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）认为骨关节炎是一种严重的疾病， 对减缓、停止或逆转关节损伤的治疗的未满足需求。测试新疗法的挑战是 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会反映出多少有意义的好处， 病情恶化的病人。磁共振（MR）成像有很大的潜力来解决这些关键的差距。 然而，没有人开发出一个基于MR的复合结果，反映了多个结构方面 （“全膝”）的膝关节骨性关节炎进展的影响，并对变化敏感。这仍然是一个关键的 测试和开发新疗法的技术障碍。我们最近解决了这些障碍， 膝关节骨关节炎进展的结构性指标可总结为：1）累积损伤 （整个膝关节的定量关节软骨损伤;与放射学进展相关），和2）疾病 活动（定量骨髓病变和渗出液-滑膜炎体积;与疼痛进展相关）。的 关键的下一步是证明这些结果是有效和有用的KOA预测生物标志物 通过确定1）每项测量中有多少变化转化为临床指标， 有意义的改善或恶化和2）每个复合测量的区分性能。我们 将通过评估3个巢式病例对照样本的年度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 结果（目标2）和步行速度（目标3），以及膝关节置换术（目标4）的生物学因素（例如， 性别）。为了实现我们的目标，我们将量化关节软骨和骨髓的1年或2年变化 病变和积液-滑膜炎体积的MR图像上的5，270膝关节访视。然后我们将确定 与这些结果相关的累积损伤或疾病活动的变化 期我们还将测试这些指标的变化对接受膝关节置换的成年人有多大的区别 更换.最后，我们将测试累积损伤和疾病活动是否能可靠地预测变化 在以患者为中心的结局中，性别、体重指数、影像学严重程度和观察持续时间 期本研究将支持将这些结构性终点批准为预测性终点的申请 KOA进展的生物标志物，这可以大大提高临床试验测试成功的机会 膝关节骨关节炎的疾病改善疗法。

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.