What are the other mechanisms by which RTX might be working?

[cigana]

I was just wondering if people have thought about this much. Are there any other mechanisms by which Rituximab could be working in MESEID besides the autoimmune hypothesis?

 

[Jonathan Edwards]

I was just wondering if people have thought about this much. Are there any other mechanisms by which Rituximab could be working in MESEID besides the autoimmune hypothesis?

There is a mechanism that we have been discussing amongst scientists in the UK interested in the potential role of B cells. Rituximab must be working by removing B cells, I think, since it really does nothing to anything else. If we think the Norwegian data indicate a real effect I think we have to take into account that this effect takes about 6 months to be fully apparent. That points strongly in the direction of the effect being through antibody production rather than some immediate effect of B cells through something like antigen presentation.

So how would blocking new antibody production over a six month period help if these were not autoantibodies? I think there is a genuine alternative possibility. The antibody that declines with six months of B cell depletion is antibody produced by short lived (mostly splenic?) plasma cells. This sort of antibody probably includes a relative high proportion of low affinity/broad specificity antibody - sort of rough and ready dirty antibody. If we postulate that ME in the chronic phase is due to a hypersensitivity of brain stem/autonomic circuits to very low level immune danger signals it might be that what generates symptoms are the normally trivial levels of cytokine or other signal that occur as part of normal daily clearance of toxic material and low grade microbes. A good part of those signals may be triggered by interactions with 'rough and ready' antibody. So if the immune system is 'flushed out' of such antibody without the ability to top it up then symptoms may improve.

We considered this idea because we needed to to think about how one might see improvement with rituximab and yet find no apparent 'abnormality' in B cells or antibody levels or specificities.

 

[cigana]

There is a mechanism that we have been discussing amongst scientists in the UK interested in the potential role of B cells. Rituximab must be working by removing B cells, I think, since it really does nothing to anything else. If we think the Norwegian data indicate a real effect I think we have to take into account that this effect takes about 6 months to be fully apparent. That points strongly in the direction of the effect being through antibody production rather than some immediate effect of B cells through something like antigen presentation.

So how would blocking new antibody production over a six month period help if these were not autoantibodies? I think there is a genuine alternative possibility. The antibody that declines with six months of B cell depletion is antibody produced by short lived (mostly splenic?) plasma cells. This sort of antibody probably includes a relative high proportion of low affinity/broad specificity antibody - sort of rough and ready dirty antibody. If we postulate that ME in the chronic phase is due to a hypersensitivity of brain stem/autonomic circuits to very low level immune danger signals it might be that what generates symptoms are the normally trivial levels of cytokine or other signal that occur as part of normal daily clearance of toxic material and low grade microbes. A good part of those signals may be triggered by interactions with 'rough and ready' antibody. So if the immune system is 'flushed out' of such antibody without the ability to top it up then symptoms may improve.

We considered this idea because we needed to to think about how one might see improvement with rituximab and yet find no apparent 'abnormality' in B cells or antibody levels or specificities.

That is a very interesting idea!
I wonder if that could explain why some PWME's report huge improvements when practising "extreme avoidance" - i.e. living in the desert and being away from low levels of environmental toxins.
I also wonder if it explains why long-term anti-viral or anti-microbe therapies can sometimes bring partial improvement, simply because they reduce the number of targets that these rough and ready antibodies are responding to.
If the problem were simply autoimmune, perhaps neither of these things would occur (?)

Maybe this also explains why cytokine studies often show "something is up" but are so non-specific and noisy.

Is there a thread already started on this idea?

 

[Jonathan Edwards]

That is a very interesting idea!
I wonder if that could explain why some PWME's report huge improvements when practising "extreme avoidance" - i.e. living in the desert and being away from low levels of environmental toxins.
I also wonder if it explains why long-term anti-viral or anti-microbe therapies can sometimes bring partial improvement, simply because they reduce the number of targets that these rough and ready antibodies are responding to.
If the problem were simply autoimmune, perhaps neither of these things would occur (?)

Maybe this also explains why cytokine studies often show "something is up" but are so non-specific and noisy.

Is there a thread already started on this idea?

I think all those things are worth pondering. No thread that I know of.

Jo Cambridge has actually been looking for clues to 'rough and readiness' if you like, by studying antibody VH families. It is all a bit obscure and complicated and the theory above does not require that anything would show up but there are various ways one can thing of antibodies triggering symptoms without actually being autoantibodies.

