膝關(guān)節(jié)骨性關(guān)節(jié)炎 中英文合并版.pptx

1、New Tools for Identifying Inflammatory andOsteoarthritis Phenotypes,Virginia Byers Kraus, MD, PhD Professor of Medicine 醫(yī)學(xué)教授 Duke University School of Medicine 杜克大學(xué)醫(yī)學(xué)院 Duke Institute for Molecular Physiology 杜克分子生理研究所 Durham, NC September 2013,識別炎癥與骨關(guān)節(jié)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”骨關(guān)節(jié) (Osteoarthritis)”(OA)這個名詞.爭論一直持續(xù)至今OA究竟是一種機械性(非炎癥) 或是一種炎癥性疾??？,骨關(guān)節(jié)炎的歷史,從希波克拉底時期，所有形式的慢性關(guān)節(jié)炎都被認為是痛風(fēng)的表現(xiàn),History of Osteoarthritis 骨關(guān)節(jié)炎的歷史,Osteoarthritis is BOTH a mechanical and an inflammatory disease.,骨關(guān)節(jié)炎既是一種機械性疾病也是一種炎癥性疾病,Why Has it Taken So Long to Recognize that Os

4、teoarthritis is an Inflammatory Disease?,NORMAL CARTILAGE 正常軟骨,The non-vascularized damaged cartilage cannot respond by a usual inflammatory response. 無血管損傷后的軟骨不能應(yīng)答正常的炎癥反應(yīng),為什么人們花了這么久才認識到骨關(guān)節(jié)炎是一種炎癥性疾??？,Signs of Inflammation in Osteoarthritis are Frequent When Sensitive Tools are Used,Frequent effusion

5、s 頻繁關(guān)節(jié)積液 Song 2008: 78% by ultrasound and 81% by MRI in 超聲檢測78%和MRI檢測81% Tarhan 2003: 70% by ultrasound, 80% by MRI 超聲檢測70%和MRI檢測80% Frequent synovial thickening 頻繁滑膜增厚 Tarhan 2003: 34% by ultrasound, 50% by MRI 超聲檢測34%和MRI檢測50% Frequent popliteal (Bakers) cysts 頻繁腘窩囊腫（Baker囊腫） Tarhan 2003: 40% by u

6、ltrasound, 35% by MRI 超聲檢測40% 和MRI檢測35%,References 參考文獻: Song et al. Ann Rheum Dis 2008;67(1):19-25 Tarhan et al. Clin Rheumatol 2003;22(3):181-8,當使用一些敏感的檢測手段時, 骨關(guān)節(jié)炎的炎癥指標就會頻繁出現(xiàn),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 補體激活及高表達 Activation by Crystals: Calcium pyrophosphate dihydrate, basic calcium phosphate and uric acid crystals 被晶體激活：二水焦磷酸鈣化合物, 堿性磷酸鈣和尿酸結(jié)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癥介質(zhì)的水平高于正常人 P

8、resence of Macrophages in synovium 滑膜中存在巨噬細胞,References 參考文獻: 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，骨關(guān)節(jié)炎的炎癥指標同樣也會頻繁出現(xiàn),Signs of Inflammation in Osteoarthritis can be Demonstrated in vivo by 99mTc-EC20 FolateSca

9、ns 在分子水平上，骨關(guān)節(jié)炎的炎癥指標同樣也會頻繁出現(xiàn),The Folate Receptor is expressed on activated but not resting macrophages (Low PS, et al. Acc Chem Res 2008;41(1):120-9). 活化非靜息的巨噬細胞能夠表達葉酸受體 A new imaging agent-99mTc-EC20 (Etarfolatide), can identify activated macrophages in vivo. 一個新型成像試劑-99mTc-EC20 (Etarfolatide),能夠識別體

10、內(nèi)活化的巨噬細胞 99mTc-EC20 (Etarfolatide) consists of the vitamin folate conjugated to 99mTc via a chelating moiety. 一個新型成像試劑-99mTc-EC20 (Etarfolatide),能夠識別體內(nèi)活化的巨噬細胞,Nuclear medicine radiopharmaceutical for IV injection,Results SPECT-CT 99mTc-EC20 Identifies Activated Macrophages in OA Joints結(jié)果 SPECT（單光子發(fā)射

11、CT）-CT 99mTc-EC20 識別OA關(guān)節(jié)內(nèi)活化的巨噬細胞,Subchondral Bone 軟骨下骨,Synovial and Joint Space,滑膜與關(guān)節(jié)腔,Study Design and Results研究設(shè)計及結(jié)果,25 subjects (50 knees) 25 例受試者(50 例膝關(guān)節(jié)) at least one knee with radiographic osteoarthritis with symptom 至少一側(cè)膝關(guān)節(jié)有影像學(xué)OA并有癥狀表現(xiàn) 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, 平均年齡62 歲, 平均BMI 29 kg/m2 76% of knees were positive for 99mTc-EC20 uptake 76% 膝關(guān)節(jié)攝取99mTc-EC20為陽性 99mTc-EC20 (especially in the synovium) was associated with knee symptoms (p0.0001) 99mTc-EC20 (特別是在滑膜中) 與膝關(guān)節(jié)癥狀相關(guān)(p0.0

13、001) 99mTc-EC20 was associated with radiographic severity of osteoarthritis (p=0.01 to 0.001) 99mTc-EC20 與OA放射學(xué)嚴重程度相關(guān)(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 強度與膝關(guān)節(jié)的癥狀相關(guān),KNEES 1-50 (ordered by synovial 99mTc-EC20 uptake),Z SCORE Z 評分,膝關(guān)節(jié)1-50 (按滑膜99mTc-EC20 攝取量排序),Results - 99mTc-EC20 Uptake in Other Joints was also Associated with Symptoms結(jié)果- 99mTc-EC20 的攝取量與其他關(guān)節(jié)的癥狀也相關(guān),Adjusted for inter-joint correlation with Generalized Esti

15、mating Equations,Understanding Osteoarthritis Phenotypes,Kraus inspired by Berenbaum 2013,INNATE IMMUNITY & MACROPHAGES 先天免疫巨噬細胞,對骨關(guān)節(jié)炎表型的理解,New Model of Osteoarthritis as Both a Mechanical and an Inflammatory Disease,MECHANICAL 機械性 Extrinsic Inciting Agents 外在刺激因子 Macroinjury 宏觀損傷 Microinjury 微觀損傷 E

16、nvironment 環(huán)境,Intrinsic Risk Factors 固有的風(fēng)險因素 Age 年齡 Obesity 肥胖 Gender 性別 Genetic susceptibility 遺傳易感性 level of repair & innate immune responses 修復(fù)和先天免疫應(yīng)答水平,INFLAMMATION 炎癥 Activated 激活 Macrophages 巨噬細胞 Complement 補體 Alarmins 警報素,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).,將OA作為機械性及炎癥性疾病的新模型,Acknowledgments 致謝,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,