title: Cytokine inhibition in chronic fatigue syndrome patients: study protocol for a randomized controlled trial.
abstract: BACKGROUND
  Chronic fatigue syndrome (CFS) is a medically unexplained syndrome for which no somatic or pharmacological treatment has been proven effective. Dysfunction of the cytokine network has been suspected to play a role in the pathophysiology of CFS. The disturbances of the cytokine network detected in CFS patients are highly variable, in part due to the lack of adequate controls in many studies. Furthermore, all studies have been performed on peripheral venous blood of patients. As cytokines mainly act in tissues, for example, the brain, the information that can be derived from peripheral blood cells is limited. The information regarding the possible role of cytokines in the pathophysiology could come from intervention studies in which the activities of relevant cytokines are reduced, for example, reducing interleukin-1, interleukin-6 or tumor necrosis factor. In this study, the clinical usefulness of anakinra, an IL-1 antagonist, will be assessed in patients with CFS.
  
  
  METHODS
  A randomized placebo-controlled, double-blind trial will be conducted. Fifty adult female patients meeting the Centers for Disease Control (CDC) criteria for CFS and without psychiatric co-morbidity will be included. After inclusion, patients will be randomized between treatment with anakinra (recombinant human interleukin-1 receptor antagonist) or placebo. Each group will be treated for 4 weeks. Outcome measures will be assessed at baseline, after 4 weeks of intervention, and 6 months after baseline assessment. The primary outcome measure will be fatigue severity at 4 weeks, measured with the validated Checklist of Individual Strength (CIS). Secondary outcome measures are functional impairment, physical and social functioning, psychological distress, pain severity, presence of accompanying symptoms, and cytokine and cortisol concentrations.
  
  
  CONCLUSIONS
  This is the first randomized placebo-controlled trial that will evaluate the effect of interference with IL-1 on the experience of fatigue in patients with CFS. The results of this study may expand treatment options for patients with CFS, for whom graded exercise therapy and cognitive behavioral therapy are the only evidence-based interventions that exist at this moment.
  
  
  BACKGROUND
  Clinicaltrials.gov: NCT02108210 . Clinicaltrials.gov registration date: 8 April 2014. EudraCT: 2013-005466-19.
authors.affiliation: Department of Internal Medicine, Radboud University Medical Center, Post Box 9101, 6500 HB, Nijmegen, The Netherlands. Megan.Roerink@radboudumc.nl.
authors.forename: Megan E
authors.initials: ME
authors.lastname: Roerink
authors.affiliation: Expert Centre Chronic Fatigue, Radboud University Medical Center, Nijmegen, The Netherlands. Hans.Knoop@radboudumc.nl.
authors.forename: Hans
authors.initials: H
authors.lastname: Knoop
authors.affiliation: Department of Internal Medicine, Radboud University Medical Center, Post Box 9101, 6500 HB, Nijmegen, The Netherlands. Bas.Bredie@radboudumc.nl.
authors.forename: Sebastian J H
authors.initials: SJ
authors.lastname: Bredie
authors.affiliation: Department of Internal Medicine, Radboud University Medical Center, Post Box 9101, 6500 HB, Nijmegen, The Netherlands. Michael.Heijnen@radboudumc.nl.
authors.forename: Michael
authors.initials: M
authors.lastname: Heijnen
authors.affiliation: Department of Internal Medicine, Radboud University Medical Center, Post Box 9101, 6500 HB, Nijmegen, The Netherlands. Leo.Joosten@radboudumc.nl.
authors.forename: Leo A B
authors.initials: LA
authors.lastname: Joosten
authors.affiliation: Department of Internal Medicine, Radboud University Medical Center, Post Box 9101, 6500 HB, Nijmegen, The Netherlands. Mihai.Netea@radboudumc.nl.
authors.forename: Mihai G
authors.initials: MG
authors.lastname: Netea
authors.affiliation: Department of Internal Medicine, Radboud University Medical Center, Post Box 9101, 6500 HB, Nijmegen, The Netherlands. Dinarello@ucdenever.edu.
authors.forename: Charles A
authors.initials: CA
authors.lastname: Dinarello
authors.affiliation: Department of Internal Medicine, Radboud University Medical Center, Post Box 9101, 6500 HB, Nijmegen, The Netherlands. Jos.vanderMeer@radboudumc.nl.
authors.forename: Jos W M
authors.initials: JW
authors.lastname: van der Meer
mesh_terms: D000293:Adolescent; D000328:Adult; D057189:Checklist; D002985:Clinical Protocols; D004185:Disability Evaluation; D004311:Double-Blind Method; D015673:Fatigue Syndrome, Chronic / Q000175:diagnosis / Q000188:drug therapy* / Q000276:immunology / Q000503:physiopathology / Q000523:psychology; D005260:Female; D006304:Health Status; D006801:Humans; D006854:Hydrocortisone / Q000097:blood; D007155:Immunologic Factors / Q000009:adverse effects / Q000627:therapeutic use*; D053590:Interleukin 1 Receptor Antagonist Protein / Q000009:adverse effects / Q000627:therapeutic use*; D007375:Interleukin-1 / Q000037:antagonists & inhibitors* / Q000276:immunology; D008603:Mental Health; D008875:Middle Aged; D053580:Muscle Strength; D009426:Netherlands; D010147:Pain Measurement; D012107:Research Design; D012720:Severity of Illness Index; D015398:Signal Transduction / Q000187:drug effects; D011795:Surveys and Questionnaires; D013997:Time Factors; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D007155:Immunologic Factors; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D006854:Hydrocortisone