成人Still病如何診治

1、關(guān)于成人Still病如何診治第一張，PPT共八十頁(yè)，創(chuàng)作于2022年6月Peking Union Medical College Hospital2歷史1896年，Bannatyne在Lancet上報(bào)道首例AOSD病例，但被誤診為“RA”1897年，George Still報(bào)道22例兒童慢性關(guān)節(jié)炎，即后來(lái)的JIA全身型（Systemic onset of JIA），Still病臨床三聯(lián)征長(zhǎng)期間歇性高熱一過(guò)性特征性皮疹關(guān)節(jié)炎/痛法、德風(fēng)濕學(xué)家（1943年Wissler，1946年Fanconi）亦報(bào)道類似病例，被稱為Wissler-Fanconi綜合征1964年，亞急性變應(yīng)性敗血癥1971年，E

2、ric Bywaters報(bào)道14例臨床表現(xiàn)類似的成人患者，標(biāo)志著AOSD正式做為一種疾病被認(rèn)識(shí)第二張，PPT共八十頁(yè)，創(chuàng)作于2022年6月Peking Union Medical College Hospital3現(xiàn)狀Still?。篔RA中的系統(tǒng)型39 Still病特異性一過(guò)性皮疹WBC12.0ESR40ANA及RF（）腕骨硬化次要標(biāo)準(zhǔn)（1分）發(fā)病年齡35歲關(guān)節(jié)炎前驅(qū)癥狀：咽痛網(wǎng)狀內(nèi)皮系統(tǒng)活化表現(xiàn)或肝功異常漿膜炎頸椎或跗骨硬化診斷判斷疑診AOSD：10分觀察12周確診AOSD：10分觀察6個(gè)月診斷困惑？F/21弛張高熱3周伴發(fā)熱的淺紅色斑疹雙腕輕度疼痛咽痛WBC 2.3ESR 115診斷AOS

3、D？治療？第四十一張，PPT共八十頁(yè)，創(chuàng)作于2022年6月Peking Union Medical College Hospital42日本Yamaguchi標(biāo)準(zhǔn)（1992年）主要指標(biāo)1.間歇發(fā)熱39，1wks2.關(guān)節(jié)痛，2wks3.典型皮疹4.WBC10（PMN0.80）次要指標(biāo)1.咽痛2.淋巴結(jié)和/或脾大3.肝功能異常4.RF(-)和ANA(-)排 除1.感染性疾病2.惡性腫瘤3.其他風(fēng)濕病診斷判斷：5項(xiàng)（至少2項(xiàng)主要指標(biāo)）診斷困惑？M/80間歇發(fā)熱3月固定紅色斑丘疹關(guān)節(jié)肌肉疼痛咽痛，肝脾大WBC 3.0，N 90%ESR 115低血壓/低血氧入ICU診斷AOSD？治療？第四十二張，PPT

4、共八十頁(yè)，創(chuàng)作于2022年6月Peking Union Medical College Hospital43法國(guó)Bruno標(biāo)準(zhǔn)（2002年）主要標(biāo)準(zhǔn)弛張熱39關(guān)節(jié)痛一過(guò)性紅斑咽炎PMN80%GF20%次要標(biāo)準(zhǔn)斑丘疹WBC10診斷判斷4項(xiàng)主要，或3項(xiàng)主要2項(xiàng)次要第四十三張，PPT共八十頁(yè)，創(chuàng)作于2022年6月Peking Union Medical College Hospital44三套標(biāo)準(zhǔn)孰優(yōu)孰劣？第四十四張，PPT共八十頁(yè)，創(chuàng)作于2022年6月Peking Union Medical College Hospital45Hamidou, M. A., M. Denis, et al. (2

5、004). Usefulness of glycosylated ferritin in atypical presentations of adult onset Stills disease. Ann Rheum Dis 63(5): 6052 atypical casesGF could be a powerful diagnostic tool for AOSD, particularly in atypical clinical presentations of the disease.第四十五張，PPT共八十頁(yè)，創(chuàng)作于2022年6月Peking Union Medical Coll

