New pilot study in the loop from the researchers at Haukeland

[charles shepherd]

MEA announcement and comment:

http://www.meassociation.org.uk/201...rway-for-treatment-of-mecfs-10-february-2015/

 

[A.B.]

As far as I remember, Maria Gjerpe, the founder of the RTX Crowdfunding campaign, had also a more gradual onset, was ill for 23 years and was eventually bed bound, but benefited hugely from RTX.

I'm relieved to hear that there is still hope for those who have been severely ill for so long.

 

[Joolz]

@charles shepherd Thank you very much for this link. I am thrilled that you as one of the researchers who was involved back then comments on the new trial.

But did I understand you right that cyclophosphamide wasn't tried back then, only azathioprine? I got a different impression from reading a review article from 1991 by McBride/McCluskey where they state that "immunosuppressives (such as cyclophosphamide, azathioprine and corticosteroids) have also been found ineffective" (http://bmb.oxfordjournals.org/content/47/4/895.abstract). They cite a paper by Behan & Behan on this. Unfortunately, that paper (Behan PO, Behan WMH. Post-viral fatigue syndrome. CRC Critical Reviews in Neurobiology 1988; 4: 157-178) is not available online. I wrote to prof Peter Behan a couple of weeks ago and kindly asked for the full-text version of that paper, but I didn't get any answer.

Maybe you can shed some light on the history of cyclophosphamide treatment for CFS? If cyclophosphamide was in fact tried back then, what was the outcome? What are the main differences between azathioprine and cyclophosphamide? I would love to learn more about that trial!

 

[charles shepherd]

@charles shepherd Thank you very much for this link. I am thrilled that you as one of the researchers who was involved back then comments on the new trial.

But did I understand you right that cyclophosphamide wasn't tried back then, only azathioprine? I got a different impression from reading a review article from 1991 by McBride/McCluskey where they state that "immunosuppressives (such as cyclophosphamide, azathioprine and corticosteroids) have also been found ineffective" (http://bmb.oxfordjournals.org/content/47/4/895.abstract). They cite a paper by Behan & Behan on this. Unfortunately, that paper (Behan PO, Behan WMH. Post-viral fatigue syndrome. CRC Critical Reviews in Neurobiology 1988; 4: 157-178) is not available online. I wrote to prof Peter Behan a couple of weeks ago and kindly asked for the full-text version of that paper, but I didn't get any answer.

Maybe you can shed some light on the history of cyclophosphamide treatment for CFS? If cyclophosphamide was in fact tried back then, what was the outcome? What are the main differences between azathioprine and cyclophosphamide? I would love to learn more about that trial!

Reply

Thank you for reminding me about this paper from Peter and Mina Behan

I've just looked in my library and cannot find a copy - but it may be lurking somewhere

As you say, it appears that cyclophosphamide was also on the list of experimental drugs that were being assessed in Glasgow at the time

As you may know, Peter Behan retired some time ago (which is a great loss because we don't have many neurologists here in the UK who believe this is a serious neurological illness and want to carry out research) but we are still in contact

So I will also chase this up with him

CS

 

[Joolz]

As you may know, Peter Behan retired some time ago (which is a great loss because we don't have many neurologists here in the UK who believe this is a serious neurological illness and want to carry out research) but we are still in contact

So I will also chase this up with him

Thanks so much! I wrote to Peter Behan on ResearchGate where he still seems to be quite active, twice actually. It would be great to hear more on what exactly they did in Glasgow back in the 80s!

 

[FancyMyBlood]

I still think that there are people who could be classified as having ME who do not having an antibody mediated autoimmune disease. What I continue to be puzzled about is the most common mechanism for PEM type ME.

What is it that you're most puzzled about? The often reported delayed onset, the length or only the mechanism of action per se?

 

[FancyMyBlood]

PEM is puzzling in terms of the delay in effect and the long lasting effect. I am not aware that it is a feature of the fatigue of conditions like lupus although this may not be well documented. I am not sure that I have more to add other than is on the 'Do MEs cause CFS' thread.

Ok, I probably should have read the entire thread before responding, but this is what I expected you were referring to.

I always suspected the delayed onset *might* not be that strange. As you might know in resistance training cycles it's very well known that muscle pain can take up to 3 days to manifest. It's called delayed onset muscle soreness (http://en.wikipedia.org/wiki/Delayed_onset_muscle_soreness) and relatively well-studied by sports scientists. Although I can't envision a proposed mechanism of action since I practically know nothing about biochemistry, I always suspected there might be going something haywire when DOMS kicks in in patients with ME/CFS. I might be completely wrong but the fact that the delayed onset seems to correspond pretty well with the timeframe of DOMS really makes me wonder.

 

[melihtas]

Ok, I probably should have read the entire thread before responding, but this is what I expected you were referring to.

