1、成人Still病诊治进展,北京协和医院 风湿免疫科 王 迁,（Adult Onset Stills Disease，AOSD）,AOSD 我们已经知道的,Peking Union Medical College Hospital,3,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
2、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，Eric 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,Peking Union Medical College Hospital,4,现 状,Still病：JRA中的系统型16岁 AOSD：具有Still病的类似症状，18岁 由于患病率低，临床表现复杂，目前多为病例（系列）报道或质量一般的回顾性研究，几乎没有RCT研究。,Peking Union Medical College Hospital,5,流 行 病 学,患病率: 7.3-14.7/百万人
3、 发病率 ：1.63/百万人/年 女:男：1-2：1 发病年龄：75%，1635岁 法国西部，62例，发病年龄呈双峰（1525岁，3646岁） 日本，67%发病年龄35岁 偶有70岁者 常见诱因：应激,Peking Union Medical College Hospital,6,发 病 机 制,未知，“外因通过内因起作用” 内因（遗传易感性） HLA-B17,B18, B35, DR2, B14/DR7, Bw35/Cw4, DR4/Dw6 外因（感染） 病毒：风疹, 腮腺炎,CMV,EBV,副流感,柯萨奇B4,埃可病毒7,腺病毒、流感A、人疱疹病毒6、细小病毒B19、乙肝、丙肝 其它：肺炎
4、支/衣原体,结肠耶尔森菌3/9,布氏杆菌,伯氏疏螺旋体（莱姆病）,Peking Union Medical College Hospital,7,细胞因子分泌异常 Th1-CKs IL-2, IFN-,IL-1,TNF-,IL-6增高 B细胞活化（产生IgG2a） NK、巨噬细胞活化促进细胞免疫活化 IL-18可能是更为上游的CK 黏附分子： ICAM-1 其它：sIL-2R,IL-4,sTNF-R2 T细胞活化,发 病 机 制,Peking Union Medical College Hospital,8,临 床 表 现,发热：80100%（95.7%） 多39，持续4h、体温波动1-2高峰
5、/日、午后/夜间多见 精神可，感染中毒症状不重、20%热峰之间不降至正常 常为首发症状 关节炎/痛：64100% 大关节为主（膝最常见），MCP/PIP/DIP/亦可累及，腕关节累及率RA 对称性，可有骨质侵蚀,Peking Union Medical College Hospital,9,AOSD患者常出现较为特征性的腕骨病变 腕骨间和腕掌关节间隙变窄 腕骨周强直（pericapitate ankylosis）,Peking Union Medical College Hospital,10,临 床 表 现,皮疹：5187（72.7） 典型：和发热相关，斑丘疹、多形性、分布躯干并四肢近端，不
6、痒、salmon-pink皮疹 Koebner 现象 不典型皮疹：固定、不随发热变化，皮肤间擦部位（腰，胸）；血管炎皮疹 病理：真皮浅层血管周围炎，淋巴细胞和组织细胞浸润。IHC显示C3和Ig沉积 鉴别意义：血管炎紫癜、Sweet病,Peking Union Medical College Hospital,11,特征性的“三文鱼样粉红色（salmon-pink）”斑丘疹 与发热相关 常分布于腋下、腕周，全身均可见,Peking Union Medical College Hospital,12,皮疹活检：无特异性 上图：真皮浅层水肿，轻度血管周围炎症 下图：血管周围炎性浸润，胶原间水肿明显,