6、ege Hospital46AOSD新的治療策略TNF-IL-1IL-6B細(xì)胞第四十六張，PPT共八十頁(yè)，創(chuàng)作于2022年6月Peking Union Medical College Hospital47依那西普Asherson(2002), 首例報(bào)道多種DMARDs血漿置換失敗Etanercept + MTX + GCs臨床表現(xiàn)及實(shí)驗(yàn)室指標(biāo)明顯改善Serratrice J(2003), 病例報(bào)道AOSD + 繼發(fā)性腎臟淀粉樣變引起腎病綜合征AOSD改善蛋白尿緩解第四十七張，PPT共八十頁(yè)，創(chuàng)作于2022年6月Peking Union Medical College Hospital48依那西

7、普Husni ME(2002), open label trial, a cohort of 12 pt基線狀況：prednisone, MTX, and NSAIDsET用法：25 mg 2/周, 第8周如無(wú)改善增至每周3次隨訪6個(gè)月療效：壓關(guān)節(jié)數(shù)改善67%，腫脹關(guān)節(jié)數(shù)63%第四十八張，PPT共八十頁(yè)，創(chuàng)作于2022年6月Peking Union Medical College Hospital49英夫利昔單抗Cavagna L(2001), 3 例慢性關(guān)節(jié)型AOSDPred+MTX無(wú)效infliximab (3 mg/kg wk 0, 2, 6,之后每8 wksESR, CRP, 鐵蛋白，

8、發(fā)熱均改善第2周PtGA，PGA均改善，并維持至第50周GCs減量：from 1530 mg/d to 712 mg/第四十九張，PPT共八十頁(yè)，創(chuàng)作于2022年6月Peking Union Medical College Hospital50InfliximabKokkinos A(2004), a Greek case series, 4 ptsrefractory to high doses GCs+MTXresponded favourably to infliximab 3 mg/kgAll went into remission soon after their first inf

9、usionserum inflammation indices closely followed the clinical improvementSystemic corticosteroids were quickly tapered off and long term remission was sustained第五十張，PPT共八十頁(yè)，創(chuàng)作于2022年6月Peking Union Medical College Hospital51InfliximabMartin Carrasco C(2005), A European series of 8 pts, long term outco

10、me GCs+DMARDs failed, infliximab (35 mg/kg) added7/8 positive response with rapid improvement in both clinical and serological response5/8 went into long term remission, even after discontinuation of treatment第五十一張，PPT共八十頁(yè)，創(chuàng)作于2022年6月Peking Union Medical College Hospital52英夫利昔單抗Fautrel B(2005), 法國(guó)大型觀

11、察性研究20 pts ,平均隨訪13個(gè)月GCMTX無(wú)效患者10例 IFX, 5例 ET, 5例序貫ETIFX CR: 5pt (1 ET, 4 IFX)PR: 16/25 例次(7/10 ET, 9/15 IFX每組均4例失敗（均為JIA，對(duì)anti-TNF效果差）85最終停藥（失效，或不良反應(yīng))第五十二張，PPT共八十頁(yè)，創(chuàng)作于2022年6月Peking Union Medical College Hospital53阿那白滯素Godinho F（2004)，one case report難治性AOSD: MTX, SASP, CsA, IVIG, TNF拮抗劑 均失敗 + 長(zhǎng)期GCs引起嚴(yán)

12、重不良反應(yīng)Anakinra 100 mg/d sc +MTX 25 mg/wk + predl(20 mg/d), and naproxen關(guān)節(jié)炎和全身癥狀數(shù)天周緩解ESR/CRP正常長(zhǎng)期維持MTX+anakinra第五十三張，PPT共八十頁(yè)，創(chuàng)作于2022年6月Peking Union Medical College Hospital54IL-1 blockadeIn the 2004 EULAR meeting, a report by Haraoui et al described the successful treatment of three patients with refra

13、ctory chronicAOSD with daily subcutaneous anakinra 100 mg. Clinicalimprovement was seen within days of starting treatment andeventually allowed the prednisone dose to be taperedsignificantly.105 Also in this meeting, Aelion et al reportedthe successful outcome of daily anakinra 100 mg subcutaneously

