title: Plasma Levels of Eicosapentaenoic Acid Are Associated with Anti-TNF Responsiveness in Rheumatoid Arthritis and Inhibit the Etanercept-driven Rise in Th17 Cell Differentiationin Vitro.
abstract: To determine whether levels of plasma n-3 polyunsaturated fatty acids are associated with response to antitumor necrosis factor (anti-TNF) agents in rheumatoid arthritis (RA), and whether this putative effect may have its basis in altering anti-TNF-driven Th17 cell differentiation.
  
  
  
  Plasma was collected at baseline and after 3 months of anti-TNF treatment in 22 patients with established RA, and fatty acid composition of the phosphatidylcholine (PC) component was measured. CD4+CD25- T cells and monocytes were purified from the blood of healthy donors and cocultured in the presence of anti-CD3, with or without etanercept (ETN), eicosapentaenoic acid (EPA), or the control fatty acid, linoleic acid (LA). Expression of interleukin 17 and interferon-γ was measured by intracellular staining and flow cytometry.
  
  
  
  Plasma PC EPA levels and the EPA/arachidonic acid ratio correlated inversely with change in the Disease Activity Score at 28 joints (DAS28) at 3 months (-0.51, p = 0.007 and -0.48, p = 0.01, respectively), indicating that higher plasma EPA was associated with a greater reduction in DAS28. Plasma PC EPA was positively associated with European League Against Rheumatism response (p = 0.02). An increase in Th17 cells post-therapy has been associated with nonresponse to anti-TNF. ETN increased Th17 frequenciesin vitro. Physiological concentrations of EPA, but not LA, prevented this.
  
  
  
  EPA status was associated with clinical improvements to anti-TNF therapyin vivoand prevented the effect of ETN on Th17 cellsin vitro. EPA supplementation might be a simple way to improve anti-TNF outcomes in patients with RA by suppressing Th17 frequencies.
authors.affiliation: From the Rheumatology Research Group and Arthritis Research UK Rheumatoid Arthritis Pathogenesis Centre of Excellence (RACE), University of Birmingham, Birmingham; Human Development and Health Academic Unit, Faculty of Medicine, University of Southampton; UK National Institute for Health Research (NIHR) Southampton Biomedical Research Centre, University Hospital Southampton National Health Service (NHS) Foundation Trust; University of Southampton, Southampton; Glasgow Biomedical Research Centre, University of Glasgow, Glasgow; Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK.|L. Jeffery, PhD, Rheumatology Research Group and Arthritis Research UK RACE, University of Birmingham; H.L. Fisk, BSc, Human Development and Health Academic Unit, Faculty of Medicine, University of Southampton, and NIHR Southampton Biomedical Research Centre, University Hospital Southampton NHS Foundation Trust, and University of Southampton; P.C. Calder, PhD, Human Development and Health Academic Unit, Faculty of Medicine, University of Southampton, and NIHR Southampton Biomedical Research Centre, University Hospital Southampton NHS Foundation Trust, and University of Southampton; A. Filer, PhD, Rheumatology Research Group and Arthritis Research UK RACE, University of Birmingham; K. Raza, PhD, Rheumatology Research Group and Arthritis Research UK RACE, University of Birmingham; C.D. Buckley, PhD, Rheumatology Research Group and Arthritis Research UK RACE, University of Birmingham; I. McInnes, PhD, Glasgow Biomedical Research Centre, University of Glasgow; P.C. Taylor, PhD, Kennedy Institute of Rheumatology, University of Oxford; B.A. Fisher, MD(Res), Rheumatology Research Group and Arthritis Research UK RACE, University of Birmingham.
authors.forename: Louisa
authors.initials: L
authors.lastname: Jeffery
authors.affiliation: From the Rheumatology Research Group and Arthritis Research UK Rheumatoid Arthritis Pathogenesis Centre of Excellence (RACE), University of Birmingham, Birmingham; Human Development and Health Academic Unit, Faculty of Medicine, University of Southampton; UK National Institute for Health Research (NIHR) Southampton Biomedical Research Centre, University Hospital Southampton National Health Service (NHS) Foundation Trust; University of Southampton, Southampton; Glasgow Biomedical Research Centre, University of Glasgow, Glasgow; Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK.|L. Jeffery, PhD, Rheumatology Research Group and Arthritis Research UK RACE, University of Birmingham; H.L. Fisk, BSc, Human Development and Health Academic Unit, Faculty of Medicine, University of Southampton, and NIHR Southampton Biomedical Research Centre, University Hospital Southampton NHS Foundation Trust, and University of Southampton; P.C. Calder, PhD, Human Development and Health Academic Unit, Faculty of Medicine, University of Southampton, and NIHR Southampton Biomedical Research Centre, University Hospital Southampton NHS Foundation Trust, and University of Southampton; A. Filer, PhD, Rheumatology Research Group and Arthritis Research UK RACE, University of Birmingham; K. Raza, PhD, Rheumatology Research Group and Arthritis Research UK RACE, University of Birmingham; C.D. Buckley, PhD, Rheumatology Research Group and Arthritis Research UK RACE, University of Birmingham; I. McInnes, PhD, Glasgow Biomedical Research Centre, University of Glasgow; P.C. Taylor, PhD, Kennedy Institute of Rheumatology, University of Oxford; B.A. Fisher, MD(Res), Rheumatology Research Group and Arthritis Research UK RACE, University of Birmingham.
