Rituximab and placebo response

Fair enough. It made sense to me, but if it doesn't to you, that's fine.

I can't help thinking of my own non-zero expectations of being able to make myself a bit better by gradually increasing my activity. I know from research and 30+ years bitter experience that whenever I try to do a bit more I get sicker, yet still somewhere hiding in my psyche is the expectation/hope that next time, if I just do it more cleverly, try a different activity, break it up differently, I'll be able to trick my body into accepting a bit more activity without punching me in the gut. Such is the insidious effect of hope.

Edit: I've also got noticeably 'better' for a few weeks after trying the 'cold bath' treatment, and homeopathy. And crashed badly after those few weeks both times. Placebo effect is very strange.
 
Trish said:
Edit: I've also got noticeably 'better' for a few weeks after trying the 'cold bath' treatment, and homeopathy. And crashed badly after those few weeks both times. Placebo effect is very strange.
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This is why I think the RituxME trial left some important unanswered questions. There could very likely be certain subsets who are more likely to get a placebo effect from a particular treatment, whereas many others won’t from that treatment, and then many others like me who don’t get a placebo effect at all from anything. The astounding effects I got from keto lasted months! It wasn’t placebo effect and wasn’t due to something unrelated to the treatment.
 
I also think drugs like rituximab, and possibly antivirals are another good example, are much more susceptible to patients exhibiting a placebo effect because the effects of these drugs in ME, when there are effects, take a long time to slowly manifest.

I’m sure most if not all the patients in the RituxME trial certainly knew that going in based on the previous trials and reports. So because things take so long and are so slow to manifest it can certainly play with people’s minds to believe they are improving due to the drug.

But with treatments like Abilify and keto, almost everyone has reported it taking only a few days to a couple weeks before seeing significant and sometimes dramatic improvements. It’s so much faster, and at least with this dimension it’s less likely to make people think it’s working when it’s not.
 
Sorry for slightly off topic post but,

Jonathan Edwards said:
Cyclo really doesn't do much to B cell activity on its own at the doses given so it is highly unlikely that it had an effect through B cells (particularly as even rituximab did nothing). Cyclo might conceivably have had a useful effect through some other means but my estimate of the likelihood is close to zero.
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I thought we were interested in cyclophosphamide due to its effect on T-cells?

E.g.

https://www.sciencedirect.com/science/article/abs/pii/S0305737215002030


Low dose cyclophosphamide: Mechanisms of T cell modulation
Author links open overlay panelMutsa TatendaMadondoaMagdalenaPlebanskia
https://doi.org/10.1016/j.ctrv.2015.11.005Get rights and content

Highlights

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Regulatory T cells and effector T cells have a differential capacity to detoxify cyclophosphamide metabolites.

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Gut microbiota plays an important role in the polarisation of T cells to a Th1 and Th17 phenotype in response to low dose cyclophosphamide.

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The duration of drug free intervals affects the efficacy of metronomic low dose cyclophosphamide therapy.

Abstract
Cyclophosphamide is considered one of the most successful chemotherapy drugs and is listed on the World Health Organisations List of Essential Medicines. Since its initial synthesis in 1958, it has been widely used to treat a range of cancers but its use has been declining due to the advent of platinum based and other chemotherapy agents. However, cyclophosphamide is still used either as a single agent or as adjuvant therapy to treat lymphomas, and breast and ovarian cancers at much lower doses. The efficacy of low dose cyclophosphamide is primarily due to its ability to promote anti-tumour immunity, by selectively depleting regulatory T cells and enhancing effector T cell function. Compared to effecter T cells, regulatory T cells have metabolic adaptations that make them more susceptible to cyclophosphamide-mediated cytotoxicity. In this review, we highlight the potential for improving the efficacy of low dose cyclophosphamide by combining insights on the mechanisms of cyclophosphamide-mediated cytotoxicity, and how these cytotoxic effects of cyclophosphamide influence T cell function, thereby contributing to anti-tumour immunity.
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leokitten said:
That you feel there isn’t any point on this forum for members to give their anecdotal accounts of improvements on specific treatments, and that you seem to know, with such certainty, that any major, rapid, and fairly long lasting improvement anyone’s experienced is due to placebo effect or something else not related at all to treatment efficacy. I know you have no idea or basis for making such a statement.
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And I did not say it. I can understand why my comments my be irksome but please read what I say each time and note that I am simply advising caution and raising a specific factual example (rituximab) where we know the answer.

