原发性干燥综合征[共71页]

单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,原发性干燥综合征,北京协和医院 风湿免疫科,张 文,1,干燥综合征,自身免疫性上皮炎,浅表,唾腺、泪腺、呼吸道、胃肠道、皮肤、阴道、膀胱,深层,肾小管、 胰腺、 肝内小胆管,血管炎,紫癜样皮疹,肾小球肾炎,神经系统,肺,雷诺现象,淋巴结反应性增生,坏死性淋巴结炎,非何杰金淋巴瘤,B,淋巴细胞增殖,2,干燥综合征的免疫学异常,3,内 容,口腔和眼科检查,系统表现,诊断标准,治疗,4,干燥性角结膜炎（干眼症）,5,Schirmer test,眼部未行任何检查以及未滴用眼药水的情况下进行：,将,Schirmer,滤纸条头端折叠，小心拉开下睑，放置在下睑外侧约,1/3,的位置，避免滤纸条损伤角膜或者结膜。,滤纸条有左（,L,）和右（,R,）标记，不要放反。,放置好后立刻开始计时,5,分钟。,检查时患者应保持眼睑闭合。,SS,患者的阳性标准为,Schirmer5mm/5,分钟,6,泪膜破碎时间（,tear Break-up Time, BUT,）,BUT,为眨眼后保持睁眼状态泪膜表面出现第一个干燥斑的时间,评价泪膜稳定性。,将一滴,0.5%,荧光素钠滴入下方结膜囊，嘱患者轻轻闭眼等待,1-2,分钟，自然眨眼数次，使染料均匀分布于眼表。,裂隙灯放大,10,倍，透过黄色滤光片观察。,令患者自然眨眼一次后双眼睁开并按下秒表，保持双眼睁开，记录角膜表面出现一个深蓝色点状或条状并迅速扩大的干燥斑时间。,阳性标准为,BUT10,秒。,7,角膜荧光染色,角膜上皮点状缺损（,PEE,）表现为高荧光点,8,唇腺病理在,pSS,中的作用,研究发病机制,在诊断方面的价值,脏器损伤的窗口,指导治疗的意义,9,炎性细胞浸润：,Minor salivary gland lesions,10,Th17,在唇腺中的表达,Zhang W, et al. Clin Rheumatol. 2014;33(4):523-9,IL17在唇腺GC表达,IL17在导管旁淋巴浸润灶表达,NC pSS,11,浆细胞、树突样细胞,灶性指数高的,pSS,患者唾液腺中浆细胞显示 长寿命,浆细胞表型,.,ART,2011,13R2;,Clin Exp Immunol. 2010;159(3):315-26.,在,pSS,不成熟的髓样树突状细胞（,mDCs,）在血液中表达减少，而成熟的,mDCs,在唾液腺中聚集；,结论：,mDCs,从血液中迁移至唾液腺。,浆细胞,12,Interleukin-15 as a potential new target in SS associated inflammation,Pathology, 2016:206,13,趋化因子,ICAM,VCAM,IP-10,Rheumatology (Oxford). 2010;49(9):1747. Clin Rheumatol (2016).,Selectin L,CXCL13,14,慢性唾液腺炎的病理类型,灶性淋巴细胞浸润性唾液腺炎,非特异性慢性唾液腺炎,硬化性唾液腺炎,肉芽肿性炎症如：结节病，,TB,等,15,（,1,个或多个,50,个以上淋巴细胞聚集灶，通常位于血管或导管周围。灶周围的腺泡基本正常，无萎缩或导管扩张或纤维化，浆细胞占少数）,灶性淋巴细胞浸润性唾液腺炎,:,focal lymphocytic sialadenitis, FLS,16,FLS,的三种类型,少量淋巴细胞浸润（,50),多个淋巴细胞浸润灶,生发中心形成,17,散在或灶性淋巴细胞、巨噬细胞和浆细胞浸润，伴周围的腺体萎缩、间质纤维化、导管扩张、管腔有浓厚的粘液。,非特异性慢性唾液腺炎：,Nonspecific chronic sialadenitis, NSCS,18,为,NSCS,的进展期，间质纤维化,多种炎症表现，腺体萎缩显著。,x16,硬化性唾液腺炎,:,sclerosing chronic sialadenitis, SCS,19,NSCS,与,SCS,NSCS,和,SCS,散在淋巴细胞和浆细胞浸润,间质纤维化突出,SCS,导管扩张、间质纤维化，淋巴浸润显著，,但周围无正常腺泡。,SCS,严重间质纤维化，淋巴细胞聚集，,较多导管样结构，无正常腺泡。,20,FLS,：,11 LSGs, 33 foci, 65 mm,2, FS = 2 foci / 4 mm,2,唇腺灶性指数：,focus score (FS),FS,分级：,FS/per 4 mm2,0: no lymphocytic infiltration;,1: 0 FS 1;,2: 1 FS 2 .,Morbini P, et al. Arthritis Res Ther. 2005;7(2):R343-8.,21,除了是否存在,FLS,外，还应该描述腺体萎缩的程度（无、轻度、中度、重度），纤维化、导管扩张和非特异性慢性唾液腺炎。,还应描述是否存在生发中心样结构和淋巴上皮病变,临床研究中干燥综合征组织病理学的标准（,EULAR,）,Ann Rheum Dis. 2016 Dec 13. pii: annrheumdis-2016-210448.,一般性指南,临床研究指南指南,22,FLSFLSNS/SCS,Phenotypic features of SS,FS 1FS 1no FS,n=730n=328n=668,P,(chi2),Serum anti-SS-A/-B,Positive487 (76)63 (10)91 (14),Negative243 (22)265 (24)575 (53) .0001,Rheumatoid factor,Positive458 (72)64 (10)113 (18),Negative270 (37)264 (24)555 (51) .0001,Ocular Surface Staining, 3630 (50)206 (16)415 (33), 399 (21)121 (26)253 (53) .0001,唇腺病理与临床相关性,Sialadenitis Pattern,Arthritis Rheum. 