authors.forename: Helena L
authors.initials: HL
authors.lastname: Fisk
authors.affiliation: From the Rheumatology Research Group and Arthritis Research UK Rheumatoid Arthritis Pathogenesis Centre of Excellence (RACE), University of Birmingham, Birmingham; Human Development and Health Academic Unit, Faculty of Medicine, University of Southampton; UK National Institute for Health Research (NIHR) Southampton Biomedical Research Centre, University Hospital Southampton National Health Service (NHS) Foundation Trust; University of Southampton, Southampton; Glasgow Biomedical Research Centre, University of Glasgow, Glasgow; Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK.|L. Jeffery, PhD, Rheumatology Research Group and Arthritis Research UK RACE, University of Birmingham; H.L. Fisk, BSc, Human Development and Health Academic Unit, Faculty of Medicine, University of Southampton, and NIHR Southampton Biomedical Research Centre, University Hospital Southampton NHS Foundation Trust, and University of Southampton; P.C. Calder, PhD, Human Development and Health Academic Unit, Faculty of Medicine, University of Southampton, and NIHR Southampton Biomedical Research Centre, University Hospital Southampton NHS Foundation Trust, and University of Southampton; A. Filer, PhD, Rheumatology Research Group and Arthritis Research UK RACE, University of Birmingham; K. Raza, PhD, Rheumatology Research Group and Arthritis Research UK RACE, University of Birmingham; C.D. Buckley, PhD, Rheumatology Research Group and Arthritis Research UK RACE, University of Birmingham; I. McInnes, PhD, Glasgow Biomedical Research Centre, University of Glasgow; P.C. Taylor, PhD, Kennedy Institute of Rheumatology, University of Oxford; B.A. Fisher, MD(Res), Rheumatology Research Group and Arthritis Research UK RACE, University of Birmingham.
authors.forename: Philip C
authors.initials: PC
authors.lastname: Calder
authors.affiliation: From the Rheumatology Research Group and Arthritis Research UK Rheumatoid Arthritis Pathogenesis Centre of Excellence (RACE), University of Birmingham, Birmingham; Human Development and Health Academic Unit, Faculty of Medicine, University of Southampton; UK National Institute for Health Research (NIHR) Southampton Biomedical Research Centre, University Hospital Southampton National Health Service (NHS) Foundation Trust; University of Southampton, Southampton; Glasgow Biomedical Research Centre, University of Glasgow, Glasgow; Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK.|L. Jeffery, PhD, Rheumatology Research Group and Arthritis Research UK RACE, University of Birmingham; H.L. Fisk, BSc, Human Development and Health Academic Unit, Faculty of Medicine, University of Southampton, and NIHR Southampton Biomedical Research Centre, University Hospital Southampton NHS Foundation Trust, and University of Southampton; P.C. Calder, PhD, Human Development and Health Academic Unit, Faculty of Medicine, University of Southampton, and NIHR Southampton Biomedical Research Centre, University Hospital Southampton NHS Foundation Trust, and University of Southampton; A. Filer, PhD, Rheumatology Research Group and Arthritis Research UK RACE, University of Birmingham; K. Raza, PhD, Rheumatology Research Group and Arthritis Research UK RACE, University of Birmingham; C.D. Buckley, PhD, Rheumatology Research Group and Arthritis Research UK RACE, University of Birmingham; I. McInnes, PhD, Glasgow Biomedical Research Centre, University of Glasgow; P.C. Taylor, PhD, Kennedy Institute of Rheumatology, University of Oxford; B.A. Fisher, MD(Res), Rheumatology Research Group and Arthritis Research UK RACE, University of Birmingham.
