Phase III Rituximab Trial - News

[Jenny TipsforME]

he said about 30% had responded,

Oh that’s actually a lot more positive than I had interpreted from the news. I’d consider being able to treat a third of pwme (or people previously misdiagnosed) a substantial advance.

It gets better if you can know before treatment who will respond.

Though I respect the lack of spin.

But my severe POTS, breathing issues, and orthostatic intolerance were the same every day. There was no amount of pacing or resting that changed them until I did IVIG and Rituximab.

I can’t think of what I’m thinking of right now, but isn’t there some evidence already that the POTS subgroup are the likely rituximab responders?

In more than one study comorbidity is *30%* (of course quite possibly not the same people). Are they treating POTS more than ME? Or people whose ME is somehow mostly a response to POTS? Autoantibodies have been found in POTS. Or perhaps the POTS subgroup have biologically distinct ME?

I should add I have confirmed POTS so this is a very personal clutching at straws! I was shocked to discover how similar POTS is to ME, and pleasantly surprised to find how many of my symptoms improved with POTS treatment. But I definitely get delayed PEM so I believe I have genuine comorbidity.

It should be noted though that even a delayed response to exercise isn’t entirely unique to ME. I’m looking into Periodic Paralysis and that can have a similar thing of next day weakness/movement difficulty following exercise (also delayed reaction to glucose/potassium/sodium which makes trying to find patterns through a diary method very tricky). They also get brainfog and some POTS comorbidity. Not everyone who has it gets full paralysis, it can be more like episodes of weakness.

See this booklet https://docs.google.com/open?id=0B-savOlQA6QCZjRjODdlMWYtM2M4NC00ODFlLWE4MDMtMGIyOWFmZjJiMmNi

Noticeably I read something about the weakness sometimes being attributed to CFS (may not be this leaflet).

NB this is supposedly very rare, though always possible it is simply rarely diagnosed.

Re Unrest, the first time I saw one of Jen’s video clips I was struck by feeling like I saw myself reflected for the first time. But I don’t think we should fall into thinking this is the one way that ME looks. I lived with my sister, who I believe did have classic ME, and it didn’t look quite the same. When I watched Unrest in full I felt like the movement difficulties Jen has actually don’t look quite like mine. The passing as fairly healthy then crashing and feeling terrible I relate to (though I’ve not had something like when she’s on the porch in agony).

I think that’s THE message that needs to be broadcast. ME is not only a health crisis, that’s a hidden epidemic, but it’s also a horrible death row sentence for PwME that have no support at home.

I think there are many stories about our experiences that need telling. Now that Unrest is paving the way in terms of awareness of our general health plight, I think this is one of the next stories that people should hear. Isolation that can only be relieved by effective treatment because we cannot tolerate social contact. Isolation as a form of society neglect. AfME did do some work on that side.

Also the many practical ramifications of chronic inability to earn money and vicious cycle of poor housing, poor food, fuel poverty and health deterioration.

I fully agree that if ME/CFS is a metabolic disorder than Rituximab should not have any affect

I can’t explain how but I don’t think this is necessarily true. I had the impression that people like Ron Davis and the Norway team theoretically understood how they could be linked. Immunometabolism is a sub discipline eg https://www.omicsonline.org/conferences-list/immunometabolism-and-autoimmunity

 

[Woolie]

I wonder whether we're constantly coming up against the heterogeneity problem? That would certainly explain why a trial with a small group can yield positive effects, whereas one with a larger group yields null effects.

For a while there, many of us believed MECFS could represent a group of different diseases, with different disease processes, but with a common outcome. Then many began to prefer the unitary disease explanation.

I wondered with the recent cytokine trial whether we needed to return to idea that MECFS is many diseases. I can't help thinking there might be more to get from that cytokine data if we were to adopt a case series (as opposed to a group) approach.

Edit: Oh, I see scarecrow already made the same point. - and @Diwi9 too!

 

[BurnA]

I read in a Facebookthread from someone who attended Mella's lecture yesterday that he said about 30% had responded, not 50% or more, as was the limit for a positive study.

I think the key information we are missing is the placebo response rate.

50% would not typically be a requirement, really a result statistical significant over the placebo response rate should be enough to indicate a positive result.

