Article compares ME/MS and has a section on Rituximab

[Jonathan Edwards]

Is an increased number of B lymphocytes typical for diseases that respond to Rituximab? If so, how is "increased" defined? My B lymphocytes were 17% of the lymphocyte population, with a normal range being 2-18.

Edit: since I'm at it: NK lymphocytes were 31% with a range of 2-30, and T lymphocytes were decreased at 49% with a range of 55-86.

No, we do not particularly see high levels of B cells in autoimmune disease. In lupus they may be low. In other autoimmune diseases they are unremarkable as far as I know (normal in RA). B cell numbers are hugely variable. It seems that the number of cells passing through the circulation at any one time is really not very important. In MS the key thing is that B cells have got in to the brain for some reason.

 

[Woolie]

@Jonathan Edwards, Thanks so much for your clear and detailed response. (sorry if you've already given before, I did do a very careful sweep of your posts before, but still must have missed that). Interesting to see how incidence and time course of response data can be used to tease these accounts apart.

 

[Woolie]

In fact I have mentioned this on several threads but it is an issue of detailed evidence: subtle, but detail is crucial in understanding these things.

The reason why we think rituximab is working in autoimmune disease by an effect on antibody production rather than some knock on effect on other processes is the shape of the response curve. Improvement in RA, for instance, develops gradually over a period of 3-6 months. That can be tracked very accurately with C reactive protein levels going down and the fall is a long slow smooth curve. It takes much too long to be explained just by removal of early or midlife B cells. If you then track autoantibody levels - which my lab has been doing week in week out for fifteen years - you find the curve fits the improvement curve very well. It takes 3-6 months for the antibodies to decline because that depends on mature plasma cells dying off.

When rituximab was used in ME Dr Fluge and Dr Mella, who are oncologists, were no fully aware of the time course of improvement seen in autoimmune diseases. Their own disease, lymphoma, gets better very quickly because improvement is just due to the removal of the malignant b cells, which takes hours or at most a few days. So they were surprised to see that it took 3-6 months for the patients to improve until I was asked to comment on their paper and pointed out that the time course is exactly right for autoimmunity.

If rituximab was working by removing B cells full of EBV improvement should not take more than six weeks at the very most and I would expect it to be no more than three weeks. There is no reason why, if virus is removed today, that it should be producing symptoms in several weeks time. Usually when the body makes an effective immune response to EBV symptoms settle within a week or two. So the pattern of improvement with rituximab really makes no sense in terms of removing EBV.

What might be true is that EBV is necessary for a disordered autoimmune or autoinflammatory process to persist. So it might be that you will only get long term remission if you also clear away EBV. In fact this does not fit very well either since rituximab is very good at removing EBV and a lot of patients relapsed after improving - so again it does not seem to fit with continued presence of EBV being involved.

@Jonathan Edwards, I have been looking at the Fluge-Mella papers again, and my concern with trying to interpret the time course of response is that they seem to have measured response to the drug entirely by self-report. This seems to be a very different type of measure to the ones you have used in studies of RA or cancer, and more likely to be affected by factors other than those directly targeted by the treatment (general post-treatment fatigue effects, etc). So I'm not convinced any more that you can read a lot into that aspect of the results.

Your point about the absence of EBV markers in all but a minority of patients is a good one, but again, its a negative form of evidence supporting an autoimmune component. I looked at the other articles that have explored autoimmune markers in CFS - that is, positive evidence - and they are also quite variable, showing at most, elevated markers in only a subset of patients. I think the autoimmunity idea is interesting; I just wonder whether we need to apply the same degree of skepticism to it that we do to all other hypotheses regarding MECFS?

Thanks again, am finding all this very interesting.

 

[Jonathan Edwards]

@Jonathan Edwards, I have been looking at the Fluge-Mella papers again, and my concern with trying to interpret the time course of response is that they seem to have measured response to the drug entirely by self-report.

This is a very valid point. However, the trial was blinded and placebo controlled and self report of fatigue has to be the primary endpoint. It showed a significant difference at 6 months but not at 3 months. If the rituximab was having a genuine effect via removing EBV I still think one would expect that to be reflected at the early time point. At least the trial suggests that the patients did not notice much change at 3 months. I think the bigger problem is whether the result is more than a chance finding at 6 months, and I know the Norwegian physicians are very aware of that and prepared to consider it as possible. I doubt that a further trial will show evidence for an early effect consistent with removing EBV but it may show no consistent effect at either time point.