authors.forename: Andrew
authors.initials: A
authors.lastname: Filer
authors.affiliation: From the Rheumatology Research Group and Arthritis Research UK Rheumatoid Arthritis Pathogenesis Centre of Excellence (RACE), University of Birmingham, Birmingham; Human Development and Health Academic Unit, Faculty of Medicine, University of Southampton; UK National Institute for Health Research (NIHR) Southampton Biomedical Research Centre, University Hospital Southampton National Health Service (NHS) Foundation Trust; University of Southampton, Southampton; Glasgow Biomedical Research Centre, University of Glasgow, Glasgow; Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK.|L. Jeffery, PhD, Rheumatology Research Group and Arthritis Research UK RACE, University of Birmingham; H.L. Fisk, BSc, Human Development and Health Academic Unit, Faculty of Medicine, University of Southampton, and NIHR Southampton Biomedical Research Centre, University Hospital Southampton NHS Foundation Trust, and University of Southampton; P.C. Calder, PhD, Human Development and Health Academic Unit, Faculty of Medicine, University of Southampton, and NIHR Southampton Biomedical Research Centre, University Hospital Southampton NHS Foundation Trust, and University of Southampton; A. Filer, PhD, Rheumatology Research Group and Arthritis Research UK RACE, University of Birmingham; K. Raza, PhD, Rheumatology Research Group and Arthritis Research UK RACE, University of Birmingham; C.D. Buckley, PhD, Rheumatology Research Group and Arthritis Research UK RACE, University of Birmingham; I. McInnes, PhD, Glasgow Biomedical Research Centre, University of Glasgow; P.C. Taylor, PhD, Kennedy Institute of Rheumatology, University of Oxford; B.A. Fisher, MD(Res), Rheumatology Research Group and Arthritis Research UK RACE, University of Birmingham.
authors.forename: Karim
authors.initials: K
authors.lastname: Raza
authors.affiliation: From the Rheumatology Research Group and Arthritis Research UK Rheumatoid Arthritis Pathogenesis Centre of Excellence (RACE), University of Birmingham, Birmingham; Human Development and Health Academic Unit, Faculty of Medicine, University of Southampton; UK National Institute for Health Research (NIHR) Southampton Biomedical Research Centre, University Hospital Southampton National Health Service (NHS) Foundation Trust; University of Southampton, Southampton; Glasgow Biomedical Research Centre, University of Glasgow, Glasgow; Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK.|L. Jeffery, PhD, Rheumatology Research Group and Arthritis Research UK RACE, University of Birmingham; H.L. Fisk, BSc, Human Development and Health Academic Unit, Faculty of Medicine, University of Southampton, and NIHR Southampton Biomedical Research Centre, University Hospital Southampton NHS Foundation Trust, and University of Southampton; P.C. Calder, PhD, Human Development and Health Academic Unit, Faculty of Medicine, University of Southampton, and NIHR Southampton Biomedical Research Centre, University Hospital Southampton NHS Foundation Trust, and University of Southampton; A. Filer, PhD, Rheumatology Research Group and Arthritis Research UK RACE, University of Birmingham; K. Raza, PhD, Rheumatology Research Group and Arthritis Research UK RACE, University of Birmingham; C.D. Buckley, PhD, Rheumatology Research Group and Arthritis Research UK RACE, University of Birmingham; I. McInnes, PhD, Glasgow Biomedical Research Centre, University of Glasgow; P.C. Taylor, PhD, Kennedy Institute of Rheumatology, University of Oxford; B.A. Fisher, MD(Res), Rheumatology Research Group and Arthritis Research UK RACE, University of Birmingham.
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Buckley
authors.affiliation: From the Rheumatology Research Group and Arthritis Research UK Rheumatoid Arthritis Pathogenesis Centre of Excellence (RACE), University of Birmingham, Birmingham; Human Development and Health Academic Unit, Faculty of Medicine, University of Southampton; UK National Institute for Health Research (NIHR) Southampton Biomedical Research Centre, University Hospital Southampton National Health Service (NHS) Foundation Trust; University of Southampton, Southampton; Glasgow Biomedical Research Centre, University of Glasgow, Glasgow; Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK.|L. Jeffery, PhD, Rheumatology Research Group and Arthritis Research UK RACE, University of Birmingham; H.L. Fisk, BSc, Human Development and Health Academic Unit, Faculty of Medicine, University of Southampton, and NIHR Southampton Biomedical Research Centre, University Hospital Southampton NHS Foundation Trust, and University of Southampton; P.C. Calder, PhD, Human Development and Health Academic Unit, Faculty of Medicine, University of Southampton, and NIHR Southampton Biomedical Research Centre, University Hospital Southampton NHS Foundation Trust, and University of Southampton; A. Filer, PhD, Rheumatology Research Group and Arthritis Research UK RACE, University of Birmingham; K. Raza, PhD, Rheumatology Research Group and Arthritis Research UK RACE, University of Birmingham; C.D. Buckley, PhD, Rheumatology Research Group and Arthritis Research UK RACE, University of Birmingham; I. McInnes, PhD, Glasgow Biomedical Research Centre, University of Glasgow; P.C. Taylor, PhD, Kennedy Institute of Rheumatology, University of Oxford; B.A. Fisher, MD(Res), Rheumatology Research Group and Arthritis Research UK RACE, University of Birmingham.
