Interpretation and Utility of Novel Composite Structural Endpoints of Cumulative Damage and Disease Activity in Knee Osteoarthritis

美国食品和药物管理局（FDA）将骨关节炎视为一种严重疾病， 对减缓、停止或逆转关节损伤的治疗的需求尚未得到满足。测试新疗法的一个挑战是 缺乏包含多种结构变化的疾病进展的全面定义。 另一个挑战是不知道结构性措施的变化有多少会反映有意义的利益或 使患者病情恶化。磁共振 (MR) 成像具有解决这些关键差距的巨大潜力。 然而，没有人开发出一种基于 MR 的综合结果来反映多个结构方面 （“全膝”）膝骨关节炎进展并且对变化敏感。这仍然是一个关键 测试和开发新疗法的技术障碍。我们最近解决了这些障碍并发现 膝骨关节炎进展的结构性指标可概括为：1）累积损伤 （整个膝盖的定量关节软骨损伤；与放射学进展有关），以及 2）疾病 活动（定量骨髓病变和积液滑膜炎体积；与疼痛进展有关）。的 接下来的关键步骤是证明这些结果是有效且有用的 KOA 预测生物标志物 通过确定 1) 每个测量值的变化有多少转化为临床指标来进行进展 有意义的改善或恶化以及 2) 每个综合措施的区分性能。我们 将通过评估 3 个嵌套病例对照样本中的年度 MR 图像来确定 累积损伤和疾病活动的变化幅度可预测患者报告的变化 跨生物因素（例如， 性）。为了实现我们的目标，我们将量化关节软骨和骨髓的 1 或 2 年变化 5,270 次膝关节就诊的 MR 图像上的病变和积液滑膜炎体积。然后我们将确定金额 同一时间内与这些结果相关的累积损害或疾病活动的变化 期间。我们还将测试这些措施的变化对接受膝盖手术的成年人有何不同 更换。最后，我们将测试累积损伤和疾病活动是否能够可靠地预测变化 以患者为中心的结果，涉及性别、体重指数、放射线严重程度和观察持续时间 期间。这项研究将支持批准这些结构终点作为预测性终点的申请 KOA 进展的生物标志物，可以大大提高临床试验测试的成功机会 膝骨关节炎的疾病修饰疗法。

The United States Food and Drug Administration (FDA) recognizes osteoarthritis as a serious disease with an unmet need for therapies that slow, stop, or reverse joint damage. A challenge to testing new therapies is the lack of a comprehensive definition of disease progression that incorporates multiple structural changes. Another challenge is not knowing how much change in a structural measure would reflect meaningful benefit or worsening to a patient. Magnetic resonance (MR) imaging has great potential to address these critical gaps. However, no-one has developed an MR-based composite outcome that reflects multiple structural aspects (“whole-knee”) of knee osteoarthritis progression and is sensitive to change. This remains a critical technological obstacle to testing and developing new therapies. We recently tackled these barriers and found that structural measures of knee osteoarthritis progression can be summarized as: 1) cumulative damage (quantitative articular cartilage damage throughout a knee; relates to radiographic progression), and 2) disease activity (quantitative bone marrow lesions and effusion-synovitis volumes; relates to pain progression). The critical next steps are to demonstrate these outcomes are valid and useful predictive biomarkers of KOA progression by determining 1) how much change in each measure translates to indicators of clinically meaningful improvement or worsening and 2) the discriminative performance of each composite measure. We will accomplish this by assessing annual MR images in 3 nested case-control samples to determine the magnitude of change in cumulative damage and disease activity that predict changes in patient-reported outcomes (Aim 2) and walking speed (Aim 3), and knee replacement (Aim 4) across biological factors (e.g., sex). To achieve our goal, we will quantify 1- or 2-year change in articular cartilage as well as bone marrow lesions and effusion-synovitis volume on MR images for 5,270 knee visits. We will then determine the amount of change in cumulative damage or disease activity that relates to these outcomes during the same time period. We will also test how much change in these measures differentiates adults who will receive a knee replacement. Finally, we will test whether cumulative damage and disease activity will reliably predict changes in patient-centered outcomes across sex, body mass index, radiographic severity, and duration of observation period. This study will support an application for approval of these structural endpoints as predictive biomarkers for KOA progression, which could greatly improve the chance of success for clinical trials testing disease-modifying therapies for knee osteoarthritis.