Abstract
To investigate the efficacy of isolated and combined blockade of TNF-, IL-1- and RANKL-pathways on synovial inflammation, bone erosion and cartilage destruction in a TNF-driven arthritis model, human TNF transgenic (hTNFtg) mice were treated with anti-TNF (infliximab), IL-1 receptor antagonist (IL-1Ra) or osteoprotegerin (OPG). In addition, each of three possible double combination therapies and a triple combination therapy was applied. Therapy was followed by histological assessment of synovial inflammation, bone erosion and cartilage damage. Synovial inflammation was inhibited by anti-TNF (-51%), but not IL-1Ra or OPG monotherapy. Combinations of anti-TNF with IL-1Ra (-91%) or OPG (-81%) were additive and almost completely blocked inflammation. Bone erosion was effectively blocked by anti-TNF (-79%) and also by OPG (-60%), but not by IL-1Ra monotherapy. Combination of anti-TNF and IL-1Ra, however, completely blocked bone erosion (-98%). The effects on inhibition of bone erosion were accompanied by reduction of osteoclast numbers within synovial tissue. Cartilage destruction was inhibited by anti-TNF (-43%), weakly, but not significantly by IL-1Ra, and not at all by OPG monotherapy. Combination of anti-TNF with IL-1Ra was the most effective double combination therapy in preventing cartilage destruction (-80%). In all analyses, a triple combination of anti-TNF, IL-1Ra and OPG was not superior to double combination therapy with anti-TNF and IL-1Ra. Articular changes caused by chronic TNF overexpression are not completely blockable by monotherapies, which target TNF, IL-1 or RANKL. However, combined approaches that reduce TNF load and block IL-1 or RANKL as downstream mediators of TNF can lead to a complete remission. Differences in their efficacy to block synovial inflammation, bone erosion and cartilage destruction further strengthen the rationale for combined blockade of more than one proinflammatory pathway.
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