7、Peking Union Medical College Hospital,13,临 床 表 现,肌痛：5684，全身性，伴随发热，肌酶可增高，但IM少见 咽痛：69%，非化脓性，疼痛明显 淋巴结肿大：常见颈淋巴结良性肿大 病理诊断：反应性增生、坏死性淋巴结炎 特征表现：副皮质区有密集的免疫母细胞增生，与RA、SLE、pSS完全不同，类似淋巴瘤 IHC显示为良性的多克隆B细胞增生，不同于淋巴瘤 肝脾肿大：脾大更为常见 可有胸痛：胸膜炎，心包炎,Peking Union Medical College Hospital,14,并 发 症,心脏 心包炎心包填塞 心肌炎 肺脏 胸膜炎胸腔积液 肺间质
8、病变 ARDS 血液 反应性HLH（噬血综合征）/MAS（巨噬细胞活化综合征） MAHA：TTP 纯红再障,Peking Union Medical College Hospital,15,并 发 症,肾脏 间质性肾炎 亚急性GN 肾脏淀粉样变 塌陷性肾小球病（collapsing glomerulopathy）：FSGS一种，节段或球性基底膜断裂，足细胞明显增生，临床表现为大量蛋白尿，急性肾衰 神经 颅神经麻痹 癫痫 无菌性脑膜脑炎 Miller-Fisher综合征：Guillain-Barre综合征的变异型，眼肌麻痹共济失调腱反射消失,Peking Union Medical Colleg
9、e Hospital,16,现有的最大病例系列的症状发生率总结,Peking Union Medical College Hospital,17,慢性关节型AOSD关节受累部位,Peking Union Medical College Hospital,18,临床表现,Peking Union Medical College Hospital,19,临床表现,Peking Union Medical College Hospital,20,实 验 室 检 查,主要反映全身炎症活化和CKs级联过程 血常规： 白细胞：50%15G/L, 37%20G/L，PMN为主（继发于骨髓粒系增生） 红细胞：
10、ACD， 血小板：反应性升高 全血细胞减少警惕HLH 凝血功能：PT/aPTT延长，偶有DIC 肝酶增高：ALT/AST/LDH/GGT可升高，但Bil升高少见 肝活检：门脉周围轻度单核细胞浸润性炎症,Peking Union Medical College Hospital,21,ESR/CRP升高 铁蛋白升高，70% 由MN和坏死肝细胞产生，与病情相关 多其它AID，其它炎性疾病 1000ng/ml（5UNL时，敏感性8082%，特异性4146%），可达250000ng/ml 鉴别：血色病、高雪病、败血症、血液肿瘤、HLH 自身抗体谱阴性：ANA（10%，低滴度）、RF,实 验 室 检 查
11、,Peking Union Medical College Hospital,22,实验室表现,Peking Union Medical College Hospital,23,诊 断 原 则,为除外性诊断（Diagnosis of exclusion） 提高诊断正确率的线索 病程：越长 年龄：越小 关节：越突出 皮疹：与发热关系密切 个体化筛查流程对感染、风湿科医生的挑战 “大胆诊断，小心观察”在初步诊断和治疗过程中注意观察疗效，修正诊断,Peking Union Medical College Hospital,24,鉴别诊断发热、皮疹、关节痛,感染： 病毒综合征（多3m）：EBV、CMV
12、、HIV、风疹、腮腺炎、柯萨奇、腺病毒 其它：深部细菌感染、风湿热、TB 肿瘤：淋巴瘤、白血病、血管免疫母淋巴结病、实体肿瘤 AID：SpA（包括ReA）、SLE、RA、血管炎、皮肌炎、HLH、Kikuchi病、Sweet综合征、肉芽肿病 周期性发热综合征（自身炎症综合征） 家族性地中海热 TRAPS,Peking Union Medical College Hospital,25,治 疗 方 案,NSAIDs：单药缓解率715 有报道NSAIDs可能诱导AOSD发生MAS 糖皮质激素： 大多数患者在病程中需用GCs，有效率7695% NSAIDs无效、高热、关节症状明显、内脏累及者应用 0.