14、in two patients with persistent AOSD. Clinicalimprovement was again seen in days in one patient andwithin a few weeks in the other. The first patient wasreported to be in complete remission when receivinganakinra alone, with normalised laboratory values. The otherpatient was weaned off corticosteroi

15、ds and remained stablewith a combined regimen of anakinra and oral MTX (10 mg/week).106 More recently, another study also showed theefficacy of anakinra in the treatment of four patients withAOSD who were refractory to treatment with corticosteroidsand MTX. Interestingly, two of the four patients ha

16、d beenunsuccessfully treated earlier with etanercept, which hadbeen added to the standard regimen of MTX+corticosteroids.In all four cases, the patients responded quickly to anakinra;within days symptoms resolved and laboratory values (WBCcount, ferritin, CRP) normalised.第五十四張，PPT共八十頁(yè)，創(chuàng)作于2022年6月Peki

17、ng Union Medical College Hospital55IL-1 blockadeNaumann, L(2010), case series,8 pts大劑量GCs依賴、多種DMARDs及抗TNF-制劑無(wú)效Anakira 100mg/d，SC隨訪648m臨床癥狀、炎癥指標(biāo)均改善皮疹和關(guān)節(jié)炎在數(shù)h內(nèi)顯著緩解炎性指標(biāo)在14周內(nèi)正常激素減量至小劑量1例停藥次日癥狀復(fù)發(fā)，恢復(fù)用藥后好轉(zhuǎn)第五十五張，PPT共八十頁(yè)，創(chuàng)作于2022年6月Peking Union Medical College Hospital56托珠單抗Iwamoto M（2002)，1 pt reportMTX, CsA,

18、 GCs無(wú)效CRP, 發(fā)熱, 關(guān)節(jié)痛顯著改善De Bandt （2009），1 pt caseSabnis, G. R（2011），1 pt case伴無(wú)菌性腦膜炎第五十六張，PPT共八十頁(yè)，創(chuàng)作于2022年6月Peking Union Medical College Hospital57Rech, J.（2011）3 cases report第五十七張，PPT共八十頁(yè)，創(chuàng)作于2022年6月Peking Union Medical College Hospital58利妥昔單抗Ahmadi-Simab, K（2006)，2 cases reportsMTX、CsA、LEF、CTX、IVIG無(wú)效

19、之后EntanerceptInfliximab，EntanerceptMTX，無(wú)效Rituximab 375mg/m2，qw4多關(guān)節(jié)炎等癥狀緩解，炎癥指標(biāo)下降，激素減至5mg/dMTX/CsA隨訪6m穩(wěn)定第五十八張，PPT共八十頁(yè)，創(chuàng)作于2022年6月Peking Union Medical College Hospital59Therapeutic algorithm for AOSD（2004）第五十九張，PPT共八十頁(yè)，創(chuàng)作于2022年6月Peking Union Medical College Hospital60思考：中國(guó)患者的治療策略？危險(xiǎn)分層及時(shí)診斷強(qiáng)調(diào)規(guī)范的基礎(chǔ)治療患者教育和規(guī)

20、律隨訪生物制劑作用機(jī)制現(xiàn)有證據(jù)安全性可獲得性第六十張，PPT共八十頁(yè)，創(chuàng)作于2022年6月Peking Union Medical College Hospital61New strategeAs a general approach, we suggest starting treatment with an NSAIDbut moving quickly( days later) to glucocorticoids followed by biologic agents if ASD does not come under control. Patients who are on the

21、 sicker end of the ASD disease spectrum should be treated with glucocorticoids from the outset of therapy, followed by biologic agents if the disease proves refractorywe suggest using a TNF inhibitor as the initial biologic agent in ASD not controlled with NSAIDs and glucocorticoids, and moving to a

