1、第四军医大学西京医院临床免疫科全军风湿免疫研究所,吴振彪,“window of opportunity” for RA treatment,内 容,RA为进展性炎症性疾病，关节破坏发生早发病机制研究揭示疾病进展过程，不同阶段免疫机制不同，对治疗反应不同临床研究证实:存在时间窗早期在时间窗内治疗反应更佳,Clinical Course of RA,Severity of Arthritis,Type 1 = Self-limited-5% to 20%,Type 2 = Minimally progressive-5% to 20%,Type 3 = Progressive-60%,早期RA自发
2、缓解率低,早期UA 1/3可以自行缓解，早期RA自发缓解率低Wolfe F 报道约 10% 的早期 RA 自行缓解 US study ：14% of 458 RA followed-up for over 1000 patient years achieved remission without being treatedPrevoo ML ：10% of 227 RA patients followed-up for 4 years achieved remission,Wolfe F, Hawley DJ (1985) J Rheumatol, 12, 245252.Prevoo ML,
3、(1996). Br J Rheumatol, 35, 11011105,RA骨侵蚀破坏发生早,Scott DL 观察12年：44%早期既有骨侵蚀，4年后骨侵蚀发生率63%英国早期RA研究：最初 32%有骨侵蚀，3年后70%有骨侵蚀MRI:在症状出现4周时既有骨髓水肿等侵蚀病变超声、MRI可以发现早期骨侵蚀：早期寡关节炎在超声下50%存在多关节炎, subclinical synovitis关节镜滑膜活检显示：临床正常的关节存在滑膜炎,Quinn MA,Rheumatology 2001;40:121120Brook A, Corbett M (1977) . Ann Rheum Dis, 3
4、6, 7173.Scott DL, (2003)Clin Exp Rheumatol, 21(5 Suppl 31), S20S27 Machold KP, et al. (2002). J Rheumatol, 29, 22782287Dixey J, (2004) J Rheumatol, 69, 4854.,RA 骨侵蚀发生早,Normal radiograph of metacarpal phalangeal joint (left) and same joint on ultrasonography (middle) and magnetic resonance imaging (r
5、ight) showing erosions.M=metacarpus; P=phalange. Arrows represent erosions,BMJ 2006;332:1525,RA导致的残疾，失业、寿命缩,50% 关节炎为工作年龄 31%-8.3 million 的关节炎工作受限23%-45% 关节炎在发病10年后失业,内容,RA为进展性炎症性疾病，关节破坏发生早发病机制研究揭示疾病进展过程：早期特点临床研究证实:存在时间窗早期在时间窗内治疗治疗反应更佳,Preclinical phase,Arthralgia phase,First clinicalphase,Second cli
6、nicalphase,Third clinicalphase,window of opportunity,The stages of RA,Schett, G. ,Pathogenic mechanisms in very early RA,large numbers of leucocytes are recruited from peripheral blood into the inflamed tissue.,window of opportunity,早期RA的免疫病理特点与晚期显著不同,早期：炎症水平高，炎细胞浸润，滑膜肿，渗出 Injury to synovial microva
7、sculature Swelling of endothelial cells Early cellular infiltration of lymphocytes and macrophages Congestion，Edema，Fibrin exudation Mild hyperplasia of the superficial lining of synoviocytes,Book:review of rheumatology,2012,早期RA的免疫病理特点与晚期显著不同,晚期：生发中心，滑膜增厚，血管翳 T and B cells form aggregates Enriched
8、with CD4+ T cells Secondary lymphoid follicles Germinal center reactions with proliferating B Diffuse zones consist of CD8+ T cells Synovial pannus：Plasma cells，Mast cellsSublining characteristics：Hyperplasia， Lymphocytic infiltration，Neoangiogenesis,Book:review of rheumatology,2012,T- and B-cell cl
9、ones in early versus established RA,早期治疗方能阻止骨破坏,Early RA represents chronic synovial inflammation,The timeline of RA: Opportunities for intervention,诊断水平的提高使我们能够确定患者处于RA的那个阶段,The timeline of RA: Opportunities for intervention,Therapeutic window of opportunity,3-6 month,诊断水平的提高使我们能够确定患者处于RA的那个阶段,Prev
10、entive window of opportunity,诊断水平的提高使我们能够确定患者处于RA的那个阶段,The timeline of RA: Opportunities for intervention,window of opportunity,A period of time when the underlying inflammatory process is more susceptible to drug influences than at later time-points,. Tsakonas E,et al.J Rheumatol 2000;27:6239. Quin
11、n MA, Rheumatology 2001;40:121120.Mullan RH, Clin Exp Rheumatol 2003;21:S158S164.,内容,RA为进展性炎症性疾病，关节破坏发生早发病机制研究揭示疾病进展过程临床研究证实:存在时间窗早期在时间窗内治疗反应更佳,Singh JA, J Rheumatol 2004;31:1281-5 Raza K, et al. Arthritis Res Ther 2005;7:R784-95Nell VP, Rheumatology (Oxford) 2004;43:906-14 Finckh A, Arthritis Rheum
