New Tools for Identifying Inflammatory and Osteoarthritis PhenotypesVirginia Byers Kraus, MD, PhD Professor of Medicine 医学教授 Duke University School of Medicine 杜克大学医学院 Duke Institute for Molecular Physiology 杜克分子生理研究所 Durham, NC September 2013识别炎症与骨关节炎表型的新工具History of OsteoarthritisFrom the times of Hippocrates all forms of chronic arthritis were regarded as manifestations of gout. (Dequeker and Luyten, 2008; Ann Rheum Dis, 67: 5-10).Sir Archibald Garrod coined the term osteoarthritis (OA) in 1890. Debate has raged ever sinceis OA a mechanical (non- inflammatory) or an inflammatory disease? 1890年，Archibald Garrod 爵士提出了”骨关节 (Osteoarthritis)”(OA)这个名词.争论一直持续至今OA究竟是 一种机械性(非炎症) 或是一种炎症性疾病？骨关节炎的历史从希波克拉底时期，所有形式的慢性关节炎都被认为 是痛风的表现History of Osteoarthritis骨关节炎的历史Osteoarthritis is BOTH a mechanical and an inflammatory disease.骨关节炎既是一种机械性疾病也是一种 炎症性疾病Why Has it Taken So Long to Recognize that Osteoarthritis is an Inflammatory Disease?COLLAGEN IICOLLAGEN IIAGGRECANAGGRECANAvascular, Aneural, Alymphatic 无血管, 无神经, 无淋巴NORMAL CARTILAGE 正常软骨The non-vascularized damaged cartilage cannot respond by a usual inflammatory response.无血管损伤后的软骨不能应答正常的炎症反应Collagen fibril degradation Aggrecan swelling then loss 胶原纤维退化, 聚集蛋白聚糖肿胀 后消失OSTEOARTHRITIC CARTILAGE 关节炎软骨为什么人们花了这么久才认识到骨关节炎是一种炎症性疾病？Signs of Inflammation in Osteoarthritis are Frequent When Sensitive Tools are UsedFrequent effusions 频繁关节积液Song 2008: 78% by ultrasound and 81% by MRI in 超声检测78%和MRI检测81% Tarhan 2003: 70% by ultrasound, 80% by MRI 超声检测70%和MRI检测80%Frequent synovial thickening 频繁滑膜增厚Tarhan 2003: 34% by ultrasound, 50% by MRI 超声检测34%和MRI检测50%Frequent popliteal (Bakers) cysts 频繁腘窝囊肿（Baker囊肿） Tarhan 2003: 40% by ultrasound, 35% by MRI 超声检测40%和MRI检测35%References 参考文献: Song et al. Ann Rheum Dis 2008;67(1):19-25 Tarhan et al. Clin Rheumatol 2003;22(3):181-8 当使用一些敏感的检测手段时, 骨关节炎的炎症指标就会频繁出现Signs of Inflammation in Osteoarthritis are also Frequent at a Molecular LevelInnate immunity is triggered 先天免疫被激活High expression and activation of Complement 补体激活及高表达Activation by Crystals: Calcium pyrophosphate dihydrate, basic calcium phosphate and uric acid crystals 被晶体激活：二水焦磷酸钙化合物, 碱性磷酸钙和尿酸结晶Levels of several Inflammatory Mediators are higher in OA than healthy sera and synovial fluid OA患者血清及滑夜中一些炎症介质的水平高于正常人Presence of Macrophages in synovium 滑膜中存在巨噬细胞References 参考文献: Berenbaum F. Osteoarthritis Cartilage 2013;21(1):16-21 Denoble, Kraus et al. Proc Natl Acad Sci U S A 2011;108(5):2088- 93 在分子水平上，骨关节炎的炎症指标同样也会频繁出现Signs of Inflammation in Osteoarthritis can be Demonstrated in vivo by 99mTc-EC20 FolateScans在分子水平上，骨关节炎的炎症指标同样也会频繁出现 The Folate Receptor is expressed on activated but not resting macrophages (Low PS, et al. Acc Chem Res 2008;41(1):120-9). 活化非静息的巨噬细胞能 够表达叶酸受体A new imaging agent-99mTc-EC20 (Etarfolatide), can identify activated macrophages in vivo. 一个新型成像试剂-99mTc-EC20 (Etarfolatide),能够识别 体内活化的巨噬细胞99mTc-EC20 (Etarfolatide) consists of the vitamin folate conjugated to 99mTc via a chelating moiety. 一个新型成像试剂-99mTc-EC20 (Etarfolatide),能够识别 体内活化的巨噬细胞TcO99mNuclear medicine radiopharmaceutical for IV injectionResults SPECT-CT 99mTc-EC20 Identifies Activated Macrophages in OA Joints 结果 SPECT（单单光子发发射CT）-CT 99mTc-EC20 识别OA关节内活化的巨噬细胞Subchondral Bone 软骨下骨Synovial and Joint Space滑膜与关节腔Study Design and Results研究设计及结果25 subjects (50 knees) 25 例受试者(50 例膝关节) at least one knee with radiographic osteoarthritis with symptom 至少一侧膝 关节有影像学OA并有症状表现 KL1 (24%), KL2 (26%), KL3 (32%), KL4 (18%) KL1 (24%), KL2 (26%), KL3 (32%), KL4 (18%) 72% female, mean age 62 years, mean BMI 29 kg/m272% 女性, 平均年龄62 岁, 平均BMI 29 kg/m2 76% of knees were positive for 99mTc-EC20 uptake 76% 膝关节摄取99mTc-EC20 为为阳性99mTc-EC20 (especially in the synovium) was associated with knee symptoms (p0.0001) 99mTc-EC20 (特别是在滑膜中) 与膝关节症状相关(p0.0001)99mTc-EC20 was associated with radiographic severity of osteoarthritis (p=0.01 to 0.001) 99mTc-EC20 与OA放射学严重程度相关(p=0.01 to 0.001)Kraus et al. Osteo Cartilage 2013;21 (Supplement, April):S42KL=Kellgren Lawrence grade of knee osteoarthritis severitySynovial 99mTc-EC20 Intensity Associated with Knee Symptoms 滑膜99mTc-EC20 强度与膝关节的症状相关KNEES 1-50 (ordered by synovial 99mTc-EC20 uptake)Z SCORE Z 评分膝关节1-50 (按滑膜99mTc-EC20 摄取量排序)Results - 99mTc-EC20 Uptake in Other Joints was also Associated with Symptoms 结果- 99mTc-EC20 的摄取量与其他关节的症状也相关Adjusted for inter-joint correlation with Generalized Estimating EquationsUnderstanding Osteoarthritis PhenotypesOAPreclinical临临床前Preradiographi c影像学前Radiographic影像学Phenotypes 表型Post- trauma tic 创伤创伤 后Age- related年龄龄相 关Metabolic Syndrome related代谢综谢综 合症相关Crystal induced晶体诱发诱发Kraus inspired by Berenbaum 2013INNATE IMMUNITY & MACROPHAGES 先天免疫巨噬细胞对骨关节炎表型的理解New Model of Osteoarthritis as Both a Mechanical and an Inflammatory DiseaseActivated Innate Immunity and Impaired Wound Healing激活先天免疫及损损 伤伤愈合修复Potentiators 增强剂剂Insults 损损害OA 骨关节节炎Preclinical临临床前Preradiographic影像学前Radiographi