title: Successful tumour necrosis factor (TNF) blocking therapy suppresses oxidative stress and hypoxia-induced mitochondrial mutagenesis in inflammatory arthritis.
abstract: BACKGROUND
  To examine the effects of tumour necrosis factor (TNF) blocking therapy on the levels of early mitochondrial genome alterations and oxidative stress.
  
  
  METHODS
  Eighteen inflammatory arthritis patients underwent synovial tissue oxygen (tpO(2)) measurements and clinical assessment of disease activity (DAS28-CRP) at baseline (T0) and three months (T3) after starting biologic therapy. Synovial tissue lipid peroxidation (4-HNE), T and B cell specific markers and synovial vascular endothelial growth factor (VEGF) were quantified by immunohistochemistry. Synovial levels of random mitochondrial DNA (mtDNA) mutations were assessed using Random Mutation Capture (RMC) assay.
  
  
  RESULTS
  4-HNE levels pre/post anti TNF-α therapy were inversely correlated with in vivo tpO(2) (P < 0.008; r = -0.60). Biologic therapy responders showed a significantly reduced 4-HNE expression (P < 0.05). High 4-HNE expression correlated with high DAS28-CRP (P = 0.02; r = 0.53), tender joint count for 28 joints (TJC-28) (P = 0.03; r = 0.49), swollen joint count for 28 joints (SJC-28) (P = 0.03; r = 0.50) and visual analogue scale (VAS) (P = 0.04; r = 0.48). Strong positive association was found between the number of 4-HNE positive cells and CD4+ cells (P = 0.04; r = 0.60), CD8+ cells (P = 0.001; r = 0.70), CD20+ cells (P = 0.04; r = 0.68), CD68+ cells (P = 0.04; r = 0.47) and synovial VEGF expression (P = 0.01; r = 063). In patients whose in vivo tpO(2) levels improved post treatment, significant reduction in mtDNA mutations and DAS28-CRP was observed (P < 0.05). In contrast in those patients whose tpO2 levels remained the same or reduced at T3, no significant changes for mtDNA mutations and DAS28-CRP were found.
  
  
  CONCLUSIONS
  High levels of synovial oxidative stress and mitochondrial mutation burden are strongly associated with low in vivo oxygen tension and synovial inflammation. Furthermore these significant mitochondrial genome alterations are rescued following successful anti TNF-α treatment.
authors.affiliation: Translation Rheumatology Research Group, Dublin Academic Medical Centre, The Conway Institute of Biomolecular and Biomedical Research, St. Vincent’s University Hospital, Elm Park, Dublin 4, Ireland.
authors.forename: Monika
authors.initials: M
authors.lastname: Biniecka
authors.forename: Aisling
authors.initials: A
authors.lastname: Kennedy
authors.forename: Chin T
authors.initials: CT
authors.lastname: Ng
authors.forename: Ting C
authors.initials: TC
authors.lastname: Chang
authors.forename: Emese
authors.initials: E
authors.lastname: Balogh
authors.forename: Edward
authors.initials: E
authors.lastname: Fox
authors.forename: Douglas J
authors.initials: DJ
authors.lastname: Veale
authors.forename: Ursula
authors.initials: U
authors.lastname: Fearon
authors.forename: Jacintha N
authors.initials: JN
authors.lastname: O'Sullivan
mesh_terms: D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000235:genetics; D001688:Biological Products / Q000627:therapeutic use*; D015687:Cell Hypoxia / Q000187:drug effects; D004272:DNA, Mitochondrial; D006801:Humans; D007150:Immunohistochemistry; D008928:Mitochondria / Q000235:genetics; D016296:Mutagenesis; D009154:Mutation; D018384:Oxidative Stress / Q000187:drug effects*; D010100:Oxygen / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013583:Synovial Membrane / Q000187:drug effects*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors*
chemical_list: D001688:Biological Products; D004272:DNA, Mitochondrial; D014409:Tumor Necrosis Factor-alpha; D010100:Oxygen