22、nakinra if a response is not evident within two to four weeks (Grade 2C). DMARDs now generally play an adjunctive role in the treatment of ASD. Methotrexateis often used in conjunction with biologic therapies. 第六十一張，PPT共八十頁(yè)，創(chuàng)作于2022年6月Peking Union Medical College Hospital62參考文獻(xiàn)1.Reginato AJ, Schumach

23、er HR, Jr., Baker DG, OConnor CR, Ferreiros J. Adult onset Stills disease: experience in 23 patients and literature review with emphasis on organ failure. Semin Arthritis Rheum 1987;17:39-57.2.Efthimiou P, Georgy S. Pathogenesis and management of adult-onset Stills disease. Semin Arthritis Rheum 200

24、6;36:144-52.3.Kotter I, Wacker A, Koch S, et al. Anakinra in patients with treatment-resistant adult-onset Stills disease: four case reports with serial cytokine measurements and a review of the literature. Semin Arthritis Rheum 2007;37:189-97.4.Sabnis GR, Gokhale YA, Kulkarni UP. Tocilizumab in ref

25、ractory adult-onset Stills disease with aseptic meningitis-efficacy of interleukin-6 blockade and review of the literature. Semin Arthritis Rheum 2011;40:365-8.5.Colina M, Zucchini W, Ciancio G, Orzincolo C, Trotta F, Govoni M. The evolution of adult-onset still disease: an observational and compara

26、tive study in a cohort of 76 italian patients. Semin Arthritis Rheum 2011;41:279-85.6.Elkon KB, Hughes GR, Bywaters EG, et al. Adult-onset Stills disease. Twenty-year followup and further studies of patients with active disease. Arthritis Rheum 1982;25:647-54.7.Cush JJ, Medsger TA, Jr., Christy WC,

27、Herbert DC, Cooperstein LA. Adult-onset Stills disease. Clinical course and outcome. Arthritis Rheum 1987;30:186-94.8.Kawaguchi Y, Terajima H, Harigai M, Hara M, Kamatani N. Interleukin-18 as a novel diagnostic marker and indicator of disease severity in adult-onset Stills disease. Arthritis Rheum 2

28、001;44:1716-7.9.Iwamoto M, Nara H, Hirata D, Minota S, Nishimoto N, Yoshizaki K. Humanized monoclonal anti-interleukin-6 receptor antibody for treatment of intractable adult-onset Stills disease. Arthritis Rheum 2002;46:3388-9.10.Husni ME, Maier AL, Mease PJ, et al. Etanercept in the treatment of ad

29、ult patients with Stills disease. Arthritis Rheum 2002;46:1171-6.11.Dhote R, Simon J, Papo T, et al. Reactive hemophagocytic syndrome in adult systemic disease: report of twenty-six cases and literature review. Arthritis Rheum 2003;49:633-9.12.Fitzgerald AA, Leclercq SA, Yan A, Homik JE, Dinarello C

30、A. Rapid responses to anakinra in patients with refractory adult-onset Stills disease. Arthritis Rheum 2005;52:1794-803.13.Fardet L, Coppo P, Kettaneh A, Dehoux M, Cabane J, Lambotte O. Low glycosylated ferritin, a good marker for the diagnosis of hemophagocytic syndrome. Arthritis Rheum 2008;58:152

31、1-7.14.Franchini S, Dagna L, Salvo F, Aiello P, Baldissera E, Sabbadini MG. Efficacy of traditional and biologic agents in different clinical phenotypes of adult-onset Stills disease. Arthritis Rheum 2010;62:2530-5.15.Markusse HM, Stolk B, van der Mey AG, de Jonge-Bok JM, Heering KJ. Sensorineural h

32、earing loss in adult onset Stills disease. Ann Rheum Dis 1988;47:600-2.16.Cabane J, Michon A, Ziza JM, et al. Comparison of long term evolution of adult onset and juvenile onset Stills disease, both followed up for more than 10 years. Ann Rheum Dis 1990;49:283-5.17.Wendling D, Humbert PG, Billerey C