There is no problem with people mentioning anecdotal accounts but I wanted to point out that it is misleading to say that placebo effects are unlikely in ME. S4ME exists because there was once a forum where people were very sensitive about any critical comments about the validity of interpretation of personal reports. It was considered unacceptable to suggest that drinking bleach might be quackery, or to critique fringe immunological treatments. Two groups with different approaches went their separate ways. The ethos on S4ME is to be cautious and critical. We all make mistakes and argue things we shouldn't from time to time but having that pointed out amicably is what is so productive here. I have given clear reasons why personal reports have to be considered problematic even if the person concerned is convinced they are meaningful. It isn't easy to swallow but then learning to be critical of one's own work as a scientist isn't easy either.

Aripiprazole might be of significant value for some PWME, even if that tends to suggest that ME might be a 'psychiatric' disorder. But flurries of reports from another forum are not what would raise my interest. As the person who initiated the use of rituximab in autoimmune rheumatic diseases I ended up in the middle of the flurry over rituximab for ME with emails from physicians all over. Some PWME felt better overnight. Some got disastrously worse. And in inexperienced hands it is a seriously dangerous drug. But the bad outcomes tend not to follow the social media trail.

As I once said when on the board of the other forum I think that the Hippocratic dictum of 'First do no harm' applies just as much to the general public as to physicians. We have it formalised because it is in sharp focus at work, but its moral basis applies to everyone.
 
Jaybee00 said:
Sorry for slightly off topic post but,
I thought we were interested in cyclophosphamide due to its effect on T-cells?

E.g.

https://www.sciencedirect.com/science/article/abs/pii/S0305737215002030
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Fluge and Mella used cyclophosphamide because they thought it was an alternative to rituximab for B cell targeting. I don't know where the idea came from that it was being directed at T cells.

The paper you quote seems to be about the immunostimulatory effect seen with low dose cyclophosphamide in cancer treatment. I cannot see any relevance to ME. To be honest the paper looks like immunobabble. It seems to be almost entirely based on old speculations dragged up from the 1980s and 1990s - as so often is the case for review articles in immunology.
 
Jonathan Edwards said:
Fluge and Mella used cyclophosphamide because they thought it was an alternative to rituximab for B cell targeting. I don't know where the idea came from that it was being directed at T cells.

The paper you quote seems to be about the immunostimulatory effect seen with low dose cyclophosphamide in cancer treatment. I cannot see any relevance to ME. To be honest the paper looks like immunobabble. It seems to be almost entirely based on old speculations dragged up from the 1980s and 1990s - as so often is the case for review articles in immunology.
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I could be totally remembering it wrong, but didn’t they also choose cyclophosphamide for its potential effects at killing longer lived plasma cells?
 
leokitten said:
I could be totally remembering it wrong, but didn’t they also choose cyclophosphamide for its potential effects at killing longer lived plasma cells?
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Long lived plasma cells are part of the discussion but you need lethal (with rescue) doses of cyclo to get at them meaningfully. That was the brick wall I hit with rheumatoid. Tolerable doses of cyclo really do not dent plasma cells, even if they do a smidgin more than rituximab which does not touch them.
 
Jonathan Edwards said:
There is no problem with people mentioning anecdotal accounts but I wanted to point out that it is misleading to say that placebo effects are unlikely in ME. S4ME exists because there was once a forum where people were very sensitive about any critical comments about the validity of interpretation of personal reports. It was considered unacceptable to suggest that drinking bleach might be quackery, or to critique fringe immunological treatments. Two groups with different approaches went their separate ways. The ethos on S4ME is to be cautious and critical. We all make mistakes and argue things we shouldn't from time to time but having that pointed out amicably is what is so productive here. I have given clear reasons why personal reports have to be considered problematic even if the person concerned is convinced they are meaningful. It isn't easy to swallow but then learning to be critical of one's own work as a scientist isn't easy either.
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Im mostly in agreement regarding PR, I think the forum went a little overboard regarding treatments. People here who know me from there know I’ve been critical of that over the years and got attacked for it.

