Cytokine Blocker Does Not Ease Chronic Fatigue

Miriam E. Tucker

March 08, 2017

Inhibition of the proinflammatory cytokine interleukin 1 (IL-1) with anakinra does not significantly improve fatigue severity in patients with the illness commonly known as chronic fatigue syndrome, new research suggests.

Megan E. Roerink, MD, from Radboud University Medical Centre, Nijmegen, the Netherlands, and colleagues report their findings in an article published online March 7 in the Annals of Internal Medicine.

However, the authors say the lack of difference in fatigue scores between patients treated for 4 weeks with daily injections of the IL-1 receptor antagonist anakinra and those given placebo should not be interpreted to mean that immunomodulation is not a promising approach for the condition, now often termed myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).

"The take-home message is that anakinra, a very powerful drug with very few side effects, is not useful in [chronic fatigue syndrome]. This does not mean that cytokine inhibition is useless," lead author Jos W. M. Van der Meer, MD, PhD, professor and chair of the Department of Internal Medicine at Radboud University Medical Centre, Nijmegen, the Netherlands, told Medscape Medical News.

Indeed, Dr Van der Meer said that one possible reason anakinra did not work may be that drug delivery into the brain with an intact blood–brain barrier is insufficient. "Hence we are looking for another safe and selective cytokine-inhibiting drug, preferably a small molecule that can be taken orally and that is able to reach the brain in sufficient concentrations."

No Difference in Fatigue Scores

The study included 50 women who met the Centers for Disease Control and Prevention's chronic fatigue syndrome criteria, which require, in addition to 6 months or more of severe, persistent, and disabling fatigue, at least four of eight of the following: postexertional malaise (PEM), unrefreshing sleep, impairment of short-term memory or concentration, headache, muscle pain, tender lymph nodes, sore throat, or arthralgia. (More recent ME and ME/CFS definitions require PEM, rather than making it optional.)

Among other inclusion criteria were disease duration of 10 years or less, age 18 to 59 years, and scores of 40 or lower on the subscale fatigue severity of the Checklist of Individual Strength (CIS), and 700 or higher on the Sickness Impact Profile. The study excluded patients with significant somatic or psychiatric comorbidities.

The researchers randomly assigned patients to receive daily injections of 100 mg anakinra or placebo for 4 weeks and followed patients for another 20 weeks.

For the primary outcome, the mean between-group difference in CIS-fatigue score after 4 weeks of treatment was a nonsignificant 1.5 points (P = .59). Both groups had overall decreases in fatigue at 20 weeks, but most participants remained severely fatigued, with mean CIS-fatigue scores greater than 35.

Severe fatigue was alleviated (CIS-fatigue score < 35) in two (8%) of the anakinra patients compared with five (20%) of the placebo patients (P = .22).

There were also no significant differences between the treatment and placebo groups among the 48% of patients who reported that their illness was triggered by an infection (P = .45), nor were significant differences seen at the end of treatment or follow-up in secondary outcomes including impairment, physical and social functioning, psychological distress, or pain severity.

Adverse events were more frequent in the anakinra group (96% vs 56%), mostly as a result of injection site reactions to anakinra (68% vs 4%). None were serious, and all resolved. More of the anakinra patients correctly guessed which treatment they had been given (68% vs 60%).

"A Step in the Right Direction"

The study is "a step in the right direction," despite the negative finding, Jose G. Montoya, MD, professor of medicine in the Department of Infectious Diseases and the Department of Geographic Medicine at Stanford University Medical Center, Palo Alto, California, told Medscape Medical News.

"The plethora of clinical symptoms these patients manifest for years along with the research on the immunology converge [suggest] clearly that this is an overactive immune system.... We need randomized, placebo-controlled, double-blind studies that will give us an answer. Very few studies with this design have been done in this field," said Dr Montoya, who has also studied inflammatory cytokines in ME/CFS.

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's going to require more sustained treatment: at least 6 months, and possibly a year."

He pointed to a delayed response in recent work from Norway on the B-cell-depleting drug rituximab, which did not significantly improve symptoms before 2 months, but did in some patients by 6 months. Now that group is conducting a year-long randomized controlled trial of rituximab in ME/CFS scheduled to finish later in 2017.

Dr Montoya also noted that with ME/CFS, clinical trials of any drug need to account for the condition's hallmark symptom of PEM. "On their way to recovery, there is a time when patients really have to be careful as they're increasing their capacity to do things that they don't cross their PEM threshold and experience a crash.... I think we need to better prepare patients in clinical trials where they are trained that if they improve, they cannot overdo it or it can look as if the drug has no effect or is making the patient worse."

Nonetheless, Dr Montoya told Medscape Medical News that he is heartened by the fact that this study was conducted, given all the skepticism and stigma associated with the condition over the years. "It's a breath of fresh air in the field, because it shows that people with the right skills and the funds are working on ME/CFS. We need more groups to do studies like this."

The study was funded by the Interleukin Foundation and an anonymous independent donor. Anakinra and placebo were provided by the Swedish Orphan Biovitrum. Dr Van der Meer reports personal fees from the Swedish Orphan Biovitrum outside the submitted work. The remaining authors and Dr Montoya have disclosed no relevant financial relationships.

Ann Intern Med. Published online March 7, 2017. Abstract

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