The 30% response rate suggested in the ritux arm is also meaningless until we know placebo response rate. If that is also 30% then...

 

[Scarecrow]

Eh, not quite @Woolie I said it more simply, you put it into context.

 

[Sasha]

he said about 30% had responded,

Oh that’s actually a lot more positive than I had interpreted from the news. I’d consider being able to treat a third of pwme (or people previously misdiagnosed) a substantial advance.

I think there's maybe some confusion here from the F&M's use of the term 'responders' to denote patients who get over specific thresholds for certain questionnaire scores. It doesn't mean that they have 'responded' to the treatment (or the placebo). It just means that they fall into a certain bracket on the questionnaire scores.

So if there's no difference between the number of 'responders' in the rtx and placebo arms, there's no evidence that anyone is responding to anything.

 

[Andy]

Only recently Ian Lipkin made the point that he thinks it's either several diseases or one disease with multiple sub-groups, I can't recall exactly which but it's in the recent Solve video interview.

 

[Scarecrow]

Bottom line is we'll have to wait six or seven months until we find out the true response rate. If there are even just 10% genuine responders, it'll still be great news. It's another piece of the jigsaw.

 

[Sasha]

Bottom line is we'll have to wait six or seven months until we find out the true response rate. If there are even just 10% genuine responders, it'll still be great news. It's another piece of the jigsaw.

But if the trial is null, surely there's no statistically significant difference between the number of 'responders' in the placebo and rtx arms?

I think this term 'responders' is confusing. It just means people who are over certain questionnaire thresholds, doesn't it? Who could have just naturally had improvement over time or be responding more positively to questionnaires because they're in a clinical trial and think they might have received active treatment? It doesn't reply response to treatment. (I wish they'd used a different term!)

 

[Scarecrow]

But if the trial is null, surely there's no statistically significant difference between the number of 'responders' in the placebo and rtx arms?

I'm not sure if the trial has been declared null. Marky90 says that "rituximab failed to be clinically effective". Perhaps I'm clutching at straws ( ) but I didn't necessarily take that to mean 'no statistically significant difference', rather that the number needed to treat in the absence of a biomarker is too great to justify the use of rituximab.

I think it was deleder2k (edited: or was it Kalliope) who said that Fluge and Mella wanted to break the news to protect patients. They have always advised that people shouldn't be taking rituximab for ME/CFS outside of a clinical trial.

Marky90 also said:

They don't know if they will study Rituximab more, if they would they probably have to identify the subgroup.

 

[Adrian]

But if the trial is null, surely there's no statistically significant difference between the number of 'responders' in the placebo and rtx arms?

If that is what they are measuring rather than group means.

If the numbers of responders are low then there may not be sufficient power to make them statistically significant. But there could be a small number with really significant improvements. Then the question is why - it wouldn't suggest that Ritux is a good treatment.

 

[Jenny TipsforME]

But if the trial is null, surely there's no statistically significant difference between the number of 'responders' in the placebo and rtx arms?

Not necessarily.

I’m thinking of the Hornig study

“We report here distinct alterations in plasma immune signatures early in the course of ME/CFS (n = 52) relative to healthy controls (n = 348) that are not present in subjects with longer duration of illness (n = 246). Analyses based on disease duration revealed that early ME/CFS cases had a prominent activation of both pro- and anti-inflammatory cytokines as well as dissociation of intercytokine regulatory networks. We found a stronger correlation of cytokine alterations with illness duration than with measures of illness severity, suggesting that the immunopathology of ME/CFS is not static.”
http://advances.sciencemag.org/cont...TrendMD&utm_medium=cpc&utm_campaign=TrendMD_1

IIRC if you lump everyone in together the results are null, but if you separate groups by duration the findings are in opposite directions. A null result can mean the averaging out of group differences.

A subgroup could be statistically different from the placebo arm AND the other rituximab participants.

 

[Woolie]

I'm probably sounding like a broken record here, but I do think that B cell depletion will only have a good effect if one has a dysfunction involving the adaptive immune system. That is, a problem involving the production of antibodies.

If many of us here have a dysfunction involving the innate immune system - the one primarily responsible for inflammation and other flu-like symptoms - then removing B cells will do little to improve that.

