Cytokine inhibition - a randomized placebo-controlled, double-blind trial

[Valentijn]

fraudulous

My Dutch fiance used the same word about 10 times yesterday when I told him about the recent Dutch research which used some fake patients to contribute to the results.

"Fraudulous" is never used in American English though - only "fraudulent". I don't think it's used in British English either, since I can't find any online dictionary entries for it But it does seem to end up in a lot of translations of other languages into English!

 

[Jonathan Edwards]

Except the questionnaire being used isn't about feeling healthy, and certainly not about being healthy and able to do more. It's a questionnaire about fatigue, designed by verified psychobabblers who believe that ME/CFS == fatigue.

That may well be the case Valentijn - I fully agree. I was simply arguing that measuring symptomatic change has to be the primary end point if any single variable is. It is what Fluge and Mella use in their studies. They may well have a better score but they are assessing fatigue. Having IL-1 levels as a primary endpoint would prove absolutely nothing, as I think you realise. And at the moment surrogates like physiological measures that might add explanatory value have not been validated.

 

[Bob]

"Fraudulous" is never used in American English though - only "fraudulent". I don't think it's used in British English either, since I can't find any online dictionary entries for it But it does seem to end up in a lot of translations of other languages into English!

I like the word, but you're right; it's not a word we use in the UK. I've never seen it before.

 

[Effi]

My Dutch fiance used the same word about 10 times yesterday when I told him about the recent Dutch research which used some fake patients to contribute to the results.

"Fraudulous" is never used in American English though - only "fraudulent". I don't think it's used in British English either, since I can't find any online dictionary entries for it But it does seem to end up in a lot of translations of other languages into English!

You gotta admit though it does make that fraud sound snazzy! So I'm gonna keep on using it until it becomes a real word.

 

[Jonathan Edwards]

I actually think that if this score system is used:


I feel tired.
Physically I feel exhausted.
I feel fit.
I feel powerless.
I am rested.
Physically I feel I am in bad form.
I tire easily.
Physically I feel I am in an excellent condition.

and a truly blinded study is done then if no difference at all is seen the drug is pretty useless and if a big difference is seen the drug is worth investigating further. I would have thought it would work for almost any disease that limits mobility. I am pretty sure if I used it for my RA rituximab trial it would have given the right result. As we have discussed in the thread on end points I am sure one could do much better but if the study is truly blinded this sort of endpoint is fine.

For me the key to improving the quality of research is to get the critique precisely on target. The problem with PACE is the combination of no blinding and this sort of end point. This study does not appear to suffer from that - although blinding is easily broken. That is an important issue but if blinding is broken then none of these assessments are likely to be much good - even functional ones that might be affected by beliefs about the treatment.

 

[lansbergen]

I actually think that if this score system is used:


I feel tired.
Physically I feel exhausted.
I feel fit.
I feel powerless.
I am rested.
Physically I feel I am in bad form.
I tire easily.
Physically I feel I am in an excellent condition.

What has I feel powerless have to do with it? I am pretty sure that will be used in the sense of helpless.

For me the only constant in the list is: I tire easily. The rest is worthless.

For instance now I sleep like a baby I am rested in the morming but I still tire easily and depending on hpw much I push I will get tired or exhausted

 

[snowathlete]

I only know it was offered, but I would suspect it to be carried out AFTER the entire anakirna trial + questionaire/evaluation was finished. Otherwise the whole trial would be fraudulous to begin with. From a rational point of view they probably thought of offering CBT as an incentive for patients, as 'CBT is the only evidence based treatment for cfs'. A bit like how in other new medication trials after it is finished they offer a different, already tested and approved medicine to the patients in the placebo group, so everybody gets something out of it. Offering CBT along the same lines is a pretty hilarious concept, but let's try to be positive and imagine they offered this with the best intentions.

I'll tell you what will happen: the trial won't produce a positive result and then they will publish a follow up trial of CBT on the same patients, and report that whereas a biological intervention failed previously, a psychological one produced some benefit. Of course, this will be aided by the use of Fukuda criteria and careful patient selection.

Maybe I am too pessimistic but I honestly wouldn't be surprised.

 

[Sidereal]

I would be shocked if everyone here hasn't had CRP measured at least once if not countless times during the course of their illness. If you come in complaining of fatigue and musculoskeletal pain, even the least competent doctor will measure your CRP and sed rate. And when those come back at near 0, as they typically (though not always) do in this patient population, those results along with other normal results from the bog-standard blood workup they gave you are then used as a weapon against your claim that you are ill.

There is no conspiracy. If these standard indicators of inflammation were reliably elevated in ME, they wouldn't be sticking us into psych hospitals, they'd just be referring us on to rheumatology to be prednisoned. I don't understand why in 2015 we are still wasting time on hypotheses involving CRP, IL-1, IL-6, TNF-a etc. If only it were that bloody easy this disease wouldn't be such an excruciatingly difficult mystery to figure out and we'd have some treatments already.

 

[Bob]

Details on clinicaltrials.com in case interesting for anyone:
https://clinicaltrials.gov/show/NCT02108210

And (hands up, who remembers?) a previous thread about this study:
http://forums.phoenixrising.me/inde...bitor-in-me-cfs-dutch-study-discussion.32730/

 

[Effi]

Maybe I am too pessimistic but I honestly wouldn't be surprised.

I always try to be positive about this too, but we've seen our hopes crushed one too many times...

