Co-stimulatory pathways in the therapy of rheumatoid arthritis

  • Eric M. Ruderman
  • Richard M. Pope
Part of the Progress in Inflammation Research book series (PIR)


Although T lymphocytes are widely recognized as important effector cells in the immunopathogenesis of rheumatoid arthritis (RA), therapies targeting T cell populations have not been clinically successful, largely due to the toxicity associated with nonspecific T cell depletion. An alternative approach involves targeting T cell activation, a process that requires two distinct signals. In addition to the cognate interaction between the T cell receptor on T cells and antigen bound to the major histocompatibility complex on the antigen-presenting cell (APC), a second, co-stimulatory, signal is required for T cell activation. Therapies targeting co-stimulatory pathways, aimed at modifying the activation of T cells, rather than reducing their absolute numbers, may be an effective alternative to T cell depletion in RA and other rheumatic diseases. One such treatment, abatacept (CTLA4Ig), a fusion protein combining cytotoxic T lymphocyte antigen 4 (CTLA4) and a portion of the Fc domain of human IgG1, has been approved in the United States and the European Union for the treatment of RA. Abatacept may modulate the T cell or the APC to produce several different outcomes within the joint, including down-regulation of T cell activation, stimulation of T cell apoptosis, or possibly modulation of T regulatory cell activity. In large, controlled trials in patients with RA with an inadequate response to either methotrexate or TNF antagonists, abatacept effectively reduced disease activity. In the methotrexate-inadequate responder population, radiographic progression was slowed when compared to continued treatment with methotrexate alone. The safety profile of this therapy is similar to that of other biological response modifiers, with infection being the most concerning treatment-emergent adverse event. Additional co-stimulatory pathways may offer attractive targets in RA and other immune-mediated diseases, although, to date, none has had the clinical success of abatacept and the related CTLA4Ig fusion protein, belatacept.


Rheumatoid Arthritis Health Assessment Questionnaire Score Rheumatoid Arthritis Joint Inadequate Responder Abatacept Group 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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Copyright information

© Birkhäuser Verlag Basel/Switzerland 2009

Authors and Affiliations

  • Eric M. Ruderman
    • 1
  • Richard M. Pope
    • 1
  1. 1.Division of RheumatologyNorthwestern University Feinberg School of MedicineChicagoUSA

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