The combination of tumor necrosis factor alpha blockade with interleukin-1 and interleukin-17 blockade is more effective for controlling synovial inflammation and bone resorption in an ex vivo model

Arthritis Rheum. 2001 Jun;44(6):1293-303. doi: 10.1002/1529-0131(200106)44:6<1293::AID-ART221>3.0.CO;2-T.


Objective: Anti-tumor necrosis factor a (anti-TNFalpha) therapy has shown efficacy in the treatment of rheumatoid arthritis (RA). Since interleukin-1 (IL-1), TNFalpha, and IL-17 have many additive and/or synergistic effects in vitro, we tested whether their combined inhibition by soluble receptors would lead to an enhanced effect on ex vivo models of synovial inflammation and bone destruction.

Methods: RA synovium and bone explants were cultured for 7 days in the presence of 1 microg/ml soluble TNFalpha receptor (STNFR; as in current therapy), type II soluble IL-1 receptor (sIL-1RII), or sIL-17R either alone or in combination. Their effects on the production of IL-6 and the release of C-telopeptide of type I collagen (CTX), a marker of type I collagen destruction, were measured by enzyme-linked immunosorbent assay.

Results: In synovium, each soluble receptor alone decreased IL-6 production and CTX release by approximately 35% and approximately 55%, respectively. The combination of all 3 receptors was more effective, inhibiting IL-6 production and collagen degradation by up to 70%. Neither sIL-17R, sIL-1RII, or sTNFR alone had no effect (or an effect of <20% inhibition) on IL-6 production in 18%, 33%, and 22%, respectively, of the samples. In bone, sIL-17R, sIL-1RII, and sTNFR decreased IL-6 production by 23%, 50%, and 37%, respectively, while the combination decreased IL-6 production by 75%. A 50% inhibition of CTX release was obtained with sIL-1RII for 63% of the samples versus 38% of the samples with either sTNFR or sIL-17R. However, the combination of all 3 receptors was not more potent than sIL-1RII alone.

Conclusion: The inhibitory effect of sTNFR on IL-6 production and collagen degradation in RA synovium and bone was increased in combination with sIL-17R and sIL-1RII. These results support the concept of combination therapy, which may increase the percentage of responding patients as well as the degree of individual patient response.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Animals
  • Bone Resorption / metabolism
  • Bone Resorption / prevention & control*
  • Bone and Bones / drug effects*
  • Bone and Bones / metabolism
  • Bone and Bones / pathology
  • Cells, Cultured
  • Collagen / metabolism
  • Culture Techniques
  • Dose-Response Relationship, Immunologic
  • Drug Combinations
  • Enzyme-Linked Immunosorbent Assay
  • Female
  • Flow Cytometry
  • Humans
  • Interleukin-1 / pharmacology*
  • Interleukin-17 / pharmacology*
  • Interleukin-6 / biosynthesis
  • Male
  • Mice
  • Middle Aged
  • Synovial Membrane / drug effects*
  • Synovial Membrane / metabolism
  • Synovial Membrane / pathology
  • Synovitis / metabolism
  • Synovitis / prevention & control*
  • Tumor Necrosis Factor-alpha / antagonists & inhibitors*


  • Drug Combinations
  • Interleukin-1
  • Interleukin-17
  • Interleukin-6
  • Tumor Necrosis Factor-alpha
  • Collagen