吳振彪ra治療的時間窗windowofopportunity”forratreatment

1、第四軍醫(yī)大學(xué)西京醫(yī)院臨床免疫科全軍風(fēng)濕免疫研究所,吳振彪,“window of opportunity” for RA treatment,內(nèi) 容,RA為進(jìn)展性炎癥性疾病，關(guān)節(jié)破壞發(fā)生早發(fā)病機(jī)制研究揭示疾病進(jìn)展過程，不同階段免疫機(jī)制不同，對治療反應(yīng)不同臨床研究證實:存在時間窗早期在時間窗內(nèi)治療反應(yīng)更佳,Clinical Course of RA,Severity of Arthritis,Type 1 = Self-limite

2、d--5% to 20%,Type 2 = Minimally progressive--5% to 20%,Type 3 = Progressive--60%,早期RA自發(fā)緩解率低,早期UA 1/3可以自行緩解，早期RA自發(fā)緩解率低Wolfe F 報道約 10% 的早期 RA 自行緩解 US study ：14% of 458 RA followed-up for over 1000 patient years achieved

3、 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, 245–252.Prevoo ML, (1996). Br J Rheumatol, 35, 1101–1105,RA骨侵蝕破壞發(fā)生

4、早,Scott DL 觀察12年：44%早期既有骨侵蝕，4年后骨侵蝕發(fā)生率63%英國早期RA研究：最初 32%有骨侵蝕，3年后70%有骨侵蝕MRI:在癥狀出現(xiàn)4周時既有骨髓水腫等侵蝕病變超聲、MRI可以發(fā)現(xiàn)早期骨侵蝕：早期寡關(guān)節(jié)炎在超聲下50%存在多關(guān)節(jié)炎, subclinical synovitis關(guān)節(jié)鏡滑膜活檢顯示：臨床正常的關(guān)節(jié)存在滑膜炎,Quinn MA,Rheumatology 2001;40:1211–20Broo

5、k A, Corbett M (1977) . Ann Rheum Dis, 36, 71–73.Scott DL, (2003)Clin Exp Rheumatol, 21(5 Suppl 31), S20–S27 Machold KP, et al. (2002). J Rheumatol, 29, 2278–2287Dixey J, (2004) J Rheumatol, 69, 48–54.,RA 骨侵蝕發(fā)生早,Norma

6、l radiograph of metacarpal phalangeal joint (left) and same joint on ultrasonography (middle) and magnetic resonance imaging (right) showing erosions.M=metacarpus; P=phalange. Arrows represent erosions,BMJ 2006;332:152–

7、5,RA導(dǎo)致的殘疾，失業(yè)、壽命縮,50% 關(guān)節(jié)炎為工作年齡 31%-8.3 million 的關(guān)節(jié)炎工作受限23%-45% 關(guān)節(jié)炎在發(fā)病10年后失業(yè),內(nèi)容,RA為進(jìn)展性炎癥性疾病，關(guān)節(jié)破壞發(fā)生早發(fā)病機(jī)制研究揭示疾病進(jìn)展過程：早期特點臨床研究證實:存在時間窗早期在時間窗內(nèi)治療治療反應(yīng)更佳,Preclinical phase,Arthralgia phase,First clinicalphase,Second clinica

8、lphase,Third clinicalphase,window of opportunity,The stages of RA,Schett, G. & Gravallese, E. Nat. Rev. Rheumatol. 8, 656–664 (2012);,Pathogenic mechanisms in very early RA,large numbers of leucocytes are recruited

9、 from peripheral blood into the inflamed tissue.,window of opportunity,早期RA的免疫病理特點與晚期顯著不同,早期：炎癥水平高，炎細(xì)胞浸潤，滑膜腫，滲出 Injury to synovial microvasculature Swelling of endothelial cells Early cellular infiltration o

10、f lymphocytes and macrophages Congestion，Edema，F(xiàn)ibrin exudation Mild hyperplasia of the superficial lining of synoviocytes,Book:review of rheumatology,2012,,早期RA的免疫病理特點與晚期顯著不同,晚期：生發(fā)中心，滑膜增厚，血管翳 T

