We found a significant reduction in the clinical signs of arthritis, indicated by an increase of paw swelling and a decrease in grip strength, in IL1-/-IL6-/-hTNFtg mice when compared to their hTNFtg littermates. In line with these findings we observed a significant decrease in synovial inflammation in IL1-/-IL6-/-hTNFtg mice when compared to hTNFtg animals. Moreover, the number of synovial TRAP+ osteoclasts was markedly diminished in IL1-/-IL6-/-hTNFtg mice and reduced osteoclast formation, was accompanied by significantly less subchondral bone erosions. Additionally, we found a conserved articular cartilage structure showing almost no cartilage degradation in IL1-/-IL6-/-hTNFtg mice compared to their hTNFtg littermates. In IL1-/-IL6-/-hTNFtg mice clinical, as well as, histological signs of disease, including joint inflammation, bone destruction and cartilage damage were also significantly diminished when compared to IL6-/-hTNFtg mice. However, by comparing IL1-/-IL6-/-hTNFtg mice with IL1-/- hTNFtg mice we found a similar reduction on synovial inflammation, as well as subchondral bone erosions and articular cartilage destruction.