33、, Fest T, Dupond JL. Adult onset Stills disease and related renal amyloidosis. Ann Rheum Dis 1991;50:257-9.第六十二張，PPT共八十頁(yè)，創(chuàng)作于2022年6月Peking Union Medical College Hospital63參考文獻(xiàn)18.Godeau B, Leport C, Perronne C, Salmon-Ceron D, Vilde JL, Kahn MF. Long term evolution of adult onset Stills disease seen i

34、n an infectious diseases department. Ann Rheum Dis 1991;50:968.19.Fujii T, Akizuki M, Kameda H, et al. Methotrexate treatment in patients with adult onset Stills disease-retrospective study of 13 Japanese cases. Ann Rheum Dis 1997;56:144-8.20.Vignes S, Le Moel G, Fautrel B, Wechsler B, Godeau P, Pie

35、tte JC. Percentage of glycosylated serum ferritin remains low throughout the course of adult onset Stills disease. Ann Rheum Dis 2000;59:347-50.21.Kraetsch HG, Antoni C, Kalden JR, Manger B. Successful treatment of a small cohort of patients with adult onset of Stills disease with infliximab: first

36、experiences. Ann Rheum Dis 2001;60 Suppl 3:iii55-7.22.Asherson RA, Pascoe L. Adult onset Stills disease: response to Enbrel. Ann Rheum Dis 2002;61:859-60; author reply 60.23.Hamidou MA, Denis M, Barbarot S, Boutoille D, Belizna C, Le Moel G. Usefulness of glycosylated ferritin in atypical presentati

37、ons of adult onset Stills disease. Ann Rheum Dis 2004;63:605.24.Vasques Godinho FM, Parreira Santos MJ, Canas da Silva J. Refractory adult onset Stills disease successfully treated with anakinra. Ann Rheum Dis 2005;64:647-8.25.Aarntzen EH, van Riel PL, Barrera P. Refractory adult onset Stills diseas

38、e and hypersensitivity to non-steroidal anti-inflammatory drugs and cyclo-oxygenase-2 inhibitors: are biological agents the solution? Ann Rheum Dis 2005;64:1523-4.26.Ahmadi-Simab K, Lamprecht P, Jankowiak C, Gross WL. Successful treatment of refractory adult onset Stills disease with rituximab. Ann

39、Rheum Dis 2006;65:1117-8.27.Arlet JB, Le TH, Marinho A, et al. Reactive haemophagocytic syndrome in adult-onset Stills disease: a report of six patients and a review of the literature. Ann Rheum Dis 2006;65:1596-601.28.Efthimiou P, Paik PK, Bielory L. Diagnosis and management of adult onset Stills d

40、isease. Ann Rheum Dis 2006;65:564-72.29.Kalliolias GD, Georgiou PE, Antonopoulos IA, Andonopoulos AP, Liossis SN. Anakinra treatment in patients with adult-onset Stills disease is fast, effective, safe and steroid sparing: experience from an uncontrolled trial. Ann Rheum Dis 2007;66:842-3.30.Ruiz PJ

41、, Masliah E, Doherty TA, Quach A, Firestein GS. Cardiac death in a patient with adult-onset Stills disease treated with the interleukin 1 receptor inhibitor anakinra. Ann Rheum Dis 2007;66:422-3.31.De Bandt M, Saint-Marcoux B. Tocilizumab for multirefractory adult-onset Stills disease. Ann Rheum Dis

42、 2009;68:153-4.32.Chen DY, Chen YM, Ho WL, Chen HH, Shen GH, Lan JL. Diagnostic value of procalcitonin for differentiation between bacterial infection and non-infectious inflammation in febrile patients with active adult-onset Stills disease. Ann Rheum Dis 2009;68:1074-5.33.Naumann L, Feist E, Natus

43、ch A, et al. IL1-receptor antagonist anakinra provides long-lasting efficacy in the treatment of refractory adult-onset Stills disease. Ann Rheum Dis 2010;69:466-7.34.Rech J, Ronneberger M, Englbrecht M, et al. Successful treatment of adult-onset Stills disease refractory to TNF and IL-1 blockade by

