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

关节内类固醇对膝关节 OA 结构进展的影响：一项随机对照试验

• 批准号: 8127919
• 负责人: Timothy E McAlindon
• 金额: $ 62.26万
• 依托单位: TUFTS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-09 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8127919
• 关键词: Adrenal Cortex Hormones; Adverse effects; Affect; Animal Model; Arthritis; Arthroscopy; Bone Density; Bone Marrow; Cartilage; Clinic; Clinical; Clinical Trials; Consensus; Degenerative polyarthritis; Development; Disease; Double-Blind Method; Dual-Energy X-Ray Absorptiometry; Enrollment; Exhibits; Flare; Futility; Goals; Health Care Costs; High Prevalence; Image; Individual; Inflammation; Inflammatory; Injection of therapeutic agent; Intervention; Joints; Knee; Knee Osteoarthritis; Lead; Lesion; Magnetic Resonance Imaging; Measurement; Measures; Mediating; Medical; Modality; Modeling; Modification; Neck; Osteoarthrosis Deformans; Outcome; Pain; Participant; Physical Function; Placebos; Polyarthritides; Population; Property; Questionnaires; Randomized; Regimen; Replacement Arthroplasty; Research; Resolution; Rheumatoid Arthritis; Sampling; Scanning; Steroids; Structure; Symptoms; Synovitis; Technology; Testing; Time; Triamcinolone; Ultrasonography; Work; bone; bone health; cytokine; disability; experience; functional status; health care service utilization; interest; joint injury; morphometry; protective effect; public health relevance; substantia spongiosa; success

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.

描述（由申请人提供）：膝关节骨关节炎是一种痛苦的致残疾病，具有重大的社会影响，但尚无缓解疾病的疗法。因此，关节内皮质类固醇 (IACS) 改善 OA 作用的合理性是存在的。 IACS 在临床上用于治疗偶发性膝关节 OA 疼痛，但它们可能影响 OA 进展的概念是新的，并且源自最近对 OA 膝关节滑膜炎高患病率的观察。 OA 滑膜炎比全身性多关节炎更具局灶性且强度较低，但细胞因子的表达谱相似，其存在预示着软骨损伤。皮质类固醇可以减少类风湿性关节炎关节损伤的进展，因此 IACS 还可以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 动物模型具有保护作用。我们的假设是 IACS 减轻了对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。最近开发的定量技术可直接对关节软骨 (MRI) 进行成像、测量软骨下骨特性（DXA 和 MRI）以及在临床环境中评估滑膜炎（超声检查），现在使我们能够首次测试 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 IACS 对软骨和软骨下骨影响的临床试验来测试 IACS 改善滑膜膝 OA 疾病的潜力。我们将招募 140 名患有膝关节 OA 和滑膜炎（经超声检查证实）的患者参加一项为期 2 年的适应性随机双盲临床试验，试验为关节内注射曲安奈德 40 mg 与安慰剂，每 3 个月一次，在超声引导下给药。 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，以测试治疗组之间软骨体积随时间变化的轨迹差异。我们将在上半年参与者完成试验后进行适应性中期分析。这将使试验能够因成功或无效而提前停止，或者继续进行。 公众健康相关性：膝关节骨关节炎是一种常见的疼痛致残性关节炎，是导致工作损失和需要关节置换的主要原因。目前还没有已知的医学治疗方法可以改变这种疾病的进展速度。然而，最近的一项观察发现，有炎症的骨关节炎膝盖更有可能失去软骨，这提出了注射皮质类固醇（抑制炎症）可能会降低这些膝盖的软骨损失和关节损伤的可能性。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对患有 OA 和炎症的膝盖进行皮质类固醇注射临床试验来测试这种可能性。这一假设的证实将为膝关节骨关节炎带来一种易于部署且廉价的疾病缓解策略。