title: Tumor necrosis factor blocking therapy alters joint inflammation and hypoxia.
abstract: OBJECTIVE
  To examine the effect of tumor necrosis factor (TNF) blocking therapy on hypoxia in vivo, macroscopic and microscopic inflammation, and magnetic resonance imaging (MRI) results in patients with inflammatory arthritis.
  
  
  METHODS
  Patients with inflammatory arthritis (n = 20) underwent full clinical assessment, arthroscopy, synovial biopsy, and MRI before and after initiation of biologic therapy. Macroscopic synovitis/vascularity was assessed with a visual analog scale, and tissue PO(2) (tPO(2) ) was measured at arthroscopy using a Licox probe. Cell-specific markers (CD4, CD8, CD68, CD20, and CD19) and blood vessel maturity were quantified by immunohistologic analysis and dual-immunofluorescence factor VIII/α-smooth muscle actin staining, respectively. Contiguous gadoteric acid-enhanced MRI of the target knee was used to assess synovial enhancement.
  
  
  RESULTS
  Biologic therapy responders showed a significant increase of tPO(2) in vivo (P < 0.05). This response was associated with significant reductions in 28-joint Disease Activity Score using the C-reactive protein level (DAS28-CRP) (P = 0.012), macroscopic synovitis (P = 0.017), macroscopic vascularity (P = 0.05), CD4+ T cells (P < 0.041), and CD68+ macrophages (P < 0.011). Blood vessel numbers were also reduced in responders; however, this did not reach statistical significance. Strong inverse correlations were demonstrated between changes in tPo(2) levels and changes in DAS28-CRP (r = -0.53, P < 0.001), CD4 (r = -0.44, P < 0.026), CD68 (r = -0.46, P < 0.003), and macroscopic vascularity (r = -0.314, P = 0.049) after therapy. Furthermore, changes in inflammation as measured by MRI showed a strong inverse correlation with tPO(2) levels (r = -0.688, P < 0.002) and positive correlations with CRP levels (r = 0.707, P = 0.001), macroscopic synovitis (r = 0.457, P = 0.056), macroscopic vascularity (r = 0.528, P= 0.017), CD4 (r = 0.553, P < 0.032), and CD68 (r = 0.670, P < 0.002) after therapy.
  
  
  CONCLUSIONS
  This is the first study to show that successful biologic therapy significantly improves in vivo synovial hypoxia. Changes are strongly associated with changes in macroscopic and microscopic measures of joint inflammation and MRI improvement. These data further strengthen the concept that hypoxia is an important event driving synovial inflammation.
authors.affiliation: Dublin Academic Medical Centre, The Conway Institute for Biomolecular and Biomedical Research, University College, Dublin, Ireland.
authors.forename: Aisling
authors.initials: A
authors.lastname: Kennedy
authors.forename: Chin Teck
authors.initials: CT
authors.lastname: Ng
authors.forename: Ting Cheng
authors.initials: TC
authors.lastname: Chang
authors.forename: Monika
authors.initials: M
authors.lastname: Biniecka
authors.forename: Jacintha N
authors.initials: JN
authors.lastname: O'Sullivan
authors.forename: Eric
authors.initials: E
authors.lastname: Heffernan
authors.forename: Ursula
authors.initials: U
authors.lastname: Fearon
authors.forename: Douglas J
authors.initials: DJ
authors.lastname: Veale
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015703:Antigens, CD / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism; D018501:Antirheumatic Agents / Q000627:therapeutic use*; D001168:Arthritis / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D001691:Biological Therapy; D001706:Biopsy; D002097:C-Reactive Protein / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000473:pathology; D015331:Cohort Studies; D006801:Humans; D000860:Hypoxia / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D008279:Magnetic Resonance Imaging; D008875:Middle Aged; D009389:Neovascularization, Pathologic / Q000503:physiopathology; D012720:Severity of Illness Index; D013583:Synovial Membrane / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors*; D000097382:CD68 Molecule
chemical_list: D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D018501:Antirheumatic Agents; D002097:C-Reactive Protein; D014409:Tumor Necrosis Factor-alpha; C067980:CD68 antigen, human; D000097382:CD68 Molecule