term issue but if there were reasons to go ahead with surgery and maintain B cell depletion I do not think there would be any absolute contraindication. It would ultimately be up to the surgeon and anaesthetist to make a clinical judgment.

 

[Eeyore]

@Jonathan Edwards - An ongoing conundrum in ME for me has been that if it is autoimmune, why do we not see any reliable indicators of inflammation? Sed rates are usually very low (which can simply be a depletion of fibrinogen), CRP is normal generally and very rarely if ever elevated in a patient with ME and no comorbidities, and ferritin tends to be very low. None of the acute phase proteins seem to be reliable indicators for ME - which has been part of the problem.

Some things I've read about MS suggest this may also be true, and so I was wondering if there was a connection, and also if neuroinflammation produces a different acute phase response in peripheral blood due to the BBB.

I think you gave the example before that gout doesn't elevate CRP as it's inflammation, but not cytokine mediated inflammation - although gout does elevate sed rate if I recall correctly. In your experience as a rheum, have you noted autoimmune/autoinflammatory diseases without any elevated acute phase markers of inflammation?

 

[Jonathan Edwards]

@Jonathan Edwards - An ongoing conundrum in ME for me has been that if it is autoimmune, why do we not see any reliable indicators of inflammation? Sed rates are usually very low (which can simply be a depletion of fibrinogen), CRP is normal generally and very rarely if ever elevated in a patient with ME and no comorbidities, and ferritin tends to be very low. None of the acute phase proteins seem to be reliable indicators for ME - which has been part of the problem.

Some things I've read about MS suggest this may also be true, and so I was wondering if there was a connection, and also if neuroinflammation produces a different acute phase response in peripheral blood due to the BBB.

I think you gave the example before that gout doesn't elevate CRP as it's inflammation, but not cytokine mediated inflammation - although gout does elevate sed rate if I recall correctly. In your experience as a rheum, have you noted autoimmune/autoinflammatory diseases without any elevated acute phase markers of inflammation?

I think we have discussed this before and my answer was a bit different! Gout gives you a huge CRP rise - it can be over 100. But in lots of autoimmune processes the autoantibody effector mechanism is not through Fc receptor ligation or complement activation so there is no reason to get any signs of inflammation. If the antibody just interferes with a biological function you get the effect with no inflammatory signs. Thyrotoxicosis is a simple example, or myasthania gravis, or Addison's disease or ITP or anti-factor VIII syndrome. In all of these you sometimes get some inflammatory pathways tickled up but the main disease mechanism is nothing to do with inflammation.

 

[heapsreal]

@SOC -

Actually, reactivated herpesvirus infections are extremely normal in the general / healthy population. They are generally subclinical and not noticed by the patient. Almost everyone is infected with at least one of the 8 known human herpes viruses (counting 6A and 6B as one - which is debatable). They reactivate all the time. If they did not, titers would drop to nothing in a matter of years and immunity would be lost. Rather, the more modern model is that in all infected people (which is always for life, with all herpesviruses) there is a chronic active infection. They've studied the alpha herpesviruses (mostly VZV I think - i.e. chicken pox because of the high morbidity of shingles as people age) a lot in this respect - they are highly neurotropic - and found that infected cells chronically produce low levels of infectious virus which are continuously suppressed. Sometimes reactivations are worse than others, and if it manages to escape the immune system's suppression, shingles can develop (in the case of VZV).

I'm highly skeptical that herpesviruses play an important role in ME, although I believe they can sometimes trigger it. One piece of evidence that I would be looking for would be a substantially higher rate of shingles. I have never heard of an ME patient even getting shingles - although I'm sure there must be some - yet if their ability to control herpesvirus infections were so impaired as to cause an ongoing illness, one would expect to see it frequently. Also, many of us never had any kind of obvious herpesvirus infection at all other than chicken pox as a kid (my mother and I included). No infectious mono (caused by EBV or CMV - some use the term for both), no cold sores, etc. - and these are all common in the population. I did have roseola as a kid, but almost all kids do - and it was neither unusually severe nor prolonged, and I had a generally healthy childhood.

There are so many things that one would predict would be there if ongoing herpesvirus infections were important in ME that are not. Another really obvious one is that studies looking at titers of herpes virus antibodies in ME patients do not show any significant difference vs controls.

Also - there is huge variation in titers in the population, and in individuals over time. This is partly due to reactivations - so I agree with your point that IgG levels would rise with reactivation. I do not agree that high levels indicate any unusual level of reactivation. I do believe that a change off a person's normal baseline could potentially indicate reactivation (although other causes are possible - cytokines that induce production of antibodies are not specific for a given pathogen, so another infection might increase it by general B-cell stimulation).

If anything my experience has been that ME patients do an unusually good job of suppressing viral infections - more suggestive of excessive immune activation and elevated interferons, yet we haven't really succeeded in showing this either. We have shown (Hornig/Lipkin) that in early ME, interferon gamma and other cytokines are elevated, but we have not shown that in long duration ME patients (the opposite being true).