11、 and B cells form aggregates Enriched 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

12、cellsSublining characteristics：Hyperplasia， Lymphocytic infiltration，Neoangiogenesis,Book:review of rheumatology,2012,,T- and B-cell clones in early versus established RA,早期治療方能阻止骨破壞,Early RA represents chronic sy

13、novial inflammation,The timeline of RA: Opportunities for intervention,診斷水平的提高使我們能夠確定患者處于RA的那個階段,The timeline of RA: Opportunities for intervention,Therapeutic window of opportunity,3-6 month,診斷水平的提高使我們能夠確定患者處于RA的那個階段,P

14、reventive window of opportunity,診斷水平的提高使我們能夠確定患者處于RA的那個階段,The timeline of RA: Opportunities for intervention,window of opportunity,A period of time when the underlying inflammatory process is more susceptible to drug inf

15、luences than at later time-points,. Tsakonas E,et al.J Rheumatol 2000;27:623–9. Quinn MA, Rheumatology 2001;40:1211–20.Mullan RH, Clin Exp Rheumatol 2003;21:S158–S164.,內(nèi)容,RA為進(jìn)展性炎癥性疾病，關(guān)節(jié)破壞發(fā)生早發(fā)病機(jī)制研究揭示疾病進(jìn)展過程臨床研究證實:存在時

16、間窗早期在時間窗內(nèi)治療反應(yīng)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 2006;55:864-72.,短于 12 周的極早期RA 可能是免疫病理的特殊階

17、段12周前及12周后治療有不同的反應(yīng)：有效抑制骨侵蝕，possibly complete switching off of disease12個研究的Meta分析,比較早期治療及延遲治療對放射學(xué)進(jìn)展的影響,觀察3年早期治療較晚期治療放射學(xué)進(jìn)展可以減少 33%,“window of opportunity” may exist within the first 12 weeks of disease,早期RA的基本特征：炎癥水平處

18、于高峰，骨侵蝕發(fā)生率，炎癥關(guān)節(jié)數(shù)，骨丟失都在最高點早期治療可以獲得更大好處 炎癥對治療的反應(yīng)與病程相關(guān)盡早治療，機(jī)會。。。,關(guān)節(jié)破壞=疾病活動度（炎癥） × 時間癥狀出現(xiàn)頭3-4個月distinct therapeutic window免疫病理反應(yīng)有獨(dú)特特點 MRI:發(fā)現(xiàn)滑膜炎發(fā)生在骨髓水腫及骨侵蝕之前關(guān)節(jié)腔內(nèi)注射激素可以抑制骨髓水腫3個月內(nèi)不出現(xiàn)新的骨侵蝕早期控制滑膜炎—預(yù)后改善,Karim Raza，Rh

19、eumatology 2010;49:406–410,The first 3 months after symptom onset representing a therapeutic window,從出現(xiàn)癥狀到就診的延遲時間 0–3 4–6 6–12 >12 (月)病人數(shù) 34 34 24 91骨侵蝕病人 (%) 35 36 33

20、73,依據(jù)出現(xiàn)癥狀到初次就診時間的不同，出現(xiàn)骨侵蝕改變的病人百分?jǐn)?shù),,,,Irvine S, et al. Ann Rheum Dis. 1999(58)510-3,延遲超過1年后，出現(xiàn)骨侵蝕病人的百分?jǐn)?shù)增加1倍,早期DMARDs治療療效更好,,Lard LR et al. Am J Med 2001;111:446–51,延遲DMARD治療導(dǎo)致更多的影像學(xué)進(jìn)展,延遲DMARD治療(中位治療延遲時間 = 123天; n = 10

21、9)早期DMARD治療 (中位治療延遲時間 = 15天; n = 97),,,月,,,,,,,,,,,,,,,,,,,,,,,,,0,2,4,6,8,10,12,14,0,6,12,18,24,,,Sharp評分改變的中位值,,,,Patients should be referred early, ideally within six weeks of the onset of symptoms, and that DMARDs