Your point about the absence of EBV markers in all but a minority of patients is a good one, but again, its a negative form of evidence supporting an autoimmune component. I looked at the other articles that have explored autoimmune markers in CFS - that is, positive evidence - and they are also quite variable, showing at most, elevated markers in only a subset of patients.

I think it is important to note that there are no general markers of autoimmunity. A proportion of autoimmune diseases show evidence of inflammation as well as tell tale autoantibodies but in fact these are the minority. In most cases proof of autoimmunity comes from the autoantibody. If we have just not found the autoantibody a subset of ME that is autoimmune then we are not expecting any other markers to show up. New autoantibodies are being found for new diseases at a faster rate than ever before so it is likely that there are a number of undiscovered ones.

Having said that, I would not be surprised if the subset of ME that responds to rituximab (if it does) is dependent on antibody in a rather subtle way. Note that in MS there are no obvious autoantibodies, just antibodies being made in the brain when they should not. In ME there may be no autoantibodies but it might be that the balance of antibody types is abnromal. For instance it could be that in ME, B cells that make antibodies that use a particular heavy chain gene are allowed to expand when this is not normally allowed beyond a very acute response to infection. (There is a specific possibility here but I will not go in to detail.) The general concept of autoimmunity can have all sorts of twists and turns to it.

I think the autoimmunity idea is interesting; I just wonder whether we need to apply the same degree of skepticism to it that we do to all other hypotheses regarding MECFS?

Absolutely. I hope nobody was suggesting otherwise. It is just that rituximab working through EBV does not seem to add up (PWME did not feel noticeably better in the firs few weeks). So autoimmunity remains as one of the alternative explanations for ME that does seem to fit the rituximab data. That can still include a role for EBV in long term persistence through an indirect route rather than symptomatic infection per se.

 

[Jonathan Edwards]

I might add, Woolie, that your focus on the subjective endpoint really is important. One issue is that the curves of the response graphs are not neat and tidy as they are in RA with CRP measurements - where you can join the dots in a lovely smooth line. We desperately need more objective markers and Dr Fluge has tried to put some in to his new study.

 

[Marco]

I might add, Woolie, that your focus on the subjective endpoint really is important. One issue is that the curves of the response graphs are not neat and tidy as they are in RA with CRP measurements - where you can join the dots in a lovely smooth line. We desperately need more objective markers and Dr Fluge has tried to put some in to his new study.

That's a great question to ask. In the absence of any consistent test abnormalities and without a disease model we're back to relying on symptoms. As 'fatigue' might be expected to lead to reduced activity levels then actimeters could give us continuous (and objective) data but is it realistic to ask patients to wear them over such an extended period?

So unless Fluge and colleagues have a working model with some intermediate measure that fits the bill - what else could be measured to plot dose/response?

 

[Jonathan Edwards]

That's the hard bit. Autonomic stress tests have been suggested - vascular resistance and the like.

 

[Cheshire]

If I remember correctly they intended to do a ergospirometry test. Don't know exactly what it is, some compared it to the 2 days CPET.

http://forums.phoenixrising.me/inde...testing-of-me-cfs-patients.31776/#post-490220

 

[Valentijn]

As 'fatigue' might be expected to lead to reduced activity levels then actimeters could give us continuous (and objective) data but is it realistic to ask patients to wear them over such an extended period?

Yes - they're small, light, and unobtrusive. It's about as burdensome as wearing a watch. And these are a highly motivated group of people who are getting a great opportunity and are likely eager to help out as best they can.

 

[Bob]

...is it realistic to ask patients to wear them over such an extended period?

I don't think they'd need to wear the actometers for the whole year. It would just be needed for e.g. a week at baseline a week at 3 months, and a week at 6 months and 9 months etc.

 

[Marco]

I don't think they'd need to wear the actometers for the whole year. It would just be needed for e.g. a week at baseline a week at 3 months, and a week at 6 months and 9 months etc.

Possibly. I know the treatments may be staged but I'm not sure if sampling at discrete time points is good enough?

 

[Valentijn]

I know the treatments may be staged but I'm not sure if sampling at discrete time points is good enough?

