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

[A.B.]

Background:
Interleukin-1 (IL-1), an important proinflammatory cytokine, is suspected to play a role in chronic fatigue syndrome (CFS).

Objective:
To evaluate the effect of subcutaneous anakinra versus placebo on fatigue severity in female patients with CFS.

Design:
Randomized, placebo-controlled trial from July 2014 to May 2016. Patients, providers, and researchers were blinded to treatment assignment. (ClinicalTrials.gov: NCT02108210)

Setting:
University hospital in the Netherlands.

Patients:
50 women aged 18 to 59 years with CFS and severe fatigue leading to functional impairment.

Intervention:
Participants were randomly assigned to daily subcutaneous anakinra, 100 mg (n = 25), or placebo (n = 25) for 4 weeks and were followed for an additional 20 weeks after treatment (n = 50).

Measurements:
The primary outcome was fatigue severity, measured by the Checklist Individual Strength subscale (CIS-fatigue) at 4 weeks. Secondary outcomes were level of impairment, physical and social functioning, psychological distress, and pain severity at 4 and 24 weeks.

Results:
At 4 weeks, 8% (2 of 25) of anakinra recipients and 20% (5 of 25) of placebo recipients reached a fatigue level within the range reported by healthy persons. There were no clinically important or statistically significant differences between groups in CIS-fatigue score at 4 weeks (mean difference, 1.5 points [95% CI, −4.1 to 7.2 points]) or the end of follow-up. No statistically significant between-group differences were seen for any secondary outcome at 4 weeks or the end of follow-up. One patient in the anakinra group discontinued treatment because of an adverse event. Patients in the anakinra group had more injection site reactions (68% [17 of 25] vs. 4% [1 of 25]).

Limitation:
Small sample size and wide variability in symptom duration; inclusion was not limited to patients with postinfectious symptoms.

Conclusion:
Peripheral IL-1 inhibition using anakinra for 4 weeks does not result in a clinically significant reduction in fatigue severity in women with CFS and severe fatigue.

http://annals.org/aim/article/26078...nts-chronic-fatigue-syndrome-randomized-trial

 

[A.B.]

@Jonathan Edwards do you agree that this adds to the evidence that we're not dealing with an autoimmune disease with inflammatory effector mechanisms?

 

[Hajnalka]

20% (5 of 25) of placebo recipients reached a fatigue level within the range reported by healthy persons.

 

[NL93]

That's what happens when you include people with "severe fatigue" in a CFS study

 

[JES]

@Jonathan Edwards do you agree that this adds to the evidence that we're not dealing with an autoimmune disease with inflammatory effector mechanisms?

I don't think this study adds evidence to anything that has to do with true CFS/ME. In fact, the null result was predicted here on PR already years ago.

 

[alex3619]

Let me point out an IL-1 inhibitor can only have an effect if IL-1 is very important. At best this study shows that IL-1 is not a key player. At worst the study is not reliable. It also used subjective endpoints. I wish all researchers would move away from those except as secondary supporting measures. Furthermore I find myself starting to get annoyed these days when fatigue is a primary measure. Fatigue is secondary in ME in my current opinion. What happened to the 2 day CPET or other measures? What about OI, energy metabolism, a qEEG or measuring the post exertional metabolites the Lights found to be abnormal?

I have said this before, and I will probably keep saying it, we need some specific work to determine what good measures and endpoints are in ME, or at least a discussion of what is not acceptable. This needs to be done by the relevant biomedical researchers. Qualitative findings are fine as secondary measures, but have no place as primary measures.

I do understand though that research is advancing so fast that any current study measures might be obsolete before the end of the year.

 

[Jonathan Edwards]

@Jonathan Edwards do you agree that this adds to the evidence that we're not dealing with an autoimmune disease with inflammatory effector mechanisms?