I always suspected the delayed onset *might* not be that strange. As you might know in resistance training cycles it's very well known that muscle pain can take up to 3 days to manifest. It's called delayed onset muscle soreness (http://en.wikipedia.org/wiki/Delayed_onset_muscle_soreness) and relatively well-studied by sports scientists. Although I can't envision a proposed mechanism of action since I practically know nothing about biochemistry, I always suspected there might be going something haywire when DOMS kicks in in patients with ME/CFS. I might be completely wrong but the fact that the delayed onset seems to correspond pretty well with the timeframe of DOMS really makes me wonder.

I get PEM only sitting for more than one hour due to orthostatic intolerance. So, muscle damage is out of question for my situation. It has something to do with anaerobic metabolism but I don't know much about biochemistry either.

 

[FancyMyBlood]

I get PEM only sitting for more than one hour due to orthostatic intolerance. So, muscle damage is out of question for my situation. It has something to do with anaerobic metabolism but I don't know much about biochemistry either.

PEM for me isn't really that significant (have a pretty constant and severe baseline no matter what I do), but I can definitely relate to the orthostatic symptoms. In fact the autonomic symptoms (dizziness etc) are one of my major complaints. Don't really have the myalgia aspect either. Still, there seems to be a rather large subgroup who do fit those criteria.

 

[Joolz]

@charles shepherd: I just realised that the "first" patient in the history of rituximab treatment for CFS - the one described as "patient 1" in the 2009 paper by Fluge/Mella - received cyclophosphamide as part of the BEACOPP chemotherapy regimen. Do you have an idea why a patient would improve on both methotrexate and rituximab but not on cyclophosphamide? I guess the dosage can't have been a problem, but might she have needed maintenance treatment? Or would rituximab work for some patients, cyclo for others, but not vice versa? (I guess the trial will show if cyclo works for some of the rituximab-non-responders.. but that doesn't tell us if it's valid the other way round, too.)

To complicate things even more, Fluge and Mella state in a letter to the editor in PLoS One (http://www.meassociation.org.uk/201...-rituximab-letter-to-plosone-31-october-2011/):
"We have later treated another lymphoma patient with preexisting CFS/ME who also experienced a clear response on all CFS/ME symptoms from four months after start of treatment (8 cytotoxic chemotherapy courses (CHOP) with addition of Rituximab), and she still has response of CFS/ME symptoms 2 ½ years later." - and the C in CHOP stands for cyclophosphamide. Did the patient respond to cyclo, or rituximab, or both? How do they know? Cyclophosphamide seems to work faster than Rituximab - why?

I always thought that the trigger might have to do something with who responds to what, but I have heard of several EBV-sudden-onset patients who responded to treatment with rituximab, and of one who not only didn't respond but got considerably worse.

 

[Jonathan Edwards]

@charles shepherd: I just realised that the "first" patient in the history of rituximab treatment for CFS - the one described as "patient 1" in the 2009 paper by Fluge/Mella - received cyclophosphamide as part of the BEACOPP chemotherapy regimen. Do you have an idea why a patient would improve on both methotrexate and rituximab but not on cyclophosphamide? I guess the dosage can't have been a problem, but might she have needed maintenance treatment? Or would rituximab work for some patients, cyclo for others, but not vice versa? (I guess the trial will show if cyclo works for some of the rituximab-non-responders.. but that doesn't tell us if it's valid the other way round, too.)

To complicate things even more, Fluge and Mella state in a letter to the editor in PLoS One (http://www.meassociation.org.uk/201...-rituximab-letter-to-plosone-31-october-2011/):
"We have later treated another lymphoma patient with preexisting CFS/ME who also experienced a clear response on all CFS/ME symptoms from four months after start of treatment (8 cytotoxic chemotherapy courses (CHOP) with addition of Rituximab), and she still has response of CFS/ME symptoms 2 ½ years later." - and the C in CHOP stands for cyclophosphamide. Did the patient respond to cycle, or rituximab, or both? How do they now? Cyclophosphamide seems to work faster than Rituximab - why?

I always thought that the trigger might have to do something with who responds to what, but I have heard of several EBV-sudden-onset patients who responded to treatment with rituximab, and of one who not only didn't respond but got considerably worse.

Cyclophosphamide works quickly in inflammatory autoimmune disease because it kills inflammatory cells as well as B cells. The real problem with cyclo is that the effect does not last - certainly in RA. There is clear rapid benefit from cyclo infusions almost at once but by 3 months you are back to square one. That is because cyclo does not block the recruitment of new B cells, it just kills the ones already there.

It is all a bit complicated but it makes sense. When I treated RA with rituximab and cyclo I worked on the basis that the effect of cyclo would be gone by 3 months so I assessed patients at 6 months.

 

[deleder2k]

It seems that some patients goes into a complete remission (2-3 years with B-cells back) after treatment with several Rituximab infusions. B-cells come back with both Rituximab and Cyclo. Isn't it likely that if RTX could lead to a remission for 2-3 years, couldn't Cyclo do the same?

 

[Snow Leopard]

Isn't it likely that if RTX could lead to a remission for 2-3 years, couldn't Cyclo do the same?

Given that ME has a modest, but notable spontaneous recovery rate, I think remission without ongoing treatment is certainly possible.