12、 2006;55:864-72.,短于 12 周的极早期RA 可能是免疫病理的特殊阶段12周前及12周后治疗有不同的反应：有效抑制骨侵蚀，possibly complete switching off of disease12个研究的Meta分析,比较早期治疗及延迟治疗对放射学进展的影响,观察3年早期治疗较晚期治疗放射学进展可以减少 33%,“window of opportunity” may exist within the first 12 weeks of disease,早期RA的基本特征：炎症水平处于高峰，骨侵蚀发生率，炎症关节数，骨丢失都在最高点早期治疗可以获得更大好处 炎症对治
13、疗的反应与病程相关尽早治疗，机会。,关节破坏=疾病活动度（炎症） 时间症状出现头3-4个月distinct therapeutic window免疫病理反应有独特特点 MRI:发现滑膜炎发生在骨髓水肿及骨侵蚀之前关节腔内注射激素可以抑制骨髓水肿3个月内不出现新的骨侵蚀早期控制滑膜炎预后改善,Karim Raza，Rheumatology 2010;49:406410,The first 3 months after symptom onset representing a therapeutic window,从出现症状到就诊的延迟时间 03 46 612 12 (月)病人数 34 34 24
14、 91骨侵蚀病人 (%) 35 36 33 73,依据出现症状到初次就诊时间的不同，出现骨侵蚀改变的病人百分数,Irvine S, et al. Ann Rheum Dis. 1999(58)510-3,延迟超过1年后，出现骨侵蚀病人的百分数增加1倍,早期DMARDs治疗疗效更好,Lard LR et al. Am J Med 2001;111:44651,延迟DMARD治疗导致更多的影像学进展,延迟DMARD治疗(中位治疗延迟时间 = 123天; n = 109)早期DMARD治疗 (中位治疗延迟时间 = 15天; n = 97),月,0,2,4,6,8,10,12,14,0,6,12,18
15、,24,Sharp评分改变的中位值,Patients should be referred early, ideally within six weeks of the onset of symptoms, and that DMARDs should be started within 12 weeks of onset,Annals of the Rheumatic Diseases 2007;66:34-45,早期诊断、早期治疗，6周内开始治疗,英国：6.5%在症状出现3个月开始DMARD治疗荷兰：31.1%在症状出现3个月开始DMARD治疗加拿大一项最新研究： 41%在症状出现6个月开
16、始DMARD治疗，平均开始治疗时间为8.4个月,Real Practice:早期治疗率不高,Rheumatology 2002;41:953-5Arthritis Rheum 2010;62:3537-46.Ann Rheum Dis 2011;70:18221825.The Journal of Rheumatology 2012; 39:11,Time to Treatment for New Patients with Rheumatoid Arthritis in a Major Metropolitan City,J Rheumatol 2011;38;1282-1288,23%在症
17、状出现3个月开始DMARD治疗48%6个月开始DMARD治疗,No delays at all levels from patient at symptom onset to primary care assessment referral to rheumatology assessment and initiation of therapyStrategies from rheumatology referral to rheumatology assessmentEarly Arthritis Clinics,对于可疑的炎性关节病患者:尤其是1个以上关节持续肿胀早期晨僵 30 minut
18、es或者累及近端指间关节、掌指关节应该立即风湿科医生就诊，最好在症状出现6周内尽早开始治疗- window of opportunity,How should we change our practice,BMJ 2008;336:215-6,内容,RA为进展性炎症性疾病，关节破坏发生早发病机制研究揭示疾病进展过程临床研究证实:存在时间窗早期在时间窗内治疗反应更佳抓住时间窗,早期RA的定义window of opportunity,极早期RA（Very early RA，VERA）：病程12周,Bosello S,et al. Ann Rheum Dis 2011;70:12921295,An
19、n Rheum Dis 2012;71:19211923,PROMPT trial,Van Dongen H et al. Efficacy of methotrexate treatment in patients with probable rheumatoid arthritis: a double-blind, randomized,placebo-controlled trial. Arthritis Rheum 2007;56:1424-32.,观察MTX与安慰剂治疗未分化关节炎平均病史9个月MTX治疗可延缓RA的发生，抑制关节破坏,MTX,Benefit of very earl
20、y referral and very early therapywith disease-modifying anti-rheumatic drugs inpatients with early rheumatoid arthritis,Rheumatology 2004;43:906914,20例极早期：3个月20例晚早期：平均12个月观察3年DMARD治疗3个月两组DAS28缓解既有差别,Very early therapy in rheumatoid arthritis,The Larsen scores showed a statistically significant retar
21、dation of progression in the VERA compared with the LERA.,Rheumatology 2004;43:906914,Arthritis & Rheumatism (Arthritis Care & Research)Vol. 55, No. 6, December 15, 2006, pp 864872,早期治疗可以抑制关节损伤，平均延迟DMARDs治疗9个月，放射学进展即显著增加 早期 RA：放射学进展平均为 4.3 Sharp score units/year,The long-term impact of early treatme
22、nt ofrheumatoid arthritis on radiographic progression:a population-based cohort study,Rheumatology 2011;50:1106-1110,Ann Rheum Dis 2012;71:989992,ETN+MTX :VERA 获得更高的LDA,及DAS28缓解率,Biological targets therapy作用于不同环节，阶段？,Schett, G. & Gravallese, E. Nat. Rev. Rheumatol. 8, 656664 (2012),window of opportunity,新的挑战-个体化治疗,新的挑战-个体化预防,window of opportunity,基础研究及临床研究：window of opportunity核心：在这个时间窗内治疗可以获得长期的更好的获益12周最佳时间窗，DMARD及生物制剂治疗效果更好，个体化治疗及预防，更强调时间窗Prevention of RA,新的预言,谢 谢,