 

[daisybell]

If the issue is one of hypersensitivity of the brainstem/autonomic system, would you then expect this to calm down when the triggering antibodies are removed? Or does one then need further treatment post-Rituximab to sort this part?
Also, how does this hypothesis fit with the higher incidence of auto-immune issues e.g. Thyroid disease in our population?

 

[Jonathan Edwards]

If the issue is one of hypersensitivity of the brainstem/autonomic system, would you then expect this to calm down when the triggering antibodies are removed? Or does one then need further treatment post-Rituximab to sort this part?
Also, how does this hypothesis fit with the higher incidence of auto-immune issues e.g. Thyroid disease in our population?

If the problem is a hypersensitivity to 'ordinary rough and ready antibodies' then rituximab is only ever going to give temporary benefit. Long term use would be hard to justify so it would be nice to find a way to address the neural sensitivity - trouble is nobody knows how to do that.

The rate of autoimmunity in ME is one of the things I would like to see decent population based studies on. I have not been able to find clear evidence of a definite difference. Thyroid disease is very common anyway, as are autoantibodies. I think there may well be an increased occurrence, and this may well be relevant to the presence of an autoimmune ME subset, but I would like to see it properly documented.

 

[greeneagledown]

If the problem is a hypersensitivity to 'ordinary rough and ready antibodies' then rituximab is only ever going to give temporary benefit.

If the Phase 3 Rituximab results indicate that some treated patients are still having a major response 2 years after the first dose (and 1 year after the final dose), does that suggest that the problem probably isn't this hypersensitivity issue in those people, since the population of low affinity/broad specificity antibodies you mentioned would probably be substantially recovered by then?

 

[greeneagledown]

If the problem is a hypersensitivity to 'ordinary rough and ready antibodies' then rituximab is only ever going to give temporary benefit. Long term use would be hard to justify so it would be nice to find a way to address the neural sensitivity - trouble is nobody knows how to do that.

Also, Professor, haven't you previously opined that even if Rituximab doesn't produce long-term remission in CFS patients, it could possibly be used continuously for up to 4 or 5 years at a time before letting the patient's antibody levels recover and then starting the cycle all over again?

 

[Jonathan Edwards]

If the Phase 3 Rituximab results indicate that some treated patients are still having a major response 2 years after the first dose (and 1 year after the final dose), does that suggest that the problem probably isn't this hypersensitivity issue in those people, since the population of low affinity/broad specificity antibodies you mentioned would probably be substantially recovered by then?

Yes, that seems fair.

Also, Professor, haven't you previously opined that even if Rituximab doesn't produce long-term remission in CFS patients, it could possibly be used continuously for up to 4 or 5 years at a time before letting the patient's antibody levels recover and then starting the cycle all over again?

Yes, I have probably said that. But what about 20 years? When we first started using rituximab in RA and people relapsed my thinking was that if we could keep them well with repeated usage for 5 years then at least there might be some other drugs developed in the meantime to switch to later. In fact that has been so - we now have anti-IL6 receptor and abatacept. On the other hand there are patients who relapse as soon as their B cells come back because of autoantibodies and they seem to be still best treated with rituximab after 15 years. It is all relative. There may be a few ME patients for whom it is justified to go on giving rituximab for the next twenty years but even Dr Fluge says he sees rituximab more as a stepping stone to something better than a long term solution.

I guess with autoantibodies at least it seems to make more sense because they fulfill no useful function, whereas ordinary rough and ready antibodies presumably help to protect against colds and things. But you may be right that in practice there is not much difference in plan of action.

 

[JPV]

How does Rituximab work?

• The immune system is made up of many different parts. By interfering with the correct part, it is possible to decrease the inflammation being caused by rheumatoid arthritis and similar diseases.
• For rituximab, it binds a molecule on the surface of B cells, blocking their action and modulating the immune system’s response. This decreases inflammation, reduces pain, and improves function.

 

[greeneagledown]

There may be a few ME patients for whom it is justified to go on giving rituximab for the next twenty years but even Dr Fluge says he sees rituximab more as a stepping stone to something better than a long term solution.

Maybe it's a stepping stone in the long, long run. But seeing as we don't yet know the cause of CFS and we don't have a reliable test to diagnose it easily, it seems unlikely that we're going to find a better treatment than Rituximab over the next decade (assuming Rituximab is, indeed, effective). Is that needlessly pessimistic?

