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

描述(申请人提供)：膝骨性关节炎是一种痛苦的致残状态，具有重大的社会影响，但没有改变疾病的治疗方法。因此，关节内皮质类固醇(IAC)对骨性关节炎的调节作用存在一定的理论基础。IAC在临床上用于零星的膝骨性骨性关节炎疼痛发作，但它们可能影响骨性关节炎进展的概念是新的，源于最近观察到的膝骨性骨性关节炎滑膜炎的高患病率。与全身性多发性关节炎相比，OA滑膜炎更有局限性，强度更小，但细胞因子的表达情况相似，它的存在预示着软骨的损伤。皮质类固醇可减少类风湿关节炎患者关节损伤的进展，因此IACS也应减少由滑膜炎介导的骨性关节炎患者的软骨损伤。此外，IAC对化学诱导、机械诱导和炎性关节炎动物模型均有保护作用。我们的假设是，IAC减轻了对软骨和关节周围骨的炎性损伤，并且这种益处超过了对这些结构的任何抗合成代谢作用。随着直接成像关节软骨(MRI)、测量软骨下骨特性(DXA和MRI)以及在临床环境中评估滑膜炎(超声)的定量技术的最新发展，现在我们可以第一次测试IACS对骨关节炎结构进展的影响。这项拟议研究的主要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，以测试IACS对滑膜膝骨性关节炎的疾病改善的可能性。我们将招募140名膝关节骨关节炎和滑膜炎患者(经超声检查证实)，参加一项为期两年的适应性随机双盲临床试验，每3个月在超声引导下进行一次关节内注射曲安奈德40 mg与安慰剂对照的临床试验。我们将使用MRI、DXA和小梁形态计量学来测量软骨体积、关节周围骨的变化。我们将使用有效问卷和客观身体功能测试来评估症状、功能状态和医疗利用的变化。我们将使用纵向重复测量的混合效应回归模型来测试治疗组之间软骨体积随时间变化的轨迹的差异。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。这将允许试验提前停止，无论是成功还是失败，或者继续进行。 公共卫生相关性：膝骨性关节炎是一种常见的疼痛致残形式的关节炎，是导致工作损失和需要关节置换的主要原因。目前还没有已知的治疗方法可以改变这种疾病的进展速度。然而，最近的一项观察表明，患有关节炎的膝关节更有可能失去软骨，这增加了注射皮质类固醇(抑制炎症)的可能性，可能会降低这些膝盖的软骨丧失和关节损伤的比率。这项研究的目的是通过使用最近开发的直接测量膝关节软骨和周围骨骼变化的技术，对患有骨性关节炎和炎症的膝关节进行皮质类固醇注射的临床试验，以测试这种可能性。这一假设的确认将导致一种易于部署和廉价的膝骨性关节炎疾病修正策略。

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.