Targeting interleukin-17 in patients with active rheumatoid arthritis: rationale and clinical potential
Targeting interleukin-17 in patients with active rheumatoid arthritis: rationale and clinical potential
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DOI：
10.1177/1759720x13485328
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发表时间：
2013-06-01
影响因子：
4.2
通讯作者：
Kellner, Herbert
中科院分区：
文献类型：
--
作者：
Kellner, Herbert
临床和实验证据表明，白细胞介素-17A（IL-17 A;也称为IL-17）是类风湿性关节炎（RA）的一个有吸引力的治疗靶点。风湿性关节炎滑膜组织产生IL-17 A，其导致滑膜和骨外植体中的软骨和骨降解。IL-17 A过表达诱导RA动物模型滑膜炎症和关节破坏。这些作用在IL-17 A缺陷动物中和通过阻断IL-17 A的试剂减弱。血清IL-17 A水平，并在更大程度上，滑液IL-17 A水平在许多RA患者中升高。在一些RA队列中，较高的IL-17 A水平与更严重的临床病程相关。已在II期临床试验中评估了几种IL-17 A阻断剂，包括抗IL-17 A单克隆抗体Riskinumab和ixekizumab，以及抗IL-17受体亚单位A单克隆抗体brodalumab。其中，阿基诺单抗在RA的临床评价方面是最先进的，在对既往肿瘤坏死因子阻滞剂治疗反应不足的背景甲氨蝶呤患者中进行的III期试验正在进行中。
Clinical and experimental evidence suggest that interleukin-17A (IL-17A; also known as IL-17) is an attractive therapeutic target in rheumatoid arthritis (RA). Rheumatoid synovial tissue produces IL-17A, which causes cartilage and bone degradation in synovial and bone explants. Overexpression of IL-17A induces synovial inflammation and joint destruction in animal RA models. These effects are attenuated in IL-17A-deficient animals and by agents that block IL-17A. Serum IL-17A levels and, to a greater extent, synovial fluid IL-17A levels are elevated in many patients with RA. In some RA cohorts, higher IL-17A levels have been associated with a more severe clinical course. Several IL-17A blockers, including the anti-IL-17A monoclonal antibodies secukinumab and ixekizumab, and the anti-IL-17 receptor subunit A monoclonal antibody brodalumab have been evaluated in phase II clinical trials. Of these, secukinumab is the most advanced with respect to clinical evaluation in RA, with phase III trials ongoing in patients on background methotrexate who had inadequate responses to previous tumor necrosis factor blocker therapy.