Zwerina Jochen, Hayer Silvia, Tohidast-Akrad Makiyeh, Bergmeister Helga, Redlich Kurt, Feige Ulrich, Dunstan Colin, Kollias Giorgos, Steiner Günter, Smolen Josef, Schett Georg
University of Vienna, Vienna, Austria.
Arthritis Rheum. 2004 Jan;50(1):277-90. doi: 10.1002/art.11487.
To investigate the efficacy of single and combined blockade of tumor necrosis factor (TNF), interleukin-1 (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; anakinra), or osteoprotegerin (OPG; an OPG-Fc fusion protein), either alone or in combinations of 2 agents or all 3 agents. Synovial inflammation, bone erosion, and cartilage damage were evaluated histologically.
Synovial inflammation was inhibited by anti-TNF (-51%), but not by IL-1Ra or OPG monotherapy. The combination of anti-TNF with either IL-1Ra (-91%) or OPG (-81%) was additive and almost completely blocked inflammation. Bone erosion was effectively blocked by anti-TNF (-79%) and OPG (-60%), but not by IL-1Ra monotherapy. The combination of anti-TNF with IL-1Ra, however, completely blocked bone erosion (-98%). Inhibition of bone erosion was accompanied by a reduction of osteoclast numbers in synovial tissue. Cartilage destruction was inhibited by anti-TNF (-43%) and was weakly, but not significantly, inhibited by IL-1Ra, but was not inhibited by OPG monotherapy. The combination of anti-TNF with IL-1Ra was the most effective double combination therapy in preventing cartilage destruction (-80%). In all analyses, the triple combination of anti-TNF, IL-1Ra, and OPG was not superior to the double combination of anti-TNF and IL-1Ra.
Articular changes caused by chronic overexpression of TNF are not completely blockable by monotherapies that target TNF, IL-1, or RANKL. However, combined approaches, especially the combined blockade of TNF and IL-1 and, to a lesser extent, TNF and RANKL, lead to almost complete remission of disease. Differences in abilities to block synovial inflammation, bone erosion, and cartilage destruction further strengthen the rationale for using combined blockade of more than one proinflammatory pathway.
在肿瘤坏死因子（TNF）驱动的关节炎模型中，研究单独及联合阻断TNF、白细胞介素-1（IL-1）和核因子κB受体活化因子配体（RANKL）信号通路对滑膜炎症、骨侵蚀和软骨破坏的疗效。
用人TNF转基因（hTNFtg）小鼠，分别给予抗TNF（英夫利昔单抗）、IL-1受体拮抗剂（IL-1Ra；阿那白滞素）或骨保护素（OPG；一种OPG-Fc融合蛋白）单药治疗，或两药联合或三药联合治疗。通过组织学评估滑膜炎症、骨侵蚀和软骨损伤情况。
抗TNF可抑制滑膜炎症（-51%），但IL-1Ra或OPG单药治疗无效。抗TNF与IL-1Ra（-91%）或OPG（-81%）联合使用具有相加作用，几乎可完全阻断炎症。抗TNF（-79%）和OPG（-60%）可有效阻断骨侵蚀，但IL-1Ra单药治疗无效。然而，抗TNF与IL-1Ra联合可完全阻断骨侵蚀（-98%）。骨侵蚀的抑制伴随着滑膜组织中破骨细胞数量的减少。抗TNF可抑制软骨破坏（-43%），IL-1Ra有较弱抑制作用但不显著，OPG单药治疗无效。抗TNF与IL-1Ra联合是预防软骨破坏最有效的双药联合治疗方案（-80%）。在所有分析中，抗TNF、IL-1Ra和OPG三药联合并不优于抗TNF和IL-1Ra双药联合。
TNF慢性过表达引起的关节改变，不能通过靶向TNF、IL-1或RANKL的单药治疗完全阻断。然而，联合治疗方法，尤其是联合阻断TNF和IL-1，以及在较小程度上联合阻断TNF和RANKL，可使疾病几乎完全缓解。阻断滑膜炎症、骨侵蚀和软骨破坏能力的差异，进一步支持了联合阻断多种促炎信号通路的理论依据。