I think this is reasonably robust evidence confirming that CFS is not mediated by the sort of inflammation that is associated with an raised ESR or CRP. In broad terms it confirms the idea that we are not dealing with inflammation in any standard sense. If there is an autoimmune mechanism in some or all cases it looks more likely to be the sort of fatigue mechanism that seems to operate in Sjogren's syndrome or lupus where CRP does not rise or some other fatigue mechanism like myasthenia, although that is clearly a different sort of fatigue.ink this is reasonably robust evidence confirming that CFS is not mediated by the sort of inflammation that is associated with an raised ESR or CRP. In broad terms it confirms the idea that we are not dealing with inflammation in any standard sense. If there is an autoimmune mechanism in some or all cases it looks more likely to be the sort of fatigue mechanism that seems to operate in Sjogren's syndrome or lupus where CRP does not rise or some other fatigue mechanism like myasthenia, although that is clearly a different sort of fatigue.

However, as Alex points out, IL-1 is only one of several cytokines that are involved in inflammation and the benefit of anakinra in rheumatoid disease, for instance, is not very dramatic.

 

[Hajnalka]

Didn't realize Jos van der Meer is involved in the study. As far as I know he's kind of the Wessely of the Netherlands. What I read from him so far were recommendations to think positive, exercise and if you have pain: just think about it less. Looked him up, because the only official new information on CFS we had in Germany in the last years is a translation of one of his articles (done by the Charite in Berlin).

 

[Snow Leopard]

Not surprised at the result see previous discussion: http://forums.phoenixrising.me/inde...in-me-cfs-dutch-study-discussion.32730/page-2

Oh and the claims of patients in the "normal fatigue range" is not based on evidence, it is BS.

 

[Valentijn]

Didn't realize Jos van der Meer is involved in the study. As far as I know he's kind of the Wessely of the Netherlands.

Yes, and I fully expected the sort of self-sabotage we get from the British psychobabblers when they pretend to investigate any biological treatments. They only engage in such research so that they can proclaim it a failure which should never be investigated again.

I haven't looked at the methodology yet, but I suspect it's quite poor. In the abstract they already admit the involvement of patients who don't even meet a lax definition of CFS.

 

[A.B.]

The SF-36 physical functioning scores of the sample suggest serious impairment.

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.

 

[mfairma]

I took Kineret for eight months or so, following high IL-1 labs, and it definitely was effective. The effect was not massive, but I was much sicker at the time and the improvement was significant at that baseline, and very welcome.

 

[Valentijn]

Full text at http://annals.org.sci-hub.cc/aim/ar...nts-chronic-fatigue-syndrome-randomized-trial

Protocol is at https://www.ncbi.nlm.nih.gov/pubmed/26438161

This seems a bit unusual, since it wasn't crowd-funded at all:

Primary Funding Source: Interleukin Foundation and an independent donor who wishes to remain anonymous.

CBT and GET get plugged, of course:

The only effective treatments are cognitive behavioral therapy and graded exercise therapy (3–5), although a substantial proportion of patients do not improve with these treatments (6).

It was double-blinded, including blinding the sponsor. This seems to suggest that the sponsor/donor funding the trial was involved in it in some capacity

Participants, all study personnel, and the sponsor were blinded to treatment allocation throughout the study.

Some mid-trial changes to the methodology, such as the exclusion of long-term CFS patients and allowing unspecified meds:

Recruitment started in July 2014 and ended in November 2015; follow-up was completed in May 2016. After approval of the original protocol but before the start of the trial, the number of patients was increased to 50 and a decision was made to exclude patients with illness lasting more than 10 years. During the trial, an amendment was made to allow medication use for less than 14 consecutive days for treatment of adverse events if the medication had no known interactions with anakinra.

Sounds like they changed their mind about an outcome measurement:

The published protocol mistakenly mentioned the number of accompanying CDC symptoms as a secondary outcome measure, whereas the original protocol did not specify those symptoms as a secondary outcome.

Patients were recruited using Fukuda. The abstract may have merely been unclear on that point. But the exception for the 10 year limit stinks a bit of doing contortions to find ways to exclude and include specific patients:

Patients were included if they met the CDC criteria (1, 2), were aged 18 to 59 years, had a maximum fatigue duration of 10 years or recent progression of symptoms, had a score of at least 40 on the fatigue severity subscale of the Checklist Individual Strength (CIS-fatigue), and had a score of at least 700 on the Sickness Impact Profile.

