成人Still病如何诊治

1、关于成人Still病如何诊治第一张，PPT共八十页，创作于2022年6月Peking Union Medical College Hospital2历史1896年，Bannatyne在Lancet上报道首例AOSD病例，但被误诊为“RA”1897年，George Still报道22例儿童慢性关节炎，即后来的JIA全身型（Systemic onset of JIA），Still病临床三联征长期间歇性高热一过性特征性皮疹关节炎/痛法、德风湿学家（1943年Wissler，1946年Fanconi）亦报道类似病例，被称为Wissler-Fanconi综合征1964年，亚急性变应性败血症1971年，E

2、ric Bywaters报道14例临床表现类似的成人患者，标志着AOSD正式做为一种疾病被认识第二张，PPT共八十页，创作于2022年6月Peking Union Medical College Hospital3现状Still病：JRA中的系统型39 Still病特异性一过性皮疹WBC12.0ESR40ANA及RF（）腕骨硬化次要标准（1分）发病年龄35岁关节炎前驱症状：咽痛网状内皮系统活化表现或肝功异常浆膜炎颈椎或跗骨硬化诊断判断疑诊AOSD：10分观察12周确诊AOSD：10分观察6个月诊断困惑？F/21弛张高热3周伴发热的浅红色斑疹双腕轻度疼痛咽痛WBC 2.3ESR 115诊断AOS

3、D？治疗？第四十一张，PPT共八十页，创作于2022年6月Peking Union Medical College Hospital42日本Yamaguchi标准（1992年）主要指标1.间歇发热39，1wks2.关节痛，2wks3.典型皮疹4.WBC10（PMN0.80）次要指标1.咽痛2.淋巴结和/或脾大3.肝功能异常4.RF(-)和ANA(-)排 除1.感染性疾病2.恶性肿瘤3.其他风湿病诊断判断：5项（至少2项主要指标）诊断困惑？M/80间歇发热3月固定红色斑丘疹关节肌肉疼痛咽痛，肝脾大WBC 3.0，N 90%ESR 115低血压/低血氧入ICU诊断AOSD？治疗？第四十二张，PPT

4、共八十页，创作于2022年6月Peking Union Medical College Hospital43法国Bruno标准（2002年）主要标准弛张热39关节痛一过性红斑咽炎PMN80%GF20%次要标准斑丘疹WBC10诊断判断4项主要，或3项主要2项次要第四十三张，PPT共八十页，创作于2022年6月Peking Union Medical College Hospital44三套标准孰优孰劣？第四十四张，PPT共八十页，创作于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.第四十五张，PPT共八十页，创作于2022年6月Peking Union Medical Coll

6、ege Hospital46AOSD新的治疗策略TNF-IL-1IL-6B细胞第四十六张，PPT共八十页，创作于2022年6月Peking Union Medical College Hospital47依那西普Asherson(2002), 首例报道多种DMARDs血浆置换失败Etanercept + MTX + GCs临床表现及实验室指标明显改善Serratrice J(2003), 病例报道AOSD + 继发性肾脏淀粉样变引起肾病综合征AOSD改善蛋白尿缓解第四十七张，PPT共八十页，创作于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基线状况：prednisone, MTX, and NSAIDsET用法：25 mg 2/周, 第8周如无改善增至每周3次随访6个月疗效：压关节数改善67%，肿胀关节数63%第四十八张，PPT共八十页，创作于2022年6月Peking Union Medical College Hospital49英夫利昔单抗Cavagna L(2001), 3 例慢性关节型AOSDPred+MTX无效infliximab (3 mg/kg wk 0, 2, 6,之后每8 wksESR, CRP, 铁蛋白，

8、发热均改善第2周PtGA，PGA均改善，并维持至第50周GCs减量：from 1530 mg/d to 712 mg/第四十九张，PPT共八十页，创作于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第五十张，PPT共八十页，创作于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第五十一张，PPT共八十页，创作于2022年6月Peking Union Medical College Hospital52英夫利昔单抗Fautrel B(2005), 法国大型观

11、察性研究20 pts ,平均随访13个月GCMTX无效患者10例 IFX, 5例 ET, 5例序贯ETIFX CR: 5pt (1 ET, 4 IFX)PR: 16/25 例次(7/10 ET, 9/15 IFX每组均4例失败（均为JIA，对anti-TNF效果差）85最终停药（失效，或不良反应)第五十二张，PPT共八十页，创作于2022年6月Peking Union Medical College Hospital53阿那白滞素Godinho F（2004)，one case report难治性AOSD: MTX, SASP, CsA, IVIG, TNF拮抗剂 均失败 + 长期GCs引起严

12、重不良反应Anakinra 100 mg/d sc +MTX 25 mg/wk + predl(20 mg/d), and naproxen关节炎和全身症状数天周缓解ESR/CRP正常长期维持MTX+anakinra第五十三张，PPT共八十页，创作于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.第五十四张，PPT共八十页，创作于2022年6月Peki

17、ng Union Medical College Hospital55IL-1 blockadeNaumann, L(2010), case series,8 pts大剂量GCs依赖、多种DMARDs及抗TNF-制剂无效Anakira 100mg/d，SC随访648m临床症状、炎症指标均改善皮疹和关节炎在数h内显著缓解炎性指标在14周内正常激素减量至小剂量1例停药次日症状复发，恢复用药后好转第五十五张，PPT共八十页，创作于2022年6月Peking Union Medical College Hospital56托珠单抗Iwamoto M（2002)，1 pt reportMTX, CsA,

18、 GCs无效CRP, 发热, 关节痛显著改善De Bandt （2009），1 pt caseSabnis, G. R（2011），1 pt case伴无菌性脑膜炎第五十六张，PPT共八十页，创作于2022年6月Peking Union Medical College Hospital57Rech, J.（2011）3 cases report第五十七张，PPT共八十页，创作于2022年6月Peking Union Medical College Hospital58利妥昔单抗Ahmadi-Simab, K（2006)，2 cases reportsMTX、CsA、LEF、CTX、IVIG无效

19、之后EntanerceptInfliximab，EntanerceptMTX，无效Rituximab 375mg/m2，qw4多关节炎等症状缓解，炎症指标下降，激素减至5mg/dMTX/CsA随访6m稳定第五十八张，PPT共八十页，创作于2022年6月Peking Union Medical College Hospital59Therapeutic algorithm for AOSD（2004）第五十九张，PPT共八十页，创作于2022年6月Peking Union Medical College Hospital60思考：中国患者的治疗策略？危险分层及时诊断强调规范的基础治疗患者教育和规

20、律随访生物制剂作用机制现有证据安全性可获得性第六十张，PPT共八十页，创作于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. 第六十一张，PPT共八十页，创作于2022年6月Peking Union Medical College Hospital62参考文献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.第六十二张，PPT共八十页，创作于2022年6月Peking Union Medical College Hospital63参考文献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.第六十三张，PPT共八十页，创作于2022年6月Peking Union Medical College Hospital64第六十四张，PPT共八十页，创作于2022年6月Peking Union Medical College Hospital65谢 谢 ！第六十五张，PPT共八十页，创作于2022年6月AOSD & Acquired Hemophagocytic Lymphohistiocytosis第六十六张，PPT共八十页，创作于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第六十七张，PPT共八十页，创作于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 第六十八张，PPT共八十页，创作于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第六十九张，PPT共八十页，创作于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第七十张，PPT共八十页，创作于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第七十一张，PPT共八十页，创作于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第七十二张，PPT共八十页，创作于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第七十三张，PPT共八十页，创作于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