Rheumatoid arthritis pathophysiology: update on emerging cytokine and cytokine-associated cell targets

Rheumatology (Oxford). 2014 Sep;53(9):1560-9. doi: 10.1093/rheumatology/ket414. Epub 2014 Jan 8.


Biologic therapies that target pathogenic cytokines such as TNF, IL-1β or IL-6 have greatly improved the treatment of RA. Unfortunately, not all RA patients respond to current biologic therapies and responses are not always maintained, suggesting that there are alternative drivers of RA pathogenesis that might serve as promising therapeutic targets. Discovery of the new Th17 subset of Th cells, and their role in autoimmune disease development, has implicated the proinflammatory IL-12 and IL-17 families of cytokines in RA disease pathogenesis. Members of these cytokine families are elevated in the blood and joints of RA patients and have been shown to remain elevated in patients who do not respond to current biologics. In addition, these cytokines have been shown to play roles in joint destruction and erosion. A new subclass of biologics that target the IL-12 and/or IL-17 signalling pathways are under development. Here we review evidence for a role of Th17 cells as well as IL-12 and IL-17 cytokines in RA pathogenesis as the rationale for a subsequent discussion of the ongoing and completed clinical trials of newly emerging biologic therapies directed at IL-12 or IL-17 pathway inhibition.

Keywords: IL-12; IL-17; IL-17A; IL-23; Th17 cell; autoimmune disease; biologic; inflammation; rheumatoid arthritis; synovitis.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Antirheumatic Agents / therapeutic use
  • Arthritis, Rheumatoid / drug therapy
  • Arthritis, Rheumatoid / immunology*
  • Biological Products / therapeutic use
  • CD4-Positive T-Lymphocytes / immunology
  • Cytokines / antagonists & inhibitors
  • Cytokines / immunology*
  • Humans
  • Interleukin-12 / antagonists & inhibitors
  • Interleukin-12 / immunology
  • Interleukin-17 / antagonists & inhibitors
  • Interleukin-17 / immunology
  • Molecular Targeted Therapy / methods*
  • Molecular Targeted Therapy / trends
  • T-Lymphocyte Subsets / immunology
  • Th17 Cells / immunology


  • Antirheumatic Agents
  • Biological Products
  • Cytokines
  • Interleukin-17
  • Interleukin-12