title: Soluble OX40L is associated with presence of autoantibodies in early rheumatoid arthritis.
abstract: BACKGROUND
  OX40 and its ligand OX40L are key components in the generation of adaptive memory response and provide necessary co-stimulatory signals for activated effector T cells. Here we investigate the dual roles of the membrane and soluble (s) forms of OX40 and OX40L in plasma and synovial fluid and their association with autoantibodies and disease activity in rheumatoid arthritis (RA).
  
  
  METHODS
  Soluble OX40 and sOX40L plasma levels were measured in treatment-naïve early RA patients (eRA) at baseline and after 3, 6, and 12 months of treatment with methotrexate and adalimumab (n = 39) and with methotrexate alone (n = 37). Adalimumab was discontinued after the first year, and patients were followed for additional 12 months. For comparison, sOX40 and sOX40L were measured in patients with chronic RA (cRA, n = 15) and healthy volunteers (HV, n = 34). Membrane-bound OX40 and OX40L expression on T cells, B cells and monocytes were quantified.
  
  
  RESULTS
  Soluble OX40 plasma levels of eRA patients were not different at the time of treatment initiation, but were significantly higher after 12 months of treatment, compared with HV or cRA patients. Soluble OX40L was significantly elevated throughout the first 12 months of treatment compared with HVs and patients with cRA. Adalimumab treatment did not influence sOX40 or sOX40L plasma levels. At baseline, sOX40L levels were strongly associated with the presence of anti-citrullinated protein antibodies (ACPA) (P <0.001) and IgM-RF (P <0.0001). The sOX40/sOX40L ratio was decreased in eRA, and a low ratio at the time of adalimumab discontinuation was associated with increased DAS28CRP and risk of flare the following year. T cells in the synovial fluid had the highest expression of OX40, while monocytes and B cells were the main expressers of OX40L in the joint.
  
  
  CONCLUSIONS
  Plasma levels of sOX40 and sOX40L were increased in eRA and sOX40L was correlated with ACPA and IgM-RF. Further, expression of membrane-bound OX40 and OX40L was increased in eRA and cRA. Combined, these findings could reflect that increased activity in the OX40 systems facilitate to drive disease activity and autoantibody production in RA.
  
  
  BACKGROUND
  Clincaltrials.gov NCT00660647, 10 April 2008.
authors.forename: Julie K
authors.initials: JK
authors.lastname: Laustsen
authors.forename: Tue K
authors.initials: TK
authors.lastname: Rasmussen
authors.forename: Kristian
authors.initials: K
authors.lastname: Stengaard-Pedersen
authors.forename: Kim
authors.initials: K
authors.lastname: Hørslev-Petersen
authors.forename: Merete L
authors.initials: ML
authors.lastname: Hetland
authors.forename: Mikkel
authors.initials: M
authors.lastname: Østergaard
authors.forename: Peter
authors.initials: P
authors.lastname: Junker
authors.forename: Malene
authors.initials: M
authors.lastname: Hvid
authors.forename: Bent
authors.initials: B
authors.lastname: Deleuran
mesh_terms: D000068879:Adalimumab; D000328:Adult; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use; D018501:Antirheumatic Agents / Q000627:therapeutic use; D001172:Arthritis, Rheumatoid / Q000097:blood* / Q000188:drug therapy / Q000378:metabolism; D001323:Autoantibodies / Q000097:blood* / Q000276:immunology / Q000378:metabolism; D001402:B-Lymphocytes / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008297:Male; D008727:Methotrexate / Q000627:therapeutic use; D008875:Middle Aged; D009000:Monocytes / Q000378:metabolism; D053278:OX40 Ligand / Q000097:blood* / Q000378:metabolism; D010456:Peptides, Cyclic / Q000276:immunology; D053262:Receptors, OX40 / Q000097:blood / Q000378:metabolism; D012995:Solubility; D013582:Synovial Fluid / Q000378:metabolism*; D013601:T-Lymphocytes / Q000378:metabolism; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D018501:Antirheumatic Agents; D001323:Autoantibodies; D053278:OX40 Ligand; D010456:Peptides, Cyclic; D053262:Receptors, OX40; C505716:TNFRSF4 protein, human; C089251:TNFSF4 protein, human; C487763:cyclic citrullinated peptide; D000068879:Adalimumab; D008727:Methotrexate