 

[nandixon]

I was just wondering if people have thought about this much. Are there any other mechanisms by which Rituximab could be working in MESEID besides the autoimmune hypothesis?

If the early reports of cyclophosphamide (cyclo) working as well or better than rituximab are true, then that may be confirmation of the findings in several ME/CFS studies of increased Tregs in patients (Ref 1), since cyclo specifically targets Tregs.

[It was just recently (2014) found that Tregs, unlike other T cells, lack the ABCB1 transporter/efflux pump and thus are especially vulnerable to cyclo due to a resulting increased intracellular concentration of that agent. (Ref 2)]

In that case, then whatever rituximab is doing, it may be related to improving a problematic situation with respect to Tregs, as much as with B cells. This might also be consistent with the finding in a 2013 RA study showing that rituximab not only depletes B cells but also decreases CD4+ T cells. (Ref 3)

References
1. See, e.g., Role of adaptive and innate immune cells in chronic fatigue syndrome/myalgic encephalomyelitis (Note: Full text is available from ResearchGate.net.)

2. Human regulatory T cells lack the cyclophosphamide-extruding transporter ABCB1 and are more susceptible to cyclophosphamide-induced apoptosis (Note: Abstract only.)

3. Rituximab-Induced T Cell Depletion in Patients With Rheumatoid Arthritis: Association With Clinical Response (Note: I've read the full text of this article but haven't been able to read the follow-on Comment(s)/Reply. This study was in contradiction to two prior smaller studies in which the patients had been heavily treated with other medications prior to rituximab.)

 

[Jonathan Edwards]

In that case, then whatever rituximab is doing, it may be related to improving a problematic situation with respect to Tregs, as much as with B cells. This might also be consistent with the finding in a 2013 RA study showing that rituximab not only depletes B cells but also decreases CD4+ T cells. (Ref 3)

3. Rituximab-Induced T Cell Depletion in Patients With Rheumatoid Arthritis: Association With Clinical Response (Note: I've read the full text of this article but haven't been able to read the follow-on Comment(s)/Reply. This study was in contradiction to two prior smaller studies in which the patients had been heavily treated with other medications prior to rituximab.)

It is also a retrospective uncontrolled review and contradicts what we found in the prospective controlled phase II trial in 2001. There is a modest fall in all T cell subsets following the standard B cell depletion protocol but it was exactly the same in the controls who just got the hefty steroid premed (which reduces B cells by 50% briefly). So we can be fairly sure that it is not the rituximab that lowers T cells. The reduction in the Melet study is more than we have observed in several hundred rituximab treatments, the phase II trial and what has been found in subsequent phase III trials (not necessarily published as such). It seems likely that they noticed some unusually large drops by chance and then went back and looked at a bigger sample. It does not seem terribly relevant anyway since Campath1H produced a depletion of T cells down to almost AIDS levels for several years but produced no benefit on the RA!

The Treg story is intriguing, especially as the numbers in the circulation seem to be high in ME. We should be getting some more data from the Blanco group soon so let's see how consistent this is.

 

[voner]

I think all those things are worth pondering. No thread that I know of.

Jo Cambridge has actually been looking for clues to 'rough and readiness' if you like, by studying antibody VH families. It is all a bit obscure and complicated and the theory above does not require that anything would show up but there are various ways one can thing of antibodies triggering symptoms without actually being autoantibodies.

like @cigna and others, I find this hypotheses very intriguing. i've always been struck by the "hypersensitivity" aspect of ME/CFS. Off the top of my head I can think of hypersensitivities to mold, various types of food, sound, light, temperature, odors, exertion, and a few more....

@Jonathan Edwards, what do you mean by "anything would show up"? Do you mean no elevated antibody levels?

 

[Jonathan Edwards]

like @cigna and others, I find this hypotheses very intriguing. i've always been struck by the "hypersensitivity" aspect of ME/CFS. Off the top of my head I can think of hypersensitivities to mold, various types of food, sound, light, temperature, odors, exertion, and a few more....

@Jonathan Edwards, what do you mean by "anything would show up"? Do you mean no elevated antibody levels?

Basically I mean that PWME need not necessarily have any different range of antibodies from normal people - just be hypersensitive to normal rough and ready antibodies going about their clearing up business. So to find anything by comparing PWME with controls we would need to say that PWME maybe overdo the rough and ready antibody response all the time. That would be unlikely to show up in total antibody levels but we might find a higher proportion of antibodies being made using certain heavy chain options (this is where it gets complicated).

