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Pathophysiology of sJIA: The role of IL-6

  • The pleiotropic effects IL-6 have been shown to drive several of the processes underlying the systemic and articular pathophysiology of sJIA1–10
  • Children with sJIA have marked IL-6 elevations in both serum and synovial fluid1,4
  • At the local or articular level, IL-6 contributes to joint inflammation, and to bone destruction via its effects on osteoclasts.4,5 IL-6 contributes to the autoimmune process via its effects on neutrophils, B-cells and T-cells2,8
  • At the systemic level, IL-6 is a key regulator of hepatocytes in the liver, a major regulator of acute-phase protein synthesis (including CRP) in systemic inflammation and an inducer of hepcidin production, which leads to anaemia.3 IL-6 also affects bone metabolism via the inhibition of osteoblast function, and by promoting the activation of osteoclasts, while contributing to growth defects by inhibiting circulating growth factor, IGF-I levels6,7,8
  • Elevations in serum levels of IL-6 precedes and correlates with rising body temperature associated with the spiking fever pattern characteristic of sJIA1,4 

The role of IL-6 in systemic and articular pathophysiology of sJIA1–10

Role of IL-6

References

  1. De Benedetti F, et al. Serum soluble interleukin 6 (IL-6) receptor and IL-6/soluble IL-6 receptor complex in systemic juvenile rheumatoid arthritis. J Clin Invest 1994; 93:2114–2119.
  2. Frosch M, Roth J. New insights in systemic juvenile idiopathic arthritis–from pathophysiology to treatment. Rheumatology 2008; 47:121–125.
  3. Cazzola M, et al. Defective iron supply for erythropoiesis and adequate endogenous erythropoietin production in the anemia associated with systemic-onset juvenile chronic arthritis. Blood 1996; 87:4824–4830.
  4. De Benedetti F, et al. Correlation of serum interleukin-6 levels with joint involvement and thrombocytosis in systemic juvenile rheumatoid arthritis. Arthritis Rheum 1991; 34:1158–1163.
  5. De Benedetti F, et al. Impaired skeletal development in interleukin-6-transgenic mice. Arthritis Rheum 2006; 54:3551–3563.
  6. De Benedetti F, et al. Interleukin 6 causes growth impairment in transgenic mice through a decrease in insulin-like growth factor-I. J Clin Invest 1997; 99:643–650.
  7. De Benedetti F, et al. Effect of IL-6 on IGF binding protein-3: A study in IL-6 transgenic mice and in patients with systemic juvenile idiopathic arthritis. Endocrinology 2001; 142:4818–4826.
  8. Dayer J-M, Choy E. Therapeutic targets in rheumatoid arthritis: the interleukin-6 receptor. Rheumatology 2010; 49:15–24.
  9. Smolen J, et al. Therapeutic strategies for rheumatoid arthritis. Nat Rev Drug Disc 2003; 2:473–488.
  10. Alonzi T, et al. Interleukin 6 is required for the development of collagen-induced arthritis. JEM 1998; 187:461–468.
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