Systemic anti–tumor necrosis factor α therapy in rheumatoid arthritis down-regulates synovial tumor necrosis factor α synthesis
Abstract
Objective
To investigate the hypothesis that tumor necrosis factor α (TNFα) blockade in rheumatoid arthritis (RA) diminishes synovial synthesis of TNFα, interleukin-1α (IL-1α), and IL-1β.
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 TNFα, IL-1α, and IL-1β 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. TNFα 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 TNFα synthesis. There was a significant correlation between baseline levels of TNFα expression and change in TNFα levels in response to therapy. Both IL-1α and IL-1β synthesis were reduced in 3 patients; IL-1α synthesis alone was reduced in 2 patients and IL-1β synthesis alone was reduced in 2 patients. In 1 patient, neither IL-1α nor IL-1β 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 TNFα synthesis was reduced 2 weeks after infliximab treatment. Reductions in IL-1α and IL-1β synthesis were demonstrated in a subgroup of patients. High levels of synovial TNFα production prior to treatment may predict responsiveness to therapy.
