Cytokine Inhibition in Patients With Chronic Fatigue Syndrome: A Randomized Trial

[A.B.]

Patients who did not have a post infectious onset were included in other words patients who did not have the disease ... As usual setup to fail instead of set up to find out ...

The Naviaux study also included patients with non-infectious onset and they had the same metabolic signature. It seems we're dealing with something that can be set off by multiple things, maybe even by chance alone.

 

[Dolphin]

Miriam Tucker has written about this in Medscape:
"Cytokine Blocker Does Not Ease Chronic Fatigue"

The article includes an interview with prof. Montoya.

Dr Montoya listed several possible reasons for the negative findings. First, "I think you'd need to go after more than one cytokine," he said, adding that IL-1, one of the proinflammatory cytokines most often associated with fatigue, "was a sensible target, a logical target, but the immune system overactivation that we are seeing in these patients appears to be broader. It's possibly coming from both innate and adaptive immunity."

In addition, Dr Montoya believes that the 4-week study duration probably was not long enough. "I think if one is going to see an effect on a disease that has been present for years...it's going to require more sustained treatment: at least 6 months, and possibly a year."

 

[Dolphin]

I find it more interesting that they didn't actually measure IL-1 (if they did, it's not mentioned in the baseline patient characteristics or the outcomes). If it's not elevated to begin with, the intervention will probably do nothing.

Additional outcome measures (body temperature, heart rate, cytokine and cortisol concentrations, and microbiome) were collected and will be reported elsewhere.

 

[Dr Speedy]

The Naviaux study also included patients with non-infectious onset and they had the same metabolic signature. It seems we're dealing with something that can be set off by multiple things, maybe even by chance alone.

One was set up to find out the other to fail makes a big difference; selecting patients who don't have the disease is a trick used by the biopsychosocial model for years and was the basis for creating the Oxford criteria; which means that you are comparing apples and pears

 

[Anne]

I was expecting this study to be negative. Since it is likely to not have selected patients with actual ME (as defined by CCC or ICC), I'm afraid it doesn't really give us much information about whether or not anakinra would be effective in actual ME (with obligatory PEM).

So, @Jonathan Edwards , couldn't there still be a chance that IL-1 inhibition could work in actual ME patients? We have at least two anectodal reports of improvements for ME patients with anakinra, one with reportedly very substantial improvement.

Quotes from the previous thread (is one allowed to to this, quote from other threads? if not, please let me know and please forgive me):

http://forums.phoenixrising.me/inde...bitor-in-me-cfs-dutch-study-discussion.32730/

The principal investigator for the trial is Jos van der Meer, one of the Dutch psychobabblers. So it'll primarily include chronic fatigue patients, the results will be spun to obey the prime directive that only CBT can be helpful, and even if they're forced to publish any indication of improvement, they'll conclude that the treatment is too dangerous for patients with something as non-serious as CFS and that CBT is still the superior treatment.

Anyone wanna place some bets?

I think you are right, @Valentijn. I'm getting more convinced that the results will be negative, and they will use them for their spin. It doesn't matter that there is at least one good immunologist from elsewhere involved in the study, if patient recruitment is bad, the results will not be representative of ME.

They are using the Fukuda criteria, so no obligatory PEM as far as I understand. And am I right in assuming that the fact that they are recruiting from their "chronic fatigue" clinic means the study will have the same problems as MEGA: that the majority of the patients there don't have actual ME (CCC or ICC defined), because informed ME patients don't (as you say) go near them, and ME patients who do go there drop out because CBT/GET makes them worse, or are cut of because they don't respond to CBT/GET?

Probably. Most of the people at the clinic I went to did not have ME/CFS. There were 3 or 4 I could see it in ... most were nicely dressed and with make-up, bored and fidgeting, bouncing babies on their laps, etc, in the waiting room.

The clinic I was at (not Nijmegen) also kicks patients out after 12 months, according to the contract, though sometimes might extend the "treatment" to 18 months for an additional fee. In my case, the travel, "relaxation" therapy, and stair climbing to get to offices was making me crash, so I cancelled my future appointments. They retaliated by removing their diagnosis of me having CFS, and replaced it with a diagnosis of being overweight

I wouldn't trust a single thing coming out of a Dutch fatigue clinic, except the horror stories coming from patients!

 

[perovyscus]

I am only partially informed on the intricacies of patient selection criteria in CFS. The NIH study excludes people with CFS longer than 5 years duration, too. The cutoff was used because IL-1 is higher in recent onset patients. I know it is still run-of-the-mill pernicious data massage --- but they actually identified a rational conceptual framework to justify it.

Given the dire state of CFS treatments, a mechanistic explanation is not required, so nor should that cut-off. Anakinra is just safe enough... until you start treating people empirically with it, maybe.

I cannot speak to the track records of these researchers. I wonder about co-morbidity in the beneficial anecdotal reports of anakinra use. Fibromyalgia and periodic fever syndromes share genetic overlap, and anakinra has been successfully used to treat the latter.

If I had to guess, the study duration was designed in a mostly insufficient way due to the private funding.

I have seen some posters in this thread that know more about the biology of CFS than I do neglect to strongly point out one sentiment: the immunological rationale for using anakinra in CFS is pretty weak given the current paradigm.

I would expect it to be harmful, and be glad it was helpful.

This reminds me of in the 1990s everyone thought circumcising patients in areas endemic with HIV had limited evidence (or could be harmful), and was definitely not recommended. It had limited evidence for the next decade. People kept making the same limited evidence via observation, cross sections, drawing patient's blood, talking about how darn limited the evidence was. Finally, someone had the bright idea to run the trial. It helped. It was replicated.

The same thing was happening with IL-1 in CFS, repeatedly. I am thankful someone did a trial. Who knows how long it would have taken without that donor. I hope it is pseudo-replicated, but how often does that happen?

 

[Anne]

I wish a proper study using narrow criteria with obligatory PEM (CCC or ICC) had been done. I'm afraid all treatment studies done on "chronic fatigue" rather than ME are just muddying the waters. The patients at these Dutch Fatigue Clinics are likely to have long-term fatigue of various causes rather than actual ME.

I'm hoping another study, with CCC or ICC, gets done before anakinra is abandoned as a possibility in ME.

 

[halcyon]

I'd be interested to see anakinra (and remicade) tested in the emerging cell-based metabolic models, ala Davis, Fluge & Mella, and Wong etc to see if it abrogates the metabolic effects of exposure to patient serum. As others have mentioned before, you could basically predict that this study was going to fail for various reasons, but I still think IL-1 and TNF alpha are reasonable suspects for some of the metabolic changes seen.