 

[lansbergen]

Basically I mean that PWME need not necessarily have any different range of antibodies from normal people - just be hypersensitive to normal rough and ready antibodies going about their clearing up business. So to find anything by comparing PWME with controls we would need to say that PWME maybe overdo the rough and ready antibody response all the time. That would be unlikely to show up in total antibody levels but we might find a higher proportion of antibodies being made using certain heavy chain options (this is where it gets complicated).

How would that fit in with low to zero seroconversion after vaccination?

 

[Marco]

Caveats about mouse models of MS aside, what about this 'antibody independent' mechanism attenuating microglial activation?

Anti-CD20 inhibits T cell-mediated pathology and microgliosis in the rat brain

Interpretation

The suppression of lesion development by anti-CD20 treatment in an antibody-independent model suggests that B-cells play an important role in lesion development, independent of auto-antibody production. Thus, CD20-positive B-cell depletion has the potential to be effective in a wider population of individuals with MS than might have been predicted from our knowledge of the underlying histopathology.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4241793/

The rapid (beneficial) response on the formation of new lesions is fairly rapid (after 4 weeks) compared to the more typical response seen in the ME/CFS patients but in MS a clinical response doesn't correlate well with lesions :

The clinicoradiological paradox in MS refers to the poor association between clinical findings and the detectable radiological extent of lesion load.

 

[wastwater]

I don't know anything about all this,but that never stopped me wading in before,so my question is could this have anything to do with any version of leukemia or its mechanisms.EBV and B-cells
Also does more time need to be spent on thinking about environmental toxins?

 

[Jonathan Edwards]

Caveats about mouse models of MS aside, what about this 'antibody independent' mechanism attenuating microglial activation?

Anti-CD20 inhibits T cell-mediated pathology and microgliosis in the rat brain

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4241793/

The rapid (beneficial) response on the formation of new lesions is fairly rapid (after 4 weeks) compared to the more typical response seen in the ME/CFS patients but in MS a clinical response doesn't correlate well with lesions :

This reminds me a bit of the remarks when we used rituximab in RA that since RA was obviously a T cell mediated disease the rituximab must somehow be working on T cells. I have not read the full paper but they wade in by saying that their model is a 'robust' antibody independent disease'. But the fact that rituximab works seems to prove that it is not antibody independent. B cells can only present specific antigen to T cells if they pick up the antigen through their surface antibody. OK, that does not require secreted antibody, but it means that there must be B cells specific for the antigen that are at least potentially capable of giving rise to antibody secreting plasma cells. And if those cells are busily involved in antigen presentation that is exactly what they need to persuade them to turn into plasma cells. The rat model may not produce anti-MOG antibodies of the sort the researchers think they should find, but maybe anti-MOG antibodies are a red herring. And note that the human disease is more or less defined by oligoclonal bands of antibody in the CSF.

When I went to the conference where they presented the first data on rituximab in human MS it was clear to me that the people involved did not appreciate the complexity of the cell dynamics involved and that the implications for antibody production are quite different in MS than in standard autoimmune diseases. In MS it probably does not matter what the B cell (and its antibody) recognises. All that matters is that B cells have into the brain, where any antibody above a certain concentration causes demyelination. Rituximab works at once in MS because it removes circulating B cells and new episodes in MS probably arise from new clones of circulating B cells getting into a new piece of brain. Once there their offspring can start producing antibody within hours or days and produce demyelination. The situation in the animal models is completely different because the disease is more or less monophasic, with multiple lesions developing soon after immunisation. The effect of rituximab will then depend on when it is given in relation to the date of the immunisation. Pre-treatment with rituximab might well reduce antigen presentation to such an extent that the T cell response was blocked. But that would seem to bear no relevance to human MS being treated after the process has started.

I may be wrong but this looks like more rearguard action to save the reputations of those who insist that MS is a T cell disease - just as in RA. I will have to read the paper.

 

[Marco]

Thanks Jonathan. I didn't think you'd be overenamoured with the T cell angle.

I did find the paper rather ambiguous as regards the sequence of events. On one hand you would expect that microglia would be activated in response to the lesions in their usual repair/housekeeping role and that ritux preventing new lesions would be expected to reduce microglial activation. Elsewhere though they seem to suggest that there is diffuse inflammation not related to the lesions and that ritux may be attenuating microglial activation directly rather than as a consequence of fewer lesions. Hence my interest.