But I believe it’s a good idea that both S4ME and PR forums exist with their different rules, I think they are both very valuable and complimentary and personally feel it would be a loss if one existed and not the other.
 
Jonathan Edwards said:
Long lived plasma cells are part of the discussion but you need lethal (with rescue) doses of cyclo to get at them meaningfully. That was the brick wall I hit with rheumatoid. Tolerable doses of cyclo really do not dent plasma cells, even if they do a smidgin more than rituximab which does not touch them.
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I know this is getting off topic, but have there been reports of pwME going into remission or massive improvement after getting a bone marrow transplant for cancer?

I remember reading in a news article or review paper that this can cure MS. It would also help answer if ME is truly immune mediated.
 
Trish said:
I wonder whether the expectation is really ever zero.
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Expectation can also change during a therapy - eg you may be skeptical at the start, but after investing time/effort/money into trying something, your expectation may change to justify this time/effort/money.

Hence measures of expectation before a trial (such as in the PACE trial) don't effectively control for this bias.
 
(Off topic.. Not about Rituximab or ME, but I couldn't find a better thread.)

A Swedish psychologist/doctoral student (if that's the correct word in English?) at Karolinska Institutet is asking for reading recommendations on placebo and psychoterapy research. I believe she's genuinely interested.

 
mango said:
(Off topic.. Not about Rituximab or ME, but I couldn't find a better thread.)

A Swedish psychologist/doctoral student (if that's the correct word in English?) at Karolinska Institutet is asking for reading recommendations on placebo and psychoterapy research. I believe she's genuinely interested.

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She could start with the paper by Knoop, White and others from 2007 (Psychother. psychosom. ;76(3):171-6.
doi: 10.1159/000099844.) which says that CBT is meant to be a placebo - it is intended to work the way placebos work. White of course later denied that there was a placebo effect in ME but claimed that CBT worked in ME. If she can figure all that out she deserves a doctorate.
 
I have come across an intersting term which may be part of this discussion. Benign symptom reattribution.

In the acute primary care setting it has been shown that vague somatic complaints respond as readily to nonspecific remedies and the absenceof a disease label as they do to a specific diagnosis and conventionaltreatment. this is undoubtedly due to the effects of a benign symptom reattribution by the patient (as a result of history taking and examination), to physician reassurance, and to spontaneous remission

The management of chronic illness behaviour ,Barry Blackwell and Mary Gutmann in Illness Behaviour a multidiciplinary model eds McHugh and Vallis 1987
 
Well.. Im pretty sure I cant get a placebo with this. I took Rituximab with no placebo also, and my symptoms dont go away momentarily even if I believe in a treatment. Apparantly a lot of ME-patients can though, it puzzles me. Im not sitting on a high horse saying that, just saying I dont get it from my own experience.
 
Marky said:
Well.. Im pretty sure I cant get a placebo with this. I took Rituximab with no placebo also, and my symptoms dont go away momentarily even if I believe in a treatment. Apparantly a lot of ME-patients can though, it puzzles me. Im not sitting on a high horse saying that, just saying I dont get it from my own experience.
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Same experience here. I was fairly newly diagnosed when I tried rtx and extremely hopeful, especially during early summer when I felt a bit better (I didn’t know at the time that this is a part of my yearly pattern). In spite of all that I quickly realised it wasn’t doing anything at all.
 
andypants said:
Same experience here. I was fairly newly diagnosed when I tried rtx and extremely hopeful, especially during early summer when I felt a bit better (I didn’t know at the time that this is a part of my yearly pattern). In spite of all that I quickly realised it wasn’t doing anything at all.
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Exactly. I had the same summer spike as well, and thought to myself - this is probably nothing, so I went out to bike and see what it meant, and i got heavy PEM
 
Jonathan Edwards said:
I agree that ME is not fatigue but I think patients who still felt significantly ill would not rate fatigue as nil. 'Fatigue' is accepted as the index of feeling ill in the absence of a better term.
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I have very severe ME and I don't normally (if I get enough sleep) feel any fatigue.
 
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