Yes. Testing via actometer would usually last for several days or a week if done by researchers who take PEM into account.

 

[Marco]

Yes. Testing via actometer would usually last for several days or a week if done by researchers who take PEM into account.

The point I was making was that @Jonathan Edwards seems to like to see a particular type of response curve to Ritux which may not be apparent from sampling at discrete points. Maybe not. It may not be necessary to collect date throughout the whole period.

 

[Jonathan Edwards]

I think actometer measurements would need to be done monthly, maybe being worn for five days or something.

There is, however, another problem that has just surfaced in my mind. ME fluctuates much more than a lot of autoimmune disease symptoms I suspect. It may be a bit like lupus that has 'flares' and plateaus, or MS with 'episodes' and recoveries. These conditions are difficult to make sense of in time curve terms after treatment whether the measure is objective or subjective.

The basic problem is that ME is about the most difficult thing one could need to assess in a trial situation. Which is why other notable trials have come up with a lemon. I have a feeling that we need completely different sorts of trial designs for this condition, but I am not quite sure how best to approach it.

 

[Marco]

Possibly some more information on what may be measured on this thread :

http://forums.phoenixrising.me/index.php?threads/rituxme.34172/

 

[A.B.]

What has endothelial dysfunction to do with ME?

 

[daisybell]

I started wearing a Fitbit about a month ago, to track my activity and sleep. What I have noticed in particular is not that my overall activity gives much info, but that I record no minutes of more intense activity at all if I'm feeling bad.... Plus my sleep is more broken.
If snapshots could be taken every month, I think there would probably be enough data to give useful info. It would be hard to keep up any extra activity over a number of days beyond what feels ok.

 

[Jonathan Edwards]

What has endothelial dysfunction to do with ME?

Maybe something to do with nitric oxide, which might have to do with circulatory changes.

 

[Sasha]

I think actometer measurements would need to be done monthly, maybe being worn for five days or something.

There is, however, another problem that has just surfaced in my mind. ME fluctuates much more than a lot of autoimmune disease symptoms I suspect. It may be a bit like lupus that has 'flares' and plateaus, or MS with 'episodes' and recoveries. These conditions are difficult to make sense of in time curve terms after treatment whether the measure is objective or subjective.

The basic problem is that ME is about the most difficult thing one could need to assess in a trial situation. Which is why other notable trials have come up with a lemon. I have a feeling that we need completely different sorts of trial designs for this condition, but I am not quite sure how best to approach it.

Do we need better data about the natural course of ME? Should a thousand of us be wearing Fitbits for a year? Serious question! I'd wear a Fitbit for a year in the interests of research.

I think many of us long-term PWME have long period of stability (more's the pity, when it's stability at a low level of function) - but maybe I just think that because that's been the case for me. We all think we're 'normal'.

 

[user9876]

I think actometer measurements would need to be done monthly, maybe being worn for five days or something.

There is, however, another problem that has just surfaced in my mind. ME fluctuates much more than a lot of autoimmune disease symptoms I suspect. It may be a bit like lupus that has 'flares' and plateaus, or MS with 'episodes' and recoveries. These conditions are difficult to make sense of in time curve terms after treatment whether the measure is objective or subjective.

The basic problem is that ME is about the most difficult thing one could need to assess in a trial situation. Which is why other notable trials have come up with a lemon. I have a feeling that we need completely different sorts of trial designs for this condition, but I am not quite sure how best to approach it.

The idea of instantaneous monitoring seems quite problematic. Although ME fluctuates a lot how much is random and how much is as a response to activity (i.e. PEM). I'm wondering if measurements need to reflect the dynamic nature of the illness. For example if we used actometers how about measuring the difference or frequency of peaks and troughs. That is try to measure how fluctuations occur and the short term effects of activity. I don't see why actometers couldn't be used for a lot of the time given these days they are quite small and cheap. My concern would be that actometers only capture physical movement and hence not all activity (particularly mental activity).

I worry if things like the sf36 scale is used and you are trying to fit improvements to other things. There is no reason to believe it is a scale and hence the same numerical improvements from different start points may not represent the same improvement in physical function. In fact given the same starting point could be formed from different answers then the same numerical improvement on the scale does not necessarily represent the same improvement.