Effect of Intra-Articular Steroids on Structural Progression of Knee OA: An RCT

描述（由申请人提供）：膝关节OA是一种痛苦的致残疾病，具有重大的社会影响，但没有改善疾病的治疗方法。因此，关节内皮质类固醇（IACS）的oa调节作用存在一个明显的理论基础。IACS在临床上用于治疗散发性膝关节OA疼痛，但它们可能影响OA进展的概念是新的，并且源于最近对OA膝关节滑膜炎高患病率的观察。OA滑膜炎比全身性多发性关节炎更具有局灶性，强度更小，但细胞因子表达谱相似，其存在预示软骨损伤。皮质类固醇可减少类风湿关节炎中关节损伤的进展，因此IACS也应减少由滑膜炎介导的OA软骨损伤。此外，IACS对化学诱导、机械诱导和炎症性OA动物模型均有保护作用。我们的假设是IACS减轻了软骨和关节周围骨的炎症损伤，并且这种益处超过了对这些结构的任何抗合成代谢作用。最近定量技术的发展，直接成像关节软骨（MRI），测量软骨下骨特性（DXA和MRI），并在临床环境中评估滑膜炎（超声），现在允许我们第一次测试IACS对OA结构进展的影响。本研究的总体目标是通过临床试验直接测量其对软骨和软骨下骨的影响，来测试IACS对滑膜性膝关节OA的疾病改变的潜力。我们将招募140例膝关节OA和滑膜炎患者（经超声确诊），参加一项适应性2年随机双盲临床试验，每3个月在超声指导下给药，关节内曲安奈德40 mg与安慰剂对照。我们将使用MRI、DXA和小梁形态测量测量软骨体积、关节周围骨的变化。我们将通过有效的问卷调查和客观的身体功能测试来评估症状、功能状态和医疗保健利用的变化。我们将使用混合效应回归模型进行纵向重复测量，以测试治疗组间软骨体积随时间变化轨迹的差异。我们将在前半部分参与者完成试验后进行适应性中期分析。这将允许试验在成功或失败的情况下提前停止，或者继续进行。

DESCRIPTION (provided by applicant): Knee OA is a painful disabling condition that has major societal impact yet has no disease-modifying therapies. It is, therefore, salient that a rationale exists for OA-modifying effects from intra-articular corticosteroids (IACS). IACS are in clinical use for sporadic knee OA pain flares, but the notion that they might influence OA progression is new, and derives from the recent observation of a high prevalence of synovitis in OA knees. OA synovitis is more focal and less intense than that of systemic polyarthritis, but the profile of cytokine expression is similar and its presence predicts cartilage damage. Corticosteroids reduce progression of joint damage in rheumatoid arthritis, so IACS should also reduce cartilage damage in OA that is mediated by synovitis. Moreover, IACS have protective effects in chemically-induced, mechanically-induced and inflammatory animal models of OA. Our hypothesis is that IACS mitigate inflammatory damage to cartilage and peri-articular bone, and that this benefit outweighs any anti-anabolic effects on these structures. The recent development of quantitative technologies that directly image joint cartilage (MRI), measure subchondral bone properties (DXA and MRI), and evaluate synovitis in a clinical setting (ultrasonography), now allows us to test for the first time the effects of IACS on the structural progression of OA. The overarching goal of this proposed research is to test the potential for disease modification of synovitic knee OA by IACS through a clinical trial directly measuring its effects on cartilage and subchondral bone. We will enroll 140 individuals with knee OA and synovitis (confirmed by ultrasonography), into an adaptive 2-year randomized double-blind clinical trial of intra-articular triamcinolone 40 mg vs. placebo, every 3 months, administered with ultrasound guidance. We will measure changes in cartilage volume, peri-articular bone using MRI and DXA and trabecular morphometry. We will evaluate changes in symptoms, functional status and healthcare utilization using validated questionnaires and objective physical function tests. We will use mixed effects regression models for longitudinal repeated measures to test for a difference in the trajectory of cartilage volume over time between the treatment groups. We will conduct an adaptive interim analysis after the first half of participants has completed the trial. This will allow the trial to be stopped early for either success or futility, or otherwise continue. PUBLIC HEALTH RELEVANCE: Knee OA is a common painful disabling form of arthritis that is a major cause of work-loss and need for joint replacement. There are no medical treatments known to change the rate at which this disease progresses. However, a recent observation that knees with OA that have inflammation are more likely to lose cartilage raises the possibility that injection of corticosteroids (which suppress inflammation) might reduce the rate of cartilage loss and joint damage in these knees. The objective of this research is to test this possibility by performing a clinical trial of corticosteroid injections in knees with OA and inflammation using recently-developed technologies that directly measure changes in knee cartilage and surrounding bone. Confirmation of this hypothesis would lead to an easily-deployable and inexpensive disease-modification strategy for knee OA.