Treatment of Chronic Fatigue/Myalgic Encephalitis Syndrome: Blocking the IL-1 Component to the Inflammatory Response Is Ineffective
Roerink and colleagues at Radboud University Medical Center in Nijmegen randomized 50 females with chronic fatigue syndrome (CFS) to receive either a saline placebo or the interleukin-1 (IL-1) receptor antagonist anakinra. Each was given daily by subcutaneous injection for four weeks; the daily anakinra dose was 100 mg. The diagnosis of CFS was based on CDC criteria, and the primary outcome measure was the Checklist Individual Strength subscale (CIS-fatigue), a validated measure of fatigue severity at four weeks.
At four weeks, both the experimental and control groups demonstrated a reduction in CIS-fatigue score with no significant difference between them. Furthermore, while most patients remained severely fatigued, two (8%) of anakinra recipients and five (20%) placebo recipients were no longer severely fatigued (i.e., they reached a level of fatigue considered within the normal range). Limiting the analysis to the 48% of patients who reported that their fatigue was triggered by an infection also did not detect a significant difference in CIS-fatigue score between treatment groups. There also was no significant difference in the following secondary outcomes at four weeks and 24 weeks: impairment, physical and social functioning, psychological distress, and pain severity.
Seventeen (68%) anakinra recipients had injection site reactions, as did one (4%) of the controls.
COMMENTARY
In 2015, the Institute of Medicine issued a report that concluded that CFS is a biologically based illness and proposed a set of diagnostic criteria (see Table) that differs from the CDC criteria used in the study reviewed here. They also proposed that the illness be called systemic exertion intolerance disease (SEID) rather than chronic fatigue syndrome/myalgic encephalitis (CFS/ME). Research into the cause or causes of this illness and its management have burgeoned since.
The study by Roerink and colleagues was based on a number of observations suggesting that excess proinflammatory cytokine activity, perhaps within the central nervous system, was the underlying pathophysiology accounting for the reported symptoms. Studies of cytokines in peripheral blood sometimes have produced contradictory results.This includes studies of IL-1, some of which have demonstrated elevated levels while others have not. It has been proposed that one reason for this is that the critical site of IL-1 production in causing the symptoms of CFS is not the peripheral blood but the central nervous system. In this regard, Roerink et al note that anakinra can be detected in cerebrospinal fluid in low concentrations after intravenous or subcutaneous administration.
The placebo effect in this study was significant and similar to that seen in at least one other study. Of note is that the high frequency of injection site reactions associated with anakinra administration should have caused a bias favoring anakinra since it is likely that patients with such reactions may have assumed they were receiving active drug, but this was not the case.
This study failed to identify benefit from anakinra administration in relief of the symptoms of CFS. The only therapies with demonstrated benefit to date are cognitive behavioral therapy and graded exercise, although patients may benefit from symptomatic therapies such as the administration of nonsteroidal anti-inflammatory agents for pain.
REFERENCE
- Institute of Medicine. Beyond myalgic encephalomyelitis/chronic fatigue syndrome: Redefining an illness. Washington, DC: The National Academies Press; 2015. Available at: http://www.nationalacademies.org/hmd/reports/2015/me-cfs.aspx. Accessed April 7, 2017.
TABLE. Institute of Medicine Criteria for Diagnosis of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
Patient has each of the following three symptoms at least half of the time, to at least a moderately severe degree:
- A substantial reduction or impairment in the ability to engage in pre-illness levels of occupational, educational, social, or personal activities that persists for > 6 months and is accompanied by fatigue, which is often profound, is of new or definite onset (not lifelong), is not the result of ongoing excessive exertion, and is not substantially alleviated by rest.
- Postexertional malaise*
- Unrefreshing sleep*
Plus at least one of the two following manifestations (chronic, severe):
- Cognitive impairment*
- Orthostatic intolerance
* Frequency and severity of symptoms should be assessed. The diagnosis of myalgic encephalomyelitis/chronic fatigue syndrome should be questioned if patients do not have these symptoms at least half of the time with moderate, substantial, or severe intensity.
Reprinted with permission from: Beyond myalgic encephalomyelitis/chronic fatigue syndrome: Redefining an illness. 2015 by the National Academy of Sciences, Courtesy of the national Academies Press, Washington, DC. http://www.nationalacademies.org/hmd/reports/2015/me-cfs.aspx
Blockade of IL-1 activity with anakinra failed to reduce fatigue in patients with chronic fatigue syndrome.
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