Only subjective outcome measurements were used:

Primary and secondary outcome measures were assessed using Web-based questionnaires, which were completed at baseline, 4 weeks, and 24 weeks. Questionnaires on fatigue and pain severity were completed weekly during the intervention and monthly during follow-up.

A diagram shows the exclusions. Indeed, the "10 years of fatigue unless it got worse recently" excluded exactly 1 patient. 4 were excluded for meds, and 12 for co-morbidity. The Beck Depression Inventory was used, which equates disability with depression - if you can't do something, it's taken as a sign of depression. So more disabled patients were likely excluded as a result.

They're saving the objective data for another day, a tactic also used by Dutch psychobabblers when they needed to bury null actometer outcomes:

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

This is blatant bullshit, and they cite to the study that proves it. The difference in inflammatory markers was happening at the 3-year point, not after 10 years:

We excluded patients with illness lasting more than 10 years because recent studies suggest an inflammatory pattern early in the course of CFS (15).

One of the few intelligent things they've said:

A possible explanation for our findings is that peripherally administered anakinra does not reach the brain in sufficient concentrations to have a biological effect.

The Anakinra group did have a larger improvement in SF36-PF of about 10 points compared to 5 points for the controls. It's also bizarre that every single endpoint score (Table 2) has a range for the standard deviations which is identical for both groups. Unless I'm missing something very basic, there seems to be a major problem with those figures.

The conclusion isn't as bad as I was expecting:

In conclusion, we found no clinically meaningful effect of anakinra on fatigue severity in patients with CFS. We believe that if IL-1 plays a role in CFS, blockade of IL-1 in the peripheral tissues, such as the neuromuscular compartment, has no effect. Future studies should focus on intracerebral processes in patients with CFS and on reducing inflammation with agents that reduce IL-1 activity in the brain (55, 56).

 

[Solstice]

Ah good old v.d. Meer en Knoop getting a last few papers in before their empire finally crumbles at the end of the year/beginning of next year.

 

[alex3619]

Ah good old v.d. Meer en Knoop getting a last few papers in before their empire finally crumbles at the end of the year/beginning of next year.

Next year is looking like it might be a good year.

 

[charles shepherd]

MEA comment on the results from this clinical trial:

http://www.meassociation.org.uk/201...nals-of-internal-medicine-paper-8-march-2017/

 

[charles shepherd]

Clinical trial from the Norwegian group involving etanercept - which inhibits tumour necrosis factor:

https://clinicaltrials.gov/ct2/show/NCT01730495

NB: This trial was terminated after 2/4 patients developed what was described as a moderate exacerbation of symptoms

 

[MeSci]

It's unusual that this trial was reported in Physician's First Watch - they don't usually deal with CFS. Here is the write-up from there yesterday:

No Benefit of Rheumatoid Arthritis Drug in Chronic Fatigue Syndrome
By Kelly Young
Edited by
- David G. Fairchild, MD, MPH, and
- Jaye Elizabeth Hefner, MD

The interleukin-1 receptor antagonist anakinra doesn't seem to reduce fatigue in women with chronic fatigue syndrome, according to a small trial in the Annals of Internal Medicine. Anakinra was approved in 2001 for rheumatoid arthritis.

Fifty women with chronic fatigue syndrome that included severe fatigue and functional impairment were randomized to receive daily subcutaneous injections of either anakinra or placebo for 4 weeks. After treatment, the primary outcome -- fatigue severity -- was similar between the groups. Both groups saw improvements in fatigue over time, but most patients were still severely fatigued during the 24 weeks of follow-up.

The authors say it's possible that concentrations of anakinra were not high enough in the brain to have an effect; additionally, interleukin-1 may play a limited role in chronic fatigue syndrome.

Link(s):
Annals of Internal Medicine article (Free abstract) http://response.jwatch.org/t?ctl=13CB2:5FF9B588B7CB016CE2D6905BEE2746EA&
Background: NEJM Journal Watch General Medicine coverage of anakinra for rheumatoid arthritis (Your NEJM Journal Watch registration required) http://response.jwatch.org/t?ctl=13CB3:5FF9B588B7CB016CE2D6905BEE2746EA&

 

[Kalliope]

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

The article includes an interview with prof. Montoya.

 

[Dr Speedy]

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 ...