authors.forename: Iain
authors.initials: I
authors.lastname: McInnes
authors.affiliation: From the Rheumatology Research Group and Arthritis Research UK Rheumatoid Arthritis Pathogenesis Centre of Excellence (RACE), University of Birmingham, Birmingham; Human Development and Health Academic Unit, Faculty of Medicine, University of Southampton; UK National Institute for Health Research (NIHR) Southampton Biomedical Research Centre, University Hospital Southampton National Health Service (NHS) Foundation Trust; University of Southampton, Southampton; Glasgow Biomedical Research Centre, University of Glasgow, Glasgow; Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK.|L. Jeffery, PhD, Rheumatology Research Group and Arthritis Research UK RACE, University of Birmingham; H.L. Fisk, BSc, Human Development and Health Academic Unit, Faculty of Medicine, University of Southampton, and NIHR Southampton Biomedical Research Centre, University Hospital Southampton NHS Foundation Trust, and University of Southampton; P.C. Calder, PhD, Human Development and Health Academic Unit, Faculty of Medicine, University of Southampton, and NIHR Southampton Biomedical Research Centre, University Hospital Southampton NHS Foundation Trust, and University of Southampton; A. Filer, PhD, Rheumatology Research Group and Arthritis Research UK RACE, University of Birmingham; K. Raza, PhD, Rheumatology Research Group and Arthritis Research UK RACE, University of Birmingham; C.D. Buckley, PhD, Rheumatology Research Group and Arthritis Research UK RACE, University of Birmingham; I. McInnes, PhD, Glasgow Biomedical Research Centre, University of Glasgow; P.C. Taylor, PhD, Kennedy Institute of Rheumatology, University of Oxford; B.A. Fisher, MD(Res), Rheumatology Research Group and Arthritis Research UK RACE, University of Birmingham.
authors.forename: Peter C
authors.initials: PC
authors.lastname: Taylor
authors.affiliation: From the Rheumatology Research Group and Arthritis Research UK Rheumatoid Arthritis Pathogenesis Centre of Excellence (RACE), University of Birmingham, Birmingham; Human Development and Health Academic Unit, Faculty of Medicine, University of Southampton; UK National Institute for Health Research (NIHR) Southampton Biomedical Research Centre, University Hospital Southampton National Health Service (NHS) Foundation Trust; University of Southampton, Southampton; Glasgow Biomedical Research Centre, University of Glasgow, Glasgow; Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK. b.fisher@bham.ac.uk.|L. Jeffery, PhD, Rheumatology Research Group and Arthritis Research UK RACE, University of Birmingham; H.L. Fisk, BSc, Human Development and Health Academic Unit, Faculty of Medicine, University of Southampton, and NIHR Southampton Biomedical Research Centre, University Hospital Southampton NHS Foundation Trust, and University of Southampton; P.C. Calder, PhD, Human Development and Health Academic Unit, Faculty of Medicine, University of Southampton, and NIHR Southampton Biomedical Research Centre, University Hospital Southampton NHS Foundation Trust, and University of Southampton; A. Filer, PhD, Rheumatology Research Group and Arthritis Research UK RACE, University of Birmingham; K. Raza, PhD, Rheumatology Research Group and Arthritis Research UK RACE, University of Birmingham; C.D. Buckley, PhD, Rheumatology Research Group and Arthritis Research UK RACE, University of Birmingham; I. McInnes, PhD, Glasgow Biomedical Research Centre, University of Glasgow; P.C. Taylor, PhD, Kennedy Institute of Rheumatology, University of Oxford; B.A. Fisher, MD(Res), Rheumatology Research Group and Arthritis Research UK RACE, University of Birmingham. b.fisher@bham.ac.uk.
authors.forename: Benjamin A
authors.initials: BA
authors.lastname: Fisher
mesh_terms: D000328:Adult; D000368:Aged; D018501:Antirheumatic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001172:Arthritis, Rheumatoid / Q000097:blood / Q000188:drug therapy*; D002454:Cell Differentiation / Q000187:drug effects*; D015118:Eicosapentaenoic Acid / Q000097:blood*; D000068800:Etanercept / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D058504:Th17 Cells / Q000187:drug effects*; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors
chemical_list: D018501:Antirheumatic Agents; D014409:Tumor Necrosis Factor-alpha; D015118:Eicosapentaenoic Acid; D000068800:Etanercept
keywords: ANTI-TNF; EICOSAPENTAENOIC ACID; OMEGA-3; POLYUNSATURATED FATTY ACIDS; RHEUMATOID ARTHRITIS; Th17