Evidence that anti-tumor necrosis factor therapy with both etanercept and infliximab induces apoptosis in macrophages, but not lymphocytes, in rheumatoid arthritis joints: extended report

Arthritis Rheum. 2005 Jan;52(1):61-72. doi: 10.1002/art.20764.


Objective: Treatment of rheumatoid arthritis (RA) with tumor necrosis factor (TNF) antagonists is highly effective, but their mechanisms of action are not completely clear. Since anti-TNF therapy induces a decrease in synovial cellularity, this study focused on the modulation of RA synovial apoptosis following treatment with either soluble TNF receptor (etanercept) or TNF chimeric monoclonal antibody (infliximab).

Methods: Apoptosis (TUNEL and active caspase 3 staining) and cell surface markers were evaluated by immunohistochemistry in synovial biopsy samples obtained before and after 8 weeks of treatment with etanercept (12 patients) or infliximab (9 patients). We also determined by flow cytometry the in vitro effect of etanercept and infliximab on apoptosis of RA mononuclear cells derived from the synovial fluid (SF) and peripheral blood (PB).

Results: Eight weeks of treatment with etanercept and with infliximab significantly increased synovial apoptosis. This change was accompanied by a significant decrease in the synovial monocyte/macrophage population. The decrease in lymphocyte numbers did not reach statistical significance. In vitro, 24 hours of incubation with either etanercept or infliximab induced apoptosis of the SF monocyte/macrophage population. PB monocyte/macrophages were less susceptible to anti-TNF-mediated apoptosis. No changes in the rate of apoptosis were observed in the lymphocyte population derived from either SF or PB.

Conclusion: In RA patients, both etanercept and infliximab are able to induce cell type-specific apoptosis in the monocyte/macrophage population. This suggests a potential pathway that would account for the diminished synovial inflammation and the decreased numbers of synovial macrophages evident after TNF blockade.

Publication types

  • Clinical Trial
  • Controlled Clinical Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Antibodies, Monoclonal / therapeutic use*
  • Antirheumatic Agents / therapeutic use*
  • Apoptosis*
  • Arthritis, Rheumatoid / drug therapy*
  • Arthritis, Rheumatoid / pathology
  • Arthritis, Rheumatoid / physiopathology
  • Etanercept
  • Female
  • Flow Cytometry
  • Humans
  • Immunoglobulin G / therapeutic use*
  • Immunohistochemistry
  • In Situ Nick-End Labeling
  • Infliximab
  • Joints / pathology
  • Joints / physiopathology*
  • Lymphocytes / drug effects
  • Macrophages / drug effects*
  • Male
  • Middle Aged
  • Receptors, Tumor Necrosis Factor / therapeutic use*
  • Synovial Fluid
  • Synovial Membrane / pathology
  • Synovial Membrane / physiopathology
  • Treatment Outcome
  • Tumor Necrosis Factor Inhibitors*


  • Antibodies, Monoclonal
  • Antirheumatic Agents
  • Immunoglobulin G
  • Receptors, Tumor Necrosis Factor
  • Tumor Necrosis Factor Inhibitors
  • Infliximab
  • Etanercept