膝关节骨性关节炎 中英文合并版.pptx

1、New Tools for Identifying Inflammatory andOsteoarthritis Phenotypes,Virginia 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 Osteoarthritis,From the times

2、 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?

3、 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 Os

4、teoarthritis is an Inflammatory Disease?,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,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 Used,Frequent effusion

5、s 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 u

6、ltrasound, 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 Level,Innate immunity is triggered 先天免疫被激活 High ex

7、pression 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 P

8、resence 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 FolateSca

9、ns 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

10、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,Nuclear medicine radiopharmaceutical for IV injection,Results SPECT-CT 99mTc-EC20 Identifies Activated Macrophages in OA Joints结果 SPECT（单光子发射

11、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

12、 (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(p0.0

13、001) 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):S42,KL=Kellgren Lawrence grade of knee osteoarthritis severity,Synovial 99mTc-EC20 Intensity Associated with

14、 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 Esti

15、mating Equations,Understanding Osteoarthritis Phenotypes,Kraus inspired by Berenbaum 2013,INNATE 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 Disease,MECHANICAL 机械性 Extrinsic Inciting Agents 外在刺激因子 Macroinjury 宏观损伤 Microinjury 微观损伤 E

16、nvironment 环境,Intrinsic Risk Factors 固有的风险因素 Age 年龄 Obesity 肥胖 Gender 性别 Genetic susceptibility 遗传易感性 level of repair & innate immune responses 修复和先天免疫应答水平,INFLAMMATION 炎症 Activated 激活 Macrophages 巨噬细胞 Complement 补体 Alarmins 警报素,Kraus, VB. 2014. Preclinical Osteoarthritis. In: Rheumatology, 6th edit

17、ion, Ed. MC Hochberg, AJ Silman, JS Smolen, ME Weinblatt, MH Weisman (Mosby Elsevier, Philadelphia) Chapter 179 (in press).,将OA作为机械性及炎症性疾病的新模型,Acknowledgments 致谢,Co-investigators 共同研究者: Gary McDaniel, Janet L Huebner, Thomas Stabler, Carl Pieper, R Edward Coleman, Neil A Petry, Philip S Low, Jaiyin Shen,