I guess the problem is that Cyclo doesn't completely eliminate B-cells and so there is less chance of it leading to the long-term elimination of the B-cell lineages producing pathological antibodies.

 

[Jonathan Edwards]

It seems that some patients goes into a complete remission (2-3 years with B-cells back) after treatment with several Rituximab infusions. B-cells come back with both Rituximab and Cyclo. Isn't it likely that if RTX could lead to a remission for 2-3 years, couldn't Cyclo do the same?

Yes, I agree with Snow Leopard. In terms of the rationale we set up for using rituximab in autoimmunity there is also a specific mechanistic argument about vicious cycles. The idea is that autoimmunity continues through a positive feedback cycle with one arm being plasma cells secreting antibody and the other arm being new B cells being stimulated by that antibody to become further plasma cells - and so on. To break the cycle you probably need to block the process for long enough for plasma cells to die off while no new B cells are arriving. Rituximab blocks new B cell arrival for 6 months, or with repeat dosing this can be extended to years. Cyclophosphamide kills B cells but it does not kill plasma cells very well nor does it block arrival of new B cells from stem cells. Cyclophosphamide is eliminated from the body within about 24hrs so there is no long term effect unless you take it orally and that is very toxic.

 

[deleder2k]

Thank you for your answer professor.

In the upcoming study by Øystein Fluge and Olav Mella they will give 6 infusions for 6 months with cyclophosphamide. I guess this means that the patients won't have little or no B-cells for at least 6 months. Could this be enough to eradicate or "reset" the B-cells? It looks like there longer one receives B-cell depletion with RTX, the bigger the change for a remission that lasts 2-3 years (and possibly more). I thought that cyclo was better killing antibodies than RTX, since RTX only targets CD20, while Cyclo kill b-cells and stop cells from dividing.

I've tried to read this http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2211779/ which says "The current view holds that chronic autoimmune diseases are driven by the continuous activation of autoreactive B and T lymphocytes. However, despite the use of potent immunosuppressive drugs designed to interfere with this activation the production of autoantibodies often persists and contributes to progression of the immunopathology."

This is getting advanced for me!

 

[Joolz]

@Jonathan Edwards: Thanks for your reply!

I doubt that Fluge/Mella would start a study with a drug like cyclo - that has relatively serious potential side effects - if the pilot patients had only seen 1-3 months of improvement. But we don't know, of course.

But cyclo also affects T cells, right, in contrast to rituximab? Yeah this is getting advanced...
Since some patients don't respond to rituximab: could it be that B cells are not the only problem - at least for a subset of patients? Wasn't that one of the possible theories?

One would think that they could try cyclo on a group of rituximab-non-responders and cyclo+rituximab on a group of patients who haven't received treatment before? I know that this is not what the study protocol is saying, but: why not?

 

[deleder2k]

I think they are trying Cyclophosphamide on subjects that was Rituximab non-responders, Rituximab responders with relapse, and new, previously untreated subjects. No Cyclo+RTX group though.

 

[Joolz]

I know. But why not?

 

[deleder2k]

I have no clue.. Maybe they will do that in a phase 3 study.

 

[Jonathan Edwards]

Thank you for your answer professor.

In the upcoming study by Øystein Fluge and Olav Mella they will give 6 infusions for 6 months with cyclophosphamide. I guess this means that the patients won't have little or no B-cells for at least 6 months. Could this be enough to eradicate or "reset" the B-cells? It looks like there longer one receives B-cell depletion with RTX, the bigger the change for a remission that lasts 2-3 years (and possibly more). I thought that cyclo was better killing antibodies than RTX, since RTX only targets CD20, while Cyclo kill b-cells and stop cells from dividing.

I've tried to read this http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2211779/ which says "The current view holds that chronic autoimmune diseases are driven by the continuous activation of autoreactive B and T lymphocytes. However, despite the use of potent immunosuppressive drugs designed to interfere with this activation the production of autoantibodies often persists and contributes to progression of the immunopathology."

This is getting advanced for me!

The repeated dosing with rituximab that our Norwegian friends have been using will potentially keep B cells away for up to two years continuously. This may be a very good way of breaking a loop. We found it difficult to document an advantage of longer term B cell suppression in RA but RA very rarely remits spontaneously and we suspect we do not yet have the tools to break the loop completely in RA. In other autoimmune diseases like immune thrombocytopenia it seems that the loop is easier to break. If ME fits with that then it makes sense to try longer periods of B cell depletion to try to break a loop.

Cyclo can kill some plasma cells but you nee very high doses to kill many - doses that cause neutropenia. Rituximab only kills the CD20 stage B cells but has the advantage of keeping them away longer so plasma cells die off just with the time. The paper you quote by Radbruch and colleagues is a very fair analysis - much in line with what we proposed around 2000 - that targeting long lived plasma cells is something we need to consider. (Although they say autoreactive B and T lymphocytes they are only really interested in autoantibodies. I am not sure why they mention the T cells since we have no evidence for autoreactive T cells for most diseases, but old habits die hard.)