title: In vitro response pattern of monocytes after tmTNF reverse signaling predicts response to anti-TNF therapy in rheumatoid arthritis.
abstract: BACKGROUND
  Treatment with TNF inhibitors is very efficient in the majority of the patients with rheumatoid arthritis (RA), but it does not achieve a sufficient treatment response in 40-50% of the cases. Goal of the study was to assess functional ex vivo-tests of RA monocytes as prognostic parameters of the subsequent treatment response.
  
  
  METHODS
  20 anti-TNF naïve RA patients were enrolled in a prospective, open-label trial, and Etanercept therapy was initiated. Prior to treatment, reverse signaling was induced in peripheral blood monocytes by tmTNF crosslinking via TNFR2:Ig construct Etanercept in a standardized ex vivo-assay. Released cytokine and cytokine receptor concentrations were determined as parameters of the monocyte response.
  
  
  RESULTS
  Crosslinking of tmTNF and consecutive reverse signaling led to production of pro- and anti-inflammatory cytokines and of soluble cytokine decoy receptors such as sTNFR1 and sIL-1R2. Several of the measured concentrations were found to correlate with the treatment response according to the EULAR criteria. The correlation was most pronounced in sTNFR1 concentrations (r = -0.657, p = 0.0031), which also predicted a good clinical response with the highest sensitivity and specificity according to EULAR criteria.
  
  
  CONCLUSIONS
  Herein we propose that the tmTNF crosslinking-triggered shedding of soluble decoy receptors and production of anti-inflammatory cytokines could contribute to the clinical efficacy of TNF inhibitors, and that in vitro quantification of this secretion by RA monocytes prior to treatment can be used to predict the clinical response. Further development of such standardized tests could be a step towards personalized medicine by providing rheumatologists with a rational choice for first line biological therapy in patients with RA.
authors.affiliation: Rheumatology Unit, Department of Internal Medicine, University of Leipzig, Liebigstr. 20, 04103, Leipzig, Germany. undine.meusch@medizin.uni-leipzig.de.
authors.forename: Undine
authors.initials: U
authors.lastname: Meusch
authors.affiliation: Rheumatology Unit, Department of Internal Medicine, University of Leipzig, Liebigstr. 20, 04103, Leipzig, Germany. marco.krasselt@medizin.uni-leipzig.de.
authors.forename: Marco
authors.initials: M
authors.lastname: Krasselt
authors.affiliation: Rheumatology Unit, Department of Internal Medicine, University of Leipzig, Liebigstr. 20, 04103, Leipzig, Germany. manuela.rossol@medizin.uni-leipzig.de.
authors.forename: Manuela
authors.initials: M
authors.lastname: Rossol
authors.affiliation: Rheumatology Unit, Department of Internal Medicine, University of Leipzig, Liebigstr. 20, 04103, Leipzig, Germany. christoph.baerwald@medizin.uni-leipzig.de.
authors.forename: Christoph
authors.initials: C
authors.lastname: Baerwald
authors.affiliation: Rheumatology Unit, Department of Internal Medicine, University of Leipzig, Liebigstr. 20, 04103, Leipzig, Germany. maria.klingner@web.de.
authors.forename: Maria
authors.initials: M
authors.lastname: Klingner
authors.affiliation: Rheumatology Unit, Department of Internal Medicine, University of Leipzig, Liebigstr. 20, 04103, Leipzig, Germany. ulf.wagner@medizin.uni-leipzig.de.
authors.forename: Ulf
authors.initials: U
authors.lastname: Wagner
mesh_terms: D018501:Antirheumatic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001172:Arthritis, Rheumatoid / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D002452:Cell Count; D003432:Cross-Linking Reagents / Q000494:pharmacology; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D016753:Interleukin-10 / Q000097:blood / Q000378:metabolism; D008875:Middle Aged; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism*; D012372:ROC Curve; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
chemical_list: D018501:Antirheumatic Agents; D003432:Cross-Linking Reagents; D047888:Receptors, Tumor Necrosis Factor, Type I; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1; D016753:Interleukin-10