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

描述（由申请人提供）：膝关节骨性关节炎是一种疼痛性致残性疾病，具有重大社会影响，但尚无疾病缓解疗法。因此，关节内皮质类固醇（IACS）的OA调节作用存在合理性。IACS在临床上用于偶发性膝关节OA疼痛发作，但它们可能影响OA进展的概念是新的，并且来自于最近观察到的OA膝关节滑膜炎的高患病率。OA滑膜炎比全身性多关节炎更集中，强度更低，但细胞因子表达谱相似，其存在预示软骨损伤。皮质类固醇减少类风湿性关节炎中关节损伤的进展，因此IACS也应该减少由滑膜炎介导的OA中的软骨损伤。此外，IACS在化学诱导、机械诱导和炎症性OA动物模型中具有保护作用。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。最近发展的定量技术，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。这项拟议研究的总体目标是通过直接测量其对软骨和软骨下骨的影响的临床试验，测试IACS对滑膜膝关节OA疾病改善的潜力。我们将招募140名患有膝关节OA和滑膜炎（经超声检查证实）的患者，进行一项适应性2年随机双盲临床试验，在超声引导下每3个月关节内注射40 mg曲安西龙与安慰剂。 我们将使用MRI和DXA以及小梁形态测量来测量软骨体积、关节周围骨的变化。我们将使用经过验证的问卷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，以检验治疗组之间软骨体积随时间变化的轨迹差异。我们将在前一半参与者完成试验后进行适应性中期分析。这将允许试验因成功或无效而提前停止，或以其他方式继续。 公共卫生相关性：膝关节骨性关节炎是一种常见的疼痛致残性关节炎，是导致工作丧失和需要关节置换的主要原因。没有已知的药物治疗可以改变这种疾病的进展速度。然而，最近的一项观察表明，患有炎症的OA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）可能降低这些膝关节软骨丢失和关节损伤率的可能性。本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在患有OA和炎症的膝关节中进行皮质类固醇注射的临床试验来测试这种可能性。这一假设的证实将导致一个易于部署和廉价的疾病修改策略的膝关节骨性关节炎。

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.