I was reading a discussion about this trial on a local forum a couple of months ago and something was said about anakinra being used for other immune-related illnesses like RA. In RA it takes 4 months for patients to start seeing real benefits. So the question was: why are they doing a 4 week trial? Is this even long enough to get any benefits from it? This clinic and some of the researchers in this paper have an extremely bad reputation in the local me/cfs community. So people were really questioning if their intentions were genuinely good, or if they were playing another one of their dirty games, i.e. halfheartedly testing a drug which they know will probably not work in such a short time span, only to prove that CBT is still the only real evidence based treatment. This is all just hearsay and subjective speculation, but it's not like we haven't seen them play these games before...

 

[Valentijn]

In regards to CRP in ME/CFS:

• http://europepmc.org/abstract/med/9034999 (Fukuda CFS) - "Compared to control subjects, mean concentrations of C-reactive protein, beta 2-microglobulin, and neopterin were higher in patients with CFS (p < or = 0.01)"
• http://jid.oxfordjournals.org/content/177/2/451.full.pdf html (Oxford CFS) - "Values for patients were similar to those for controls (median, 0.5 and 0.7 mg/L, respectively)"
• http://www.sciencedirect.com/science/article/pii/S0889159108004261 (Empirical CFS) - "Log-transformed mean plasma concentrations of hs-CRP were increased in subjects with CFS (n = 102) and in subjects with unwellness symptoms that did not meet diagnostic criteria for CFS (defined as “insufficient fatigue” [ISF]) (n = 240) when compared to subjects who were well (n = 115)"
• http://www.clinsci.org/content/114/8/561 (Fukuda CFS) - "Patients with CFS also had significantly increased levels of CRP (C-reactive protein) (2.58±2.91 compared with 1.07±2.16 μg/ml respectively; P<0.01)"
  
• http://www.termedia.pl/Clinical-res...th-chronic-fatigue-syndrome,19,19713,1,1.html (Altered Fukuda CFS - No PEM, OI exclusionary) - "C-reactive protein, fibrinogen and blood glucose levels were also in the normal range and did not differ between the groups"

Out of the first 10 pages (100 entries) on google scholar when searching for "C-reactive protein" and "chronic fatigue syndrome", these seem to be the only relevant results, though there were also a few pay-walled articles without the necessary info in the abstracts. By page 10, there were only one or two CFS articles per page, and the rest were only citing to CFS research.

Oxford CFS (general chronic fatigue) does not seem to be associated with elevated CRP. Nor does a version of Fukuda CFS where PEM was not one of the potential symptoms listed during recruitment, and hypotension was exclusionary. Patients recruited with normal Fukuda CFS do show increased CRP compared to controls. The increased CRP in patients recruited with the Empiric criteria disappeared after they made about a dozen irrelevant "corrections", so I have no idea what to make of that.

But it's possible that the subset of ME patients in the Fukuda and/or Empirical groups might have an even more marked increase of CRP, if looked at in isolation or as part of a larger group only consisting of ME patients.

Overall, CRP has rarely been studied. It is used in nearly every study to exclude a CFS diagnosis, as a presumed indication that the patient has a "real" medical disease. Though no one ever says what those excluded patients actually have instead

 

[Valentijn]

You gotta admit though it does make that fraud sound snazzy! So I'm gonna keep on using it until it becomes a real word.

Yeah. I took it a little further and started using "fraudulicious"

 

[Effi]

What has I feel powerless have to do with it?

I had the exact same reaction. But I think it's just a clumsy translation from Dutch ('ik voel me krachteloos'). In Dutch it makes sense physically, as in 'I feel devoid of strength'.

 

[Effi]

Yeah. I took it a little further and started using "fraudulicious"

ha! I like it!

 

[Valentijn]

If you come in complaining of fatigue and musculoskeletal pain, even the least competent doctor will measure your CRP and sed rate.

Yup, mine were measured at diagnosis in the Dutch national health system. Both were a bit elevated. Yet the diagnosis of CFS was still given, and no further tests were run.

And when those come back at near 0, as they typically (though not always) do in this patient population, those results along with other normal results from the bog-standard blood workup they gave you are then used as a weapon against your claim that you are ill.

I haven't seen any research showing low CRP values in ME/CFS patients, and I just looked for it over the past couple hours. Are we sure ESR and/or CRP values are often low in ME patients, or is that just a self-perpetuating rumor based on perceptions?

 

[Bob]

Yeah. I took it a little further and started using "fraudulicious"

supercalifrauduliciousexpialidocious ?

 

[Effi]

supercalifrauduliciousexpialidocious ?

LOL @Bob you win!

 

[Sidereal]

Yup, mine were measured at diagnosis in the Dutch national health system. Both were a bit elevated. Yet the diagnosis of CFS was still given, and no further tests were run.

Some people with a diagnosis of CFS will have autoimmune comorbidities such as RA or chronic infections like Lyme which can result in elevations of these markers but that doesn't mean that CFS in itself leads to elevated CRP/ESR.

 

[Snow Leopard]

James Coyne said this on Twitter: "This trial exploits #CFS patients, is unethical if consent does not inform no scientific basis for cytokine target."

But surely the patients would be informed that the use of the drug is highly speculative and it is uncertain if IL-1 is involved at all?

I can't tell from the article.

 

[SOC]

SOC says you needn't have bothered to do any of that 'cos nobody has measured the CRP and that would have proved ME was a biological disease just the same.'

Where do you get this stuff? I said nothing of the kind.

I said:

We don't know whether or not CRP is raised in ME. The evidence simply doesn't exist one way or the other.

I think Mady Hornig would agree with my actual statement. As for your lie... well, probably not.