OBJECTIVE: To investigate the hypothesis that tumor necrosis factor alpha (TNFalpha) blockade in rheumatoid arthritis (RA) diminishes synovial synthesis of TNFalpha, interleukin-1alpha (IL-1alpha), and IL-1beta. METHODS: Patients with active RA received a single 10 mg/kg infusion of infliximab. Multiple synovial biopsy specimens were obtained from a knee the day before infusion and 14 days later. A modified immunohistochemical method detecting cytokine-producing rather than cytokine-binding cells was applied to determine synthesis of TNFalpha, IL-1alpha, and IL-1beta in fixed, cryopreserved sections. Computerized image analysis using two different methodologies was performed by independent observers blinded to the identity of samples. RESULTS: All 8 patients met the American College of Rheumatology 20% improvement response criteria (ACR 20) at 2 weeks, and half of these patients met the ACR 50. With a few exceptions, there was concordance between both image analysis methodologies regarding the direction of change in immunopositive area fraction for all cytokines analyzed. TNFalpha synthesis was significantly reduced after treatment (P = 0.05 at the Karolinska Institute, Stockholm, Sweden; P = 0.008 at the Kennedy Institute, London, UK). Patients meeting the ACR 50 were those with the highest baseline levels of TNFalpha synthesis. There was a significant correlation between baseline levels of TNFalpha expression and change in TNFalpha levels in response to therapy. Both IL-1alpha and IL-1beta synthesis were reduced in 3 patients; IL-1alpha synthesis alone was reduced in 2 patients and IL-1beta synthesis alone was reduced in 2 patients. In 1 patient, neither IL-1alpha nor IL-1beta synthesis was reduced. CONCLUSION: Analysis of synovial tissue by means of immunomorphology and image analysis in a clinical trial setting may allow the drawing of biologically meaningful conclusions. Synovial TNFalpha synthesis was reduced 2 weeks after infliximab treatment. Reductions in IL-1alpha and IL-1beta synthesis were demonstrated in a subgroup of patients. High levels of synovial TNFalpha production prior to treatment may predict responsiveness to therapy.
OBJECTIVE: To investigate the hypothesis that tumor necrosis factor alpha (TNFalpha) blockade in rheumatoid arthritis (RA) diminishes synovial synthesis of TNFalpha, interleukin-1alpha (IL-1alpha), and IL-1beta. METHODS:Patients with active RA received a single 10 mg/kg infusion of infliximab. Multiple synovial biopsy specimens were obtained from a knee the day before infusion and 14 days later. A modified immunohistochemical method detecting cytokine-producing rather than cytokine-binding cells was applied to determine synthesis of TNFalpha, IL-1alpha, and IL-1beta in fixed, cryopreserved sections. Computerized image analysis using two different methodologies was performed by independent observers blinded to the identity of samples. RESULTS: All 8 patients met the American College of Rheumatology 20% improvement response criteria (ACR 20) at 2 weeks, and half of these patients met the ACR 50. With a few exceptions, there was concordance between both image analysis methodologies regarding the direction of change in immunopositive area fraction for all cytokines analyzed. TNFalpha synthesis was significantly reduced after treatment (P = 0.05 at the Karolinska Institute, Stockholm, Sweden; P = 0.008 at the Kennedy Institute, London, UK). Patients meeting the ACR 50 were those with the highest baseline levels of TNFalpha synthesis. There was a significant correlation between baseline levels of TNFalpha expression and change in TNFalpha levels in response to therapy. Both IL-1alpha and IL-1beta synthesis were reduced in 3 patients; IL-1alpha synthesis alone was reduced in 2 patients and IL-1beta synthesis alone was reduced in 2 patients. In 1 patient, neither IL-1alpha nor IL-1beta synthesis was reduced. CONCLUSION: Analysis of synovial tissue by means of immunomorphology and image analysis in a clinical trial setting may allow the drawing of biologically meaningful conclusions. Synovial TNFalpha synthesis was reduced 2 weeks after infliximab treatment. Reductions in IL-1alpha and IL-1beta synthesis were demonstrated in a subgroup of patients. High levels of synovial TNFalpha production prior to treatment may predict responsiveness to therapy.
Authors: G Docena; L Rovedatti; L Kruidenier; A Fanning; N A B Leakey; C H Knowles; K Lee; F Shanahan; K Nally; P G McLean; A Di Sabatino; T T MacDonald Journal: Clin Exp Immunol Date: 2010-08-20 Impact factor: 4.330
Authors: M D Smith; D Baeten; A-K Ulfgren; I B McInnes; O Fitzgerald; B Bresnihan; P P Tak; D Veale Journal: Ann Rheum Dis Date: 2005-06-23 Impact factor: 19.103
Authors: Johan Lindberg; Carla A Wijbrandts; Lisa G van Baarsen; Gustavo Nader; Lars Klareskog; Anca Catrina; Rogier Thurlings; Margriet Vervoordeldonk; Joakim Lundeberg; Paul P Tak Journal: PLoS One Date: 2010-06-25 Impact factor: 3.240
Authors: Valérie Badot; Christine Galant; Adrien Nzeusseu Toukap; Ivan Theate; Anne-Lise Maudoux; Benoît J Van den Eynde; Patrick Durez; Frédéric A Houssiau; Bernard R Lauwerys Journal: Arthritis Res Ther Date: 2009-04-23 Impact factor: 5.156
Authors: C A Wijbrandts; S I van Leuven; H D Boom; D M Gerlag; E G S Stroes; J J P Kastelein; P P Tak Journal: Ann Rheum Dis Date: 2008-08-22 Impact factor: 19.103
Authors: Erik af Klint; Anca I Catrina; Peter Matt; Petra Neregråd; Jon Lampa; Ann-Kristin Ulfgren; Lars Klareskog; Staffan Lindblad Journal: Arthritis Res Ther Date: 2009-06-02 Impact factor: 5.156