Louisa Jeffery1,2, Helena L Fisk1,2, Philip C Calder1,2, Andrew Filer1,2, Karim Raza1,2, Christopher D Buckley1,2, Iain McInnes1,2, Peter C Taylor1,2, Benjamin A Fisher3,4. 1. 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. 2. 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. 3. 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. 4. 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.
Abstract
OBJECTIVE: 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. METHODS: 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. RESULTS: 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 frequencies in vitro. Physiological concentrations of EPA, but not LA, prevented this. CONCLUSION: EPA status was associated with clinical improvements to anti-TNF therapy in vivo and prevented the effect of ETN on Th17 cells in vitro. EPA supplementation might be a simple way to improve anti-TNF outcomes in patients with RA by suppressing Th17 frequencies.
OBJECTIVE: 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. METHODS: 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. RESULTS: Plasma PCEPA 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 PCEPA 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 frequencies in vitro. Physiological concentrations of EPA, but not LA, prevented this. CONCLUSION:EPA status was associated with clinical improvements to anti-TNF therapy in vivo and prevented the effect of ETN on Th17 cells in vitro. EPA supplementation might be a simple way to improve anti-TNF outcomes in patients with RA by suppressing Th17 frequencies.