22、should be started within 12 weeks of onset,Annals of the Rheumatic Diseases 2007;66:34-45,早期診斷、早期治療，6周內(nèi)開始治療,英國：6.5%在癥狀出現(xiàn)3個月開始DMARD治療荷蘭：31.1%在癥狀出現(xiàn)3個月開始DMARD治療加拿大一項最新研究： 41%在癥狀出現(xiàn)6個月開始DMARD治療，平均開始治療時間為8.4個月,Real Practice:

23、早期治療率不高,Rheumatology 2002;41:953-5Arthritis Rheum 2010;62:3537-46.Ann Rheum Dis 2011;70:1822–1825.The Journal of Rheumatology 2012; 39:11,Time to Treatment for New Patients with Rheumatoid Arthritis in a Major Metropo

24、litan City,J Rheumatol 2011;38;1282-1288,23%在癥狀出現(xiàn)3個月開始DMARD治療48%6個月開始DMARD治療,No delays at all levels — from patient at symptom onset to primary care assessment —referral to rheumatology assessment

25、 — and initiation of therapyStrategies from rheumatology referral to rheumatology assessmentEarly Arthritis Clinics,對于可疑的炎性關(guān)節(jié)病患者:尤其是1個以上關(guān)節(jié)持續(xù)腫脹早期晨僵 ≥30 minutes或者累及近端指間關(guān)節(jié)、掌指關(guān)節(jié)應(yīng)該立即風(fēng)濕科醫(yī)生就診，最好在癥狀出現(xiàn)6周內(nèi)盡早開始

26、治療-- window of opportunity,How should we change our practice,BMJ 2008;336:215-6,內(nèi)容,RA為進(jìn)展性炎癥性疾病，關(guān)節(jié)破壞發(fā)生早發(fā)病機(jī)制研究揭示疾病進(jìn)展過程臨床研究證實:存在時間窗早期在時間窗內(nèi)治療反應(yīng)更佳—抓住時間窗,早期RA的定義window of opportunity,極早期RA（Very early RA，VERA）：病程<12周,Bos

27、ello S,et al. Ann Rheum Dis 2011;70:1292–1295,Ann Rheum Dis 2012;71:1921–1923,PROMPT trial,Van Dongen H et al. Efficacy of methotrexate treatment in patients with probable rheumatoid arthritis: a double-blind, randomize

28、d,placebo-controlled trial. Arthritis Rheum 2007;56:1424-32.,觀察MTX與安慰劑治療未分化關(guān)節(jié)炎平均病史9個月MTX治療可延緩RA的發(fā)生，抑制關(guān)節(jié)破壞,MTX,Benefit of very early referral and very early therapywith disease-modifying anti-rheumatic drugs inpatient

29、s with early rheumatoid arthritis,Rheumatology 2004;43:906–914,20例極早期：3個月20例晚早期：平均12個月觀察3年DMARD治療3個月兩組DAS28緩解既有差別,Very early therapy in rheumatoid arthritis,The Larsen scores showed a statistically significant retard

30、ation of progression in the VERA compared with the LERA.,Rheumatology 2004;43:906–914,,Arthritis & Rheumatism (Arthritis Care & Research)Vol. 55, No. 6, December 15, 2006, pp 864–872,早期治療可以抑制關(guān)節(jié)損傷，平均延遲DMARDs治療9個

31、月，放射學(xué)進(jìn)展即顯著增加 早期 RA：放射學(xué)進(jìn)展平均為 4.3 Sharp score units/year,The long-term impact of early treatment ofrheumatoid arthritis on radiographic progression:a population-based cohort study,Rheumatology 2011;50:1106-1110,Ann Rhe

32、um Dis 2012;71:989–992,ETN+MTX :VERA 獲得更高的LDA,及DAS28緩解率,,,,,Biological targets therapy—作用于不同環(huán)節(jié)，階段？,,Schett, G. & Gravallese, E. Nat. Rev. Rheumatol. 8, 656–664 (2012),window of opportunity,新的挑戰(zhàn)--個體化治療,新的挑戰(zhàn)--個體化預(yù)防,win