Why we shouldn’t dismiss the role of pro-inflammatory cytokines in ME/CFS | comment on Annals of Internal Medicine paper | 8 March 2017

March 8, 2017

Commentary by Dr Charles Shepherd, medical adviser, The ME Association.

There are now some fairly robust and consistent findings from a number of recent ME/CFS research studies which have looked at immune system dysfunction, especially the role of immune system chemicals called pro-inflammatory cytokines.

The results indicate that there appears to be low level immune system activation taking place in at least a sub-group of people with ME/CFS – in other words, the immune system is in an on-going state of low level over-activity (as occurs during the normal and immediate response to a viral infection) rather than immune system deficiency (as occurs in diseases like HIV/AIDS).

This on-going immune system activation may then contribute to some of the flu-like symptoms (sore throats, enlarged glands, muscle fatigue and pain, joint pain etc) that occur in ME/CFS.

So clinical trials involving drugs like anakinra, which can dampen down the immune system response and reduce the level of interleukin-1 in particular, are an important way of testing this hypothesis.

This new clinical trial report from a group in The Netherlands found no benefit with this particular drug.

However, there are a number of reasons why this approach to management still warrants further exploration before dismissing it entirely. In particular:

* Other pro-inflammatory cytokines appear to be involved in ME/CFS
* Other drugs that reduce or block pro-inflammatory cytokines may be worth assessing, probably over a longer period of time than the 4 weeks in this trial
* A more carefully selected sub-group of ME/CFS patients, especially in relation to immune system function and ‘inflammatory' symptoms is required
* The rather small sample size in the current study


Research into immune system dysfunction in ME/CFS can be found in the research section of the MEA purple book.

More information on the role of cytokine inhibition therapy, including previous clinical trials, can be found in the (immunotherapy) treatment section of the MEA purple book.

Information on how anakinra reduces immune system activation and inflammation in rheumatoid arthritis:

In joints, inflammation causes pain, stiffness, swelling and damage to bone and cartilage. Inflammation occurs through many pathways. In one pathway, a protein called IL-1b attaches itself to a cell. This cell then makes other proteins that cause inflammation. A different protein, called IL-1Ra, can block this interaction and prevent inflammation. Anakinra is a man-made form of the IL-1Ra protein. Anakinra blocks the interaction between IL-1b and the cell to stop inflammation that occurs through that pathway. Other pathways can cause inflammation, though, so anakinra may not relieve all symptoms.

More information on anakinra in relation to its use in rheumatoid arthritis:



From The Annals of Internal Medicine, Original Research, 7 March 2017

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

Megan E. Roerink, MD(1); Sebastian J.H. Bredie, MD(1), PhD; Michael Heijnen; Charles A. Dinarello, MD(2); Hans Knoop, PhD(3); Jos W.M. Van der Meer, MD, PhD(1)
1) Department of Internal Medicine, Radboud University Medical Centre, Geert Groteplein Zuid 8, PO Box 9101, 6500 HB Nijmegen, the Netherlands.
2) University of Colorado Medical Center, 12700 East 19th Avenue, B168, Aurora, CO 80045.
3) Department of Medical Psychology, Academic Medical Centre (AMC), University of Amsterdam, Postbox 22660 J3 209, 1100 DD Amsterdam, the Netherlands.



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


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


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


University hospital in the Netherlands.


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


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).


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.


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]).


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


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.


Interleukin Foundation and an independent donor who wishes to remain anonymous.

Shopping Basket