13、5-1mg/kg/d起始，少数需1015mg/d维持数年 MP冲击用于危重症：心包填塞、肝衰、DIC,Peking Union Medical College Hospital,26,治 疗 方 案,DMARDs：约占34%，有效率40 NSAIDsGCs无效，或激素依赖者 一线：MTX（对关节症状有效率高） 其它：LEF,CYA、HCQ、CYC、AZA、金制剂、青霉胺 IVIG：用于复发、难治性，缓解维持时间253m 生物制剂 PBSCT？,Peking Union Medical College Hospital,27,病 程 及 预 后,病程多样：以下各1/3 单次自限型：全身症状为主，
14、大多1年内缓解，预后好 间断发作型：可有关节症状，发作间期恢复正常，发作程度递减 慢性关节型：关节症状为主，可致残，预后差。危险因素：起病时有皮疹、多关节炎和根关节受累，激素疗程2年,Peking Union Medical College Hospital,28,病程及预后,预后良好 5年生存率：90-95% 无皮疹、HLA-B35阳性者病情较轻 死因： 糖皮质激素不良反应：继发感染 脏器衰竭：肝衰竭、ARDS、DIC HLH/MAS,Peking Union Medical College Hospital,29,AOSD 新的诊断工具,IL-18 糖化铁蛋白（glycosylated f
15、erritin, GF） 降钙素原（procalcitonin, PCT）,Peking Union Medical College Hospital,30,IL-18：背景知识,IL-18属于IL-1家族，通过活化NF-kB发挥促炎作用 IL-18还可诱导Th1细胞产生IFN- 增强T细胞和NK细胞表明表达Fas-L，引起肝细胞凋亡破坏肝酶增高 参与RA的滑膜炎症过程关节炎 促进IgE分泌和嗜酸性粒细胞趋化一过性皮疹,Peking Union Medical College Hospital,31,IL-18：AOSD的新型标志物,92.0208,0.0760.038,0.099 0.16,
16、0.0560.032,Kawaguchi, et al. (2001). Arthritis Rheum 44: 1716-7.,Peking Union Medical College Hospital,32,IL-18：新的AOSD病情活动指标,Group1：激素难治组 Predl40mg/d，需加用DMARDs Group2：激素有效组 Predl40mg/d,N5 249306,N9 4.93.3,Kawaguchi, et al. (2001). Arthritis Rheum 44: 1716-7.,Peking Union Medical College Hospital,33,
17、GF：背景知识,正常时：GF50%，不随炎症过程增加 在AOSD患者：GF比例降低，且不随病情变化 对于临床表现不典型的病例更有价值,Peking Union Medical College Hospital,34,Vignes, et al. (2000). ARD 59: 347-50,GF：新的AOSD病情活动指标,Peking Union Medical College Hospital,35,Fautrel, et al. J Rheumatol 2001;28:3229,GF的临界值： 20% AOSD：35/44（79.5%） 其它炎性疾病：38/113（33.6%） 联合指标：
18、铁蛋白5UNLGF20% 敏感性：43.2% 特异性： 92.9%,GF：新的AOSD疾病标志物,Peking Union Medical College Hospital,36,Fardet,et al. (2008). Arthritis Rheum 58: 1521-7,警惕：在无AOSD的HLH中亦降低,Peking Union Medical College Hospital,37,PCT：背景知识,最早用于危重症患者早期诊断细菌性感染 正常人：0.05ng/ml 感染：0.5ng/ml 已有研究应用在SLE患者,Peking Union Medical College Hospit
19、al,38,Chen, et al. (2009). ARD 68: 1074-5,Peking Union Medical College Hospital,39,Chen, et al. (2009). ARD 68: 1074-5,PCT：在AOSD中临界值的设定,Peking Union Medical College Hospital,40,PCT：结 论,PCT最佳临界值：1.4ng/ml 敏感性、特异性、NPV、PPV均为100% 高度活动的AOSD（活动评分6分）可PCT 0.51.4ng/ml，多伴有TNF- 增高，因为后者可促进PCT增高 PCT优于TNF-,Chen, e
20、t al. (2009). ARD 68: 1074-5,Peking Union Medical College Hospital,41,AOSD 新的诊断标准,Peking Union Medical College Hospital,42,美国Cush标准（1987年）,重要标准（2分） 弛张热，体温39 Still病特异性一过性皮疹 WBC12.0ESR40 ANA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、/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 23 ESR 115 诊断AOSD？治疗？,Peking Union Medical College Hospital,43,日本Yamaguchi标准（1992年）,主要指标 1.间歇发热39，1wks 2.关节痛，2wks 3.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
22、大 WBC 30，N 90% ESR 115 低血压/低血氧入ICU 诊断AOSD？治疗？,Peking Union Medical College Hospital,44,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,Peking Union Medical College Hospital,45,三套标准孰优孰劣？,Peking Union Medical College Hospital,46,Hamidou, M. A., M. Denis, et al
23、. (2004). “Usefulness of glycosylated ferritin in atypical presentations of adult onset Stills disease.“ Ann Rheum Dis 63(5): 605,2 atypical cases GF could be a powerful diagnostic tool for AOSD, particularly in atypical clinical presentations of the disease.,Peking Union Medical College Hospital,47
24、,AOSD 新的治疗策略,TNF- IL-1 IL-6 B细胞,Peking Union Medical College Hospital,48,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,Peking Union Medical College Hospital,49,依那西普,Husni ME(2002), open label trial, a coho
25、rt of 12 pt 基线状况：prednisone, MTX, and NSAIDs ET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%,Peking Union Medical College Hospital,50,英夫利昔单抗,Cavagna L(2001), 3 例慢性关节型AOSD Pred+MTX无效 infliximab (3 mg/kg wk 0, 2, 6,之后每8 wks ESR, CRP, 铁蛋白，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
26、712 mg/,Peking Union Medical College Hospital,51,Infliximab,Kokkinos A(2004), a Greek case series, 4 pts refractory to high doses GCs+MTX responded favourably to infliximab 3 mg/kg All went into remission soon after their first infusion serum inflammation indices closely followed the clinical improv