I get sick far less often than most of the people around me. My sister, who never had ME, gets at least 5-10x the number of colds as other random viruses as I do. My mom, who had something that looked very much like ME when younger, but then recovered mostly with some residual dysfunction, almost never gets sick. I can't remember the last time she had a fever - probably over a decade - and she teaches primary school kids. With me, one could argue it's because I'm a shut in and not exposed much, but not with my mom.

There is clearly some evidence that herpes viruses are sometimes the triggers (but not always). That's all the evidence I see though.

Not sure what you're trying to say but seem to be saying in healthy people herpes viruses reactivate but are controlled by the immune system. Most would agree with that.

but cfsme arent healthy people and usually have a poor functioning immune system shown by many researchers and as mentioned many times before low nk function commonly found in cfsme as well as low cd8 t cell function, is what can allow these herpes viruses to reactivate and turn into a chronic infection in some.

you say that most cfsme haven't been infected by ebv or cmv but say most healthy people have. Maybe theres a reason testing cant find it , in that the immune system cant mount a proper attack. In the early days of lake tahoe many were igg positive with life long antibodies to ebv , later were found to be totally negative. I remember reading this as it also occurred to me. Most drs explain it away as a lab 'error'.

I don't think anyone is saying herpes viruses have to initiate cfsme and or the cause but if ones immune system isnt working then it's very possible that these infections can reactivate in many of us not all but many. To dismiss it totally
I just dont understand . It's like saying someone with an immune deficiency doesnt get sick. Doesnt make sense.

 

[Eeyore]

@heapsreal - I'm not saying it's theoretically impossible, I'm saying I see no evidence for a role for herpesviruses in ME. I'm suggesting that if they were central to the pathology, that we would see that evidence. That's all.

Interesting point you make about the EBV titers dropping to zero - if those patients were then shown to have EBV by PCR, that would be interesting.

Poorly functioning immune system can mean many things, as the immune system is highly complex and accomplishes its goals through a wide variety of mechanisms. Deficiencies can cause VERY specific vulnerabilities - for example, lack of IL-28 function causes susceptibility to persistent HCV infection - but not much else (maybe HSV). Deficiency of some complement proteins causes extreme susceptibility to neisseria infection. The more common example would be gonorrhea, but actually in these patients the major cause of morbidity and mortality is frequent infections with neisseria meningitides - i.e. bacterial meningitis, which follows a very aggressive course in them. I always found it surprising that it would be SO specific for just those bacteria (gram negative cocci - a rare breed).

I think we need to be careful when we say "poorly functioning immune system" to specify exactly how it is functioning abnormally, and not assume that any deficiency increases the risk of any infection, as it does not seem that is the case.

I do agree with your point that many docs do fail to find any abnormalities in ME because they haven't looked. I have found MANY persistent, reproducible abnormalities from standard labs that my doctor can order and that my insurance covers. They form a pattern in my case. Some seem consistent with ME patients, some, so far, are only found in me. The problem is that docs sometimes seem to think that if they cannot diagnose an ME patient as having some disease OTHER THAN ME, then that patient is not sick AT ALL! I think the problem is that many of us are doing our own research on our own bodies - trying to solve a puzzle - and the docs are content with "currently unexplainable medical illness." Or worse - psychobabble.

 

[Eeyore]

@Jonathan Edwards - Thanks for that reply. I'm not sure if I falsely remembered you giving gout as an example of non-cytokine-mediated immunity not raising CRP. I could have that mixed up (probably did).

Essentially though, you are saying that lack of inflammatory markers is in no way an indicator that there is no autoimmunity. Not as familiar with all of your examples, but it makes sense with MG that it just blocks nACh receptors and blocks function rather than causing inflammation - although I'm not certain why this wouldn't trigger ADCC / classical complement pathways and nerve cell death (which it doesn't seem to do much of as MG isn't progressive). I guess this is what you mean by tickling some inflammatory pathways but not enough to really move the needle.

Another followup question based on something you mention - thanks again for your patience: Does complement activation reliably elevate acute phase markers, and if so, which? Does it matter which pathway (classical/alternative/lectin)? I know lupus often involves complement deficiencies, and that immune complex deposition is common (or perhaps just defects in c3 mediated opsonization and clearance of the complexes) - and I believe lupus almost invariably elevates sed rate and CRP.

 

[minkeygirl]

@deleder2k aside from infectiond and rutixkmab there are lots of people that have really rough times post anesthesia

Dr Cheney had some suggestions of what to do prior to anesthesia to minimize problems. In sure others here talk about it.

I can't rmemeber what it was but some IV's.

 

[redaxe]

@Jonathan Edwards

From your work in Rheumatoid Arthritis do you think there could be an association between EBV infection of B cells and RA?

I'm quoting you from an old newspaper article "If our explanation is right, auto-immune diseases may be like bugs in a computer program. If you happen to press certain keys in a particular order it crashes. The solution is to turn everything off and start up afresh - which in this case means using drugs to eliminate all the B-cells."