Alvin, I am still thinking it is the people with auto-antibodies who are the potential responders but I have always wondered what is the overlap between autoimmunity and those with MCAS and/or toxic mold exposure?

Yes, I would expect you'd have to have an autoimmune disease or some other problem involving the adaptive immune system (e.g. allergies) to benefit.

 

[lansbergen]

I'm probably sounding like a broken record here, but I do think that B cell depletion will only have a good effect if one has a dysfunction involving the adaptive immune system. That is, a problem involving the production of antibodies.

If many of us here have a dysfunction involving the innate immune system - the one primarily responsible for inflammation and other flu-like symptoms - then removing B cells will do little to improve that.

Yep

 

[Sly Saint]

I still Oystein Fluge

 

[Jenny TipsforME]

, I would expect you'd have to have an autoimmune disease

Experientially ME feels autoimmune to me.

For example, when my body switches to fighting a new virus I get an unusual brainfog holiday just before the virus symptoms.

My brainfog fluctuates a lot, but it is a noticeable pattern.

This could well be an entirely flawed perception but my experience is as if my body is mistaking part of me as a threat, until a more urgent threat is perceived and immune system attention is directed elsewhere.

That’s definitely not saying that viruses are a good thing for me. I’m sick longer than other people and my ME relapses have always been post viral (sometimes combined with too much activity).

I was expecting this research to be building up a picture that ME is an autoimmune disease (as well as metabolic).

 

[Woolie]

Yep

Yep, I AM sounding like a broken record, or Yep, you think so too?

 

[lansbergen]

Yep, I AM sounding like a broken record, or Yep, you think so too?

I think so too

 

[Valentijn]

I notice likes from both Michael Sharpe and the LP-coach Live Landmark

So "undue hype" must refer to simply conducting any biomedical research, because the authors of this study were about as anti-hype as someone could get. But I doubt that tweeter has a problem with the actual mid-trial and other hype from PACE

 

[arewenearlythereyet]

Experientially ME feels autoimmune to me.

For example, when my body switches to fighting a new virus I get an unusual brainfog holiday just before the virus symptoms.

My brainfog fluctuates a lot, but it is a noticeable pattern.

This could well be an entirely flawed perception but my experience is as if my body is mistaking part of me as a threat, until a more urgent threat is perceived and immune system attention is directed elsewhere.

That’s definitely not saying that viruses are a good thing for me. I’m sick longer than other people and my ME relapses have always been post viral (sometimes combined with too much activity).

I was expecting this research to be building up a picture that ME is an autoimmune disease (as well as metabolic).

I would go for immune dysfunction as a gut feel . However I wouldn't base that on how I respond to a virus. I find the dysfunction being more about how frequently I get skin infections and how long it takes for these to clear up. I have always been a staph aureus A carrier so have never had acne or problems with skin infections before I got sick. Now it takes 8 weeks for a simple cut to clear up once infected. Almost as if my immune system is inefficient at dealing with my skin flora.

I've just recovered from a bad cold. After 3 weeks it's still hanging around, but I seem to have a bit more energy (cognitive and physical). I got my symptom day off on Monday (2 days ago) after the main symptoms had lifted. Looking at the "controls" of healthy people who were also exposed to the virus ( my family ...big do ...about 8 of us got this cold from my lovely cousins small children), my recovery rate isn't that different to how long others have had symptoms (2 weeks). This says to me that the "remission day" is linked to my immune system dealing with a new antigen and is probably more about use/prioritisation of metabolic energy.

So there appears to be a difference in how I respond to something new vs how well I respond to antigens my immune system already recognises. Again this might be nothing to do with the immune system itself, but more about metabolic energy deficit or even poor circulation/poor wound healing. It just feels immune related in some way. (Feelings are not very scientific...so I do tell myself off periodically). Sorry if that rambled a bit.

 

[Adrian]

I wonder whether we're constantly coming up against the heterogeneity problem? That would certainly explain why a trial with a small group can yield positive effects, whereas one with a larger group yields null effects.

I wondered about that. The recruitment strategy may play a big part as well. If I remember correctly the phase 2 trial recruited from the neurology department.