27、ement Systemic corticosteroids were quickly tapered off and long term remission was sustained,Peking Union Medical College Hospital,52,Infliximab,Martin Carrasco C(2005), A European series of 8 pts, long term outcome GCs+DMARDs failed, infliximab (35 mg/kg) added 7/8 positive response with rapid imp
28、rovement in both clinical and serological response 5/8 went into long term remission, even after discontinuation of treatment,Peking Union Medical College Hospital,53,英夫利昔单抗,Fautrel B(2005), 法国大型观察性研究 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/
29、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),Peking Union Medical College Hospital,54,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,Peki
30、ng Union Medical College Hospital,55,IL-1 blockade,In the 2004 EULAR meeting, a report by Haraoui et al described the successful treatment of three patients with refractory chronic AOSD with daily subcutaneous anakinra 100 mg. Clinical improvement was seen within days of starting treatment and event
31、ually allowed the prednisone dose to be tapered significantly.105 Also in this meeting, Aelion et al reported the successful outcome of daily anakinra 100 mg subcutaneously in two patients with persistent AOSD. Clinical improvement was again seen in days in one patient and within a few weeks in the
32、other. The first patient was reported to be in complete remission when receiving anakinra alone, with normalised laboratory values. The other patient was weaned off corticosteroids and remained stable with a combined regimen of anakinra and oral MTX (10 mg/ week).106 More recently, another study als
33、o showed the efficacy of anakinra in the treatment of four patients with AOSD who were refractory to treatment with corticosteroids and MTX. Interestingly, two of the four patients had been unsuccessfully treated earlier with etanercept, which had been added to the standard regimen of MTX+corticoste
34、roids. In all four cases, the patients responded quickly to anakinra; within days symptoms resolved and laboratory values (WBC count, ferritin, CRP) normalised.,Peking Union Medical College Hospital,56,IL-1 blockade,Naumann, 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
35、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,Peking Union Medical College Hospital,57,托珠单抗,Iwamoto M（2002)，1 pt report MTX, CsA, GCs无效 CRP, 发热, 关节痛显著改善 De Bandt （2009），1 pt case Sabnis, G. R（2011），1 pt case 伴无菌性脑膜炎,Peking Union Medical College Hospital,58,Rech, J.（2011）3
36、 cases report,Peking Union Medical College Hospital,59,利妥昔单抗,Ahmadi-Simab, K（2006)，2 cases reports MTX、CsA、LEF、CTX、IVIG无效 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,Peking Union Medical College Hospital,60,Therapeutic algorithm for AOSD（
37、2004）,Peking Union Medical College Hospital,61,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 患者教育和规律随访,生物制剂 作用机制 现有证据 安全性 可获得性,Peking Union Medical College Hospital,62,New stratege,As a general approach, we suggest starting treatment with an NSAID but moving quickly( days later) to glucocorticoids followed by b
38、iologic agents if ASD does not come under control. Patients who are on the 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 refractory we suggest using a TNF inhibitor as the initial biologic a
39、gent in ASD not controlled with NSAIDs and glucocorticoids, and moving to anakinra 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. Methotrexate is often used in conjunction with biologic therapies.,Peking Union M
40、edical College Hospital,63,参考文献,1. Reginato AJ, Schumacher 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 managemen
41、t of adult-onset Stills disease. Semin Arthritis Rheum 2006;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
42、-97. 4. Sabnis GR, Gokhale YA, Kulkarni UP. Tocilizumab in refractory 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 evol
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