title: Clinical efficacy of infliximab plus methotrexate in DMARD naive and DMARD refractory rheumatoid arthritis is associated with decreased synovial expression of TNF alpha and IL18 but not CXCL12.
abstract: BACKGROUND
  Tumour necrosis alpha (TNF alpha) blocking agents lead to pronounced clinical effects and reduced synovial infiltrate in rheumatoid arthritis. Laboratory and clinical studies suggest that TNF alpha independent pathways play a role in the disease.
  
  
  OBJECTIVE
  To evaluate the immunopathological effects of combination therapy on rheumatoid synovial tissue in order to identify TNF alpha independent mechanisms.
  
  
  METHODS
  12 rheumatoid patients, including four DMARD (disease modifying antirheumatic drug) naive patients with early disease, were studied for the effect of combination therapy with infliximab and methotrexate on the synovial infiltrate. Biopsies and clinical assessments (DAS28) were carried out before the first and after the third infusion of infliximab. Synovial inflammation was scored semiquantitatively. Co-expression of CD38(+) cells was studied by an immunofluorescent double labelling technique.
  
  
  RESULTS
  Marked clinical responses were associated with a global reduction in the synovial infiltrate and expression of cytokines, notably interleukin 18 and TNF alpha, but low grade disease activity persisted. There was no effect on the expression of CXC chemokine ligand (CXCL12), and germinal centre-like structures were still detectable in synovial tissue in two patients after treatment. CD38(+) activated T cells were more resistant to treatment than CD38(+) plasma cells. No differences in clinical response or effects on synovial infiltrate were observed between DMARD refractory and DMARD naive patients.
  
  
  CONCLUSIONS
  Persistent expression of CXCL12 and incomplete resolution of lymphocytic infiltrates after infliximab plus methotrexate indicates that TNF alpha independent mechanisms are operative in rheumatoid arthritis. This may contribute to low grade disease activity, even in DMARD naive patients with early disease.
authors.affiliation: Leiden University Medical Centre, Department of Rheumatology, PO Box 9600, 2300 RC Leiden, Netherlands. M.van_Oosterhout@LUMC.nl
authors.forename: M
authors.initials: M
authors.lastname: van Oosterhout
authors.forename: E W N
authors.initials: EW
authors.lastname: Levarht
authors.forename: J K
authors.initials: JK
authors.lastname: Sont
authors.forename: T W J
authors.initials: TW
authors.lastname: Huizinga
authors.forename: R E M
authors.initials: RE
authors.lastname: Toes
authors.forename: J M
authors.initials: JM
authors.lastname: van Laar
mesh_terms: D000328:Adult; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D018501:Antirheumatic Agents / Q000627:therapeutic use*; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000276:immunology; D001182:Arthroscopy; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000378:metabolism; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D007124:Immunoenzyme Techniques; D000069285:Infliximab; D020382:Interleukin-18 / Q000378:metabolism; D008024:Ligands; D008297:Male; D008727:Methotrexate / Q000627:therapeutic use*; D008875:Middle Aged; D013583:Synovial Membrane / Q000276:immunology*; D013585:Synovitis / Q000188:drug therapy / Q000276:immunology; D017211:Treatment Failure; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D018501:Antirheumatic Agents; C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; D020382:Interleukin-18; D008024:Ligands; D014409:Tumor Necrosis Factor-alpha; D000069285:Infliximab; D008727:Methotrexate