44、 IL-6 receptor blockade. Ann Rheum Dis 2011;70:390-2.第六十三張，PPT共八十頁(yè)，創(chuàng)作于2022年6月Peking Union Medical College Hospital64第六十四張，PPT共八十頁(yè)，創(chuàng)作于2022年6月Peking Union Medical College Hospital65謝 謝 ！第六十五張，PPT共八十頁(yè)，創(chuàng)作于2022年6月AOSD & Acquired Hemophagocytic Lymphohistiocytosis第六十六張，PPT共八十頁(yè)，創(chuàng)作于2022年6月Peking Union Medic

45、al College Hospital67Bone Marrow Bx and AspBone Marrow Bx and Aspirate: Hemophagocytosis, Increased benign histiocytes, mildly hypocellular, No evidence of malignancy or lymphocyte expansionPhotomicrographs: Thanks to Friederike Kreisel第六十七張，PPT共八十頁(yè)，創(chuàng)作于2022年6月Peking Union Medical College Hospital68H

46、emophagocytic Syndromes“fever, wasting and generalized lymphoadenoapthy are associated with splenic and hepatic enlargement and in the final stages jaundice, purpura, and anaemia with profound leukopenia may occur. Post-mortem exam shows a systematised hyperplasia of histiocytes actively engaged in

47、phagocytosis of erythrocytes”Scott RB, Robb-Smith AHT. Histiocytic medullary reticulosis. Lancet 2:139, 1939 第六十八張，PPT共八十頁(yè)，創(chuàng)作于2022年6月Peking Union Medical College Hospital69HLH Diagnostic CriteriaFever ( 7 days, peak 38.5)SplenomegalyCytopenia ( 2 lineages)Hb 9.0, Plt 100k, ANC 3 SD) (also used as ma

48、rker of disease)Increased sIL-2RaDeficient/Absent NK cell activityHemophagocytosis (BM, spleen, LN)Henter et al. Sem Onc 18:29,1991Henter et al. Crit Rev Hem Onc 50:157, 2004 For Diagnosis: 5/8 of these criteria第六十九張，PPT共八十頁(yè)，創(chuàng)作于2022年6月Peking Union Medical College Hospital70HLH: PathogenesisNot Compl

49、etely UnderstoodUncontrolled immune activationCytokine over production / dysregulation by lymphocytesMacrophage (histiocytes) infiltrate tissues, hyper activation, phagocytosisDefective killing by cytotoxic lymphocytes第七十張，PPT共八十頁(yè)，創(chuàng)作于2022年6月Peking Union Medical College Hospital71HLH Pathogenesis: Cy

50、tokinesUnifying pathologic findingIncreased lymphocyte cell derived cytokines / factors:IL-2, IFN-g,TNF-a, sFasL, sIL-2RaIncreased Monocyte cytokines:IL-1, IL-6, IL-12, IL-18第七十一張，PPT共八十頁(yè)，創(chuàng)作于2022年6月Peking Union Medical College Hospital72Immune / Inflammatory Activation Loop with a Broken “Off Switch

51、”?TMfAPCIL-2IFN-g, TNF-a, MIP-1aIL-1, IL-6, IL-18, IL-12sFasLsIL-2RaINSULT/InfectionPhagocytosisExpansionInfiltration第七十二張，PPT共八十頁(yè)，創(chuàng)作于2022年6月Peking Union Medical College Hospital73Clinical Pathogenic LinksFever increased IL-1, TNF, IFN-gHSM infiltration w/ macrophages, inflammationCytopenias BM supp

52、ression by cytokines, hemophagocytosis, hypocellular marrowIncreased ferritin released from macrophages, damaged hepatocytes (sFasL)Increased sIL-2Ra shed from activated lymphoctesLow fibrinogen, coagulopathy liver dysfunction, consumption第七十三張，PPT共八十頁(yè)，創(chuàng)作于2022年6月Peking Union Medical College Hospital74Primary HLH: Pediatric SyndromesFamilial HLH (fHLH)Perforin (PFR1) mutated Science 286:1957, 1999hMunc13-4 mutations (granule exocytosis) Cell 115:461, 2003Other genes involved in perforin/granule exocyto