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.
Primary Funding Source:
Interleukin Foundation and an independent donor who wishes to remain anonymous.
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Author, Article, and Disclosure Information
From Radboud University Medical Centre, Nijmegen, and University of Amsterdam, Amsterdam, the Netherlands; and University of Colorado Denver, Aurora, Colorado.
Note: All authors had full access to the study data, take responsibility for the accuracy of the analysis, and had authority over manuscript preparation and the decision to submit the manuscript for publication. The manuscript is an honest, accurate, and transparent account of the study being reported; no important aspects of the study have been omitted.
Acknowledgment: The authors thank the drug safety monitoring board (Professor George W. Padberg and Professor Paul M.J. Stuyt) and Lianne Vermeeren, Harry R. Koene, Tom Sprong, Joris W.P. Vernooij, Mirjam Tromp, and the ME/CVS Stichting Nederland for their assistance with this study.
Financial Support: By the Interleukin Foundation and an independent donor who wishes to remain anonymous. Anakinra and placebo were provided by the Swedish Orphan Biovitrum.
Disclosures: Prof. Van der Meer reports personal fees from the Swedish Orphan Biovitrum outside the submitted work. Authors not named here have disclosed no conflicts of interest. Disclosures can also be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M16-2391.
Editors' Disclosures: Christine Laine, MD, MPH, Editor in Chief, reports that she has no financial relationships or interests to disclose. Darren B. Taichman, MD, PhD, Executive Deputy Editor, reports that he has no financial relationships or interests to disclose. Cynthia D. Mulrow, MD, MSc, Senior Deputy Editor, reports that she has no relationships or interests to disclose. Deborah Cotton, MD, MPH, Deputy Editor, reports that she has no financial relationships or interest to disclose. Jaya K. Rao, MD, MHS, Deputy Editor, reports that she has stock holdings/options in Eli Lilly and Pfizer. Sankey V. Williams, MD, Deputy Editor, reports that he has no financial relationships or interests to disclose. Catharine B. Stack, PhD, MS, Deputy Editor for Statistics, reports that she has stock holdings in Pfizer and Johnson & Johnson.
Reproducible Research Statement:Study protocol: See the Supplement or www.ncbi.nlm.nih.gov/pubmed/26438161. Statistical code: Available from Dr. Roerink (e-mail, Megan.
Corresponding Author: Megan E. Roerink, MD, Department of Internal Medicine, Radboud University Medical Centre, Geert Groteplein Zuid 8, PO Box 9101, 6500 HB Nijmegen, the Netherlands; e-mail, Megan.
Current Author Addresses: Drs. Roerink and Bredie, Mr. Heijnen, and Prof. Van der Meer: Department of Internal Medicine, Radboud University Medical Centre, Geert Groteplein Zuid 8, PO Box 9101, 6500 HB Nijmegen, the Netherlands.
Dr. Dinarello: University of Colorado Medical Center, 12700 East 19th Avenue, B168, Aurora, CO 80045.
Prof. Knoop: Department of Medical Psychology, Academic Medical Centre (AMC), University of Amsterdam, Postbox 22660 J3 209, 1100 DD Amsterdam, the Netherlands.
Author Contributions: Conception and design: M.E. Roerink, C.A. Dinarello, H. Knoop, J.W.M. Van der Meer.
Analysis and interpretation of the data: M.E. Roerink, C.A. Dinarello, H. Knoop, J.W.M. Van der Meer.
Drafting of the article: M.E. Roerink.
Critical revision of the article for important intellectual content: M.E. Roerink, S.J.H. Bredie, H. Knoop, J.W.M. Van der Meer.
Final approval of the article: M.E. Roerink, S.J.H. Bredie, M. Heijnen, C.A. Dinarello, H. Knoop, J.W.M. Van der Meer.
Provision of study materials or patients: M.E. Roerink, M. Heijnen, H. Knoop.
Statistical expertise: M.E. Roerink, H. Knoop.
Obtaining of funding: H. Knoop, J.W.M. Van der Meer.
Administrative, technical, or logistic support: M.E. Roerink, S.J.H. Bredie, M. Heijnen, H. Knoop.
Collection and assembly of data: M.E. Roerink, M. Heijnen.
This article was published at Annals.org on 7 March 2017.

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