Is it possible that EBV can be one possible bug in the system for RA? If herpes viruses do damage immune cells maybe there is a link between autoimmunity and the viruses that hide out of sight in our cells.
http://www.hindawi.com/journals/jir/2013/535738/

There may be a genetic factor at work here too with HLA-DR leaving certain people more exposed to certain viral infections. Take Herpes Simplex for example - the majority of the human race is infected with at least 1 of the 2 viruses; some are asymptomatic while others battle coldsore breakouts and other signs of infection on a regular basis. I don't see why EBV/HHV6/CMV aren't doing the same thing.

EBV has been associated with MS as well. Controlling herpes viral infections could still be a piece of the puzzle.

@Eeyore

I don't think the evidence for reactivated Herpes virus infections has been investigated thoroughly enough to say there is no association. One subset of people with CFS/ME has already potentially been identified - those with Chromosomal Integrated HHV6.

http://hhv-6foundation.org/associated-conditions/hhv-6-and-chronic-fatigue-syndrome
CFS & CIHHV-6

CFS patients who test positive for HHV-6 on a plasma PCR DNA test should have a follow-up quantitative whole blood test to rule out chromosomally integrated HHV-6 or CIHHV-6. Patients with ciHHV-6 will always test positive on a PCR test because they inherit HHV-6 genomes integrated into the chromosome of every cell. Although this inherited condition affects less than 1% of the general population, the condition appears to be overly represented in patients with CNS dysfunction. Some have theorized that ciHHV-6 patients may be unable to mount a proper immune defense against community acquired strains of HHV-6, and thus develop CNS symptoms that resemble CFS (Montoya 2012, Pantry 2013, in press).

There are 2 other issues I can think of here. Firstly for HHV6 we lack an early antigen test so we have no objective measurement of what the 'latent' virus might be doing. There was a study done on a HHV6 Protein -SITH 1 http://www.prohealth.com/library/showarticle.cfm?libid=13755
But there doesn't seem to have been any followup done on it.

Secondly our antivirals are very weak at knocking out non-permissive infections. I'm cutting the section below fromhttp://phoenixrising.me/interviews-...ntiviral-treatment-study-0510-by-cort-johnson.
Once Brincidofovir comes out we might see better response rates to antivirals. And of course if the drug DRACO ever gets released that would be a miracle cure for possibly all viral infections.

EBV replicates when the B cells it is found in divide – this is how it spreads from the original cell into the new cell. Itreactivates - ie grows inside those cells – using an entirely different procedure.

The primary treatment for EBV (either acyclovir or valtrex) is able to stop EBV reactivation; that is it is able to reach into the cell and stop the process which EBV uses to grow in the cell. Neither are able to stop EBV from replicating when the B cells its infected divide.

This is what Cohen found in the paper Dr. Lerner liked very much. The decline in infected cells after Valtrex administration was slow, however; after a year only a modest decline has occurred. This ‘modest decline’ could be why really long-termantiviral therapy is sometimes necessary. Cohen estimated that it would take6 years of Valtrex administration every day to eradicate EBV from the B-cells (and 11 years to eradicate it completely from the body). Higher doses would work more quickly. Fortunately it’s more important to reduce EBV activity than to completely eradicate it.

 

[trails]

I'm highly skeptical that herpesviruses play an important role in ME, although I believe they can sometimes trigger it. One piece of evidence that I would be looking for would be a substantially higher rate of shingles. I have never heard of an ME patient even getting shingles - although I'm sure there must be some - yet if their ability to control herpesvirus infections were so impaired as to cause an ongoing illness, one would expect to see it frequently.

@Eeyore, there is no doubt in my mind that you are significantly more science-literate than I (most are!), and I'm certainly not qualified to render an opinion on the underlying premise of your argument. Having said that, I'm not entirely sure where you're getting the information to back up the above quote.

Like you, I had chickenpox as a child. I also had shingles at the age of 29. I've read many other posts on this forum where others also indicate they've had shingles. A few quick examples:

Randomised double-blind trials or not, I can only speak from personal experience but I have a very serious on and off problem with herpes zoster (shingles) reactivation in the skin around the eyes and in the eyes themselves.

 

[trails]

@Eeyore, I'm sorry that my reply got posted before I finished. I can't figure out how to add several multiquotes to post lol!. In any event, search shingles on this forum and you will find many people reporting that they've had it in the past.

In any event, I'm again in no way intending to cast doubt on your underlying premise. In fact, like you, I seem much less susceptible to colds, flus and other common ailments than most people. Sorry again for the broken post.

 

[Bob]

I'm sorry that my reply got posted before I finished. I can't figure out how to add several multiquotes to post lol!.

Hi trails, for future reference, in case helpful, you can easily edit an earlier post by clicking on 'edit' at the bottom of your post. And to multi-quote, you can click on +multiquote underneath any post, which adds the quote to a list, and then click on 'insert quotes' underneath the text box when you come to write your post. You can use the multiquote feature to quote as many posts as you like. Hope that helps you in future.

 

[Jonathan Edwards]

@Jonathan Edwards

From your work in Rheumatoid Arthritis do you think there could be an association between EBV infection of B cells and RA?

I don't think so. No link has been found despite 30 years of people trying very hard to find one. More or less everyone has EBV and there is no link in time between infectious mononucleosis and RA.