2011;63(7):2021-30.,23,FLSFLSNS/SCS,Phenotypic,FS 1FS 1no FS,ANA, 1:320477 (72)68 (10)115 (17), 1:320253 (24)260 (24)552 (52) 1445 mg/dL424 (73)54 (9)104 (18), 1445 mg/dL305 (27)273 (24)561 (49) .0001,UWS3 flow rate, 0.1 mL/min502 (53)148 (15)306 (32), 0.1 mL/min228 (30)179 (23)362 (47) .0001,Dry mouth symptoms,Present669 (43)292 (19)595 (38),Absent60 (36)35 (21) 70 (42)0.3,Dry eye symptoms,Present624 (43)292 (20)549 (37),Absent105 (41)35 (14)117 (46)0.01,唇腺病理与临床相关性分析,Arthritis Rheum. 2011;63(7):2021-30.,24,FS,与患者临床特征的相关性,* P,0.05,费允云，张文,*,， 中华医学杂志，,2013,93,（,13,）：,976,25,FS,与患者血清学指标的相关性分析：,IgG22.537.64,，与,FS,呈显著相关，,P=0.021,；,IgA3.391.45,，与,FS,无显著相关，,P=0.396,；,IgM1.651.71,，与,FS,呈显著相关，,P=0.019,；,ESR 3023mm/h,，与,FS,无显著相关，,P=0.051,；,RF 75.7138.2,，与,FS,呈显著相关，,P=0.004,。,费允云，张文,*,， 中华医学杂志，,2013,93,（,13,）：,976,26,ILD,患者，口干症,ANA,、,RF,，或抗,SSA,、抗,SSB,阴性,唇腺活检：灶性淋巴细胞浸润，,结论：唇腺活检可帮助部分抗体阴性的患者得以诊断。,27,.,175,例 ， 平均随诊,7,年，共,1855,病人年，,7,例发生,NHL,；,6/7,例在诊断时有,GC,样结构，,1,例无,(14% GC+ vs 0.8%GC-)(p=0.001).,结论,:,诊断,pSS,时唾液腺活检,GC,样结构是预测将来发生,NHL,的高危因素。,GC,形成与淋巴瘤的相关性,Ann Rheum Dis. 2011 Aug;70(8):1363-8,28,总 结,唇腺病理是诊断,pSS,的重要依据；,唇腺淋巴浸润或可作为脏器损伤的窗口；,唇腺生发中心形成是发生,NHL,的危险因素；,唇腺是研究,pSS,发病机制的窗口。,唇腺病理改变可作为疗效评价的窗口。,29,内 容,口腔和眼科检查,系统表现,诊断标准,治疗,30,pSS,多器官受累的系统性疾病,31,病理证实的肾脏受累,32,FSGS: focal and segmental glomerulosclerosis;,局灶节段性肾小球硬化,MCD: minimal change disease;,微小病变,MN: membranous nephropathy;,膜性肾病,MPGN:membrano-proliferative glomerulonephritis (related to cryoglobulinaemia);,膜增殖性肾小球肾炎（与冷球蛋白血症相关）,TIN: tubulointerstitial nephritis.,小管间质性肾炎,33,Histological characteristics in patients with,pSS-related tubulointerstitial nephritis,34,A multicentre study of 95 biopsy-proven cases of renal disease in primary Sjgrens syndrome.,Rheumatology (Oxford).,2016 Dec 10. pii: kew376. Epub ahead of print,CSs in 80 (98.8%) and immunosuppressive agents (mostly rituximab) in 21 cases (25.9%).,Despite marked interstitial fibrosis at initial biopsy, kidney function improved significantly during the 12-month period following diagnosis,No proven benefit of immunosuppressive agents over steroid therapy alone was found in this study.,35,2016,7,干燥综合征合并肺间质病变,36,Autoimmun Rev.,2016. pii: S1568-9972(16)30212-9.,pSS,患者,ILD,的特征,37,预测发生,ILD,的因素：老年、雷诺、消化道受累，特别是食道损害,.,38,神经系统,39,SS,诊断标准的发展史,哥本哈根,1975,日本,1984,希腊,1986,美国加州,1986,欧盟,1993,中国,1993,欧盟,1996,日本,1997,US,UE 2001,国际,2002,SICCA 2012,ACR/EULAR 2016,40,2002,年修订的干燥综合征国际分类（诊断）标准,（,Revised International Classification Criteria for Sj,grens Syndrome, 2002,）,41,I,、,口腔症状：3项中有1项或1项以上,1、每日感口干持续3个月以上；,2、成年后腮腺反复或持续肿大；,3、吞咽干性食物时需用水帮助。,II、眼部症状：3项中有1项或1项以上,1、每日感到不能忍受的眼干持续3个月以上；,2、有反复的砂子进眼或砂磨感觉；,3、每日需用人工泪液3次或3次以上。,III、眼部体征：下述检查任1项或1项以上阳性,1、,Schirmer,试验（）（,5,mm/5,分）；,2,、角膜染色（）（,4 van Bijsterveld,计分法）。,IV,、,组织学检查：下唇腺病理示淋巴细胞灶,1/4mm,2,。,V,、,唾液腺受损：下述检查任1项或1项以上阳性；,1、唾液流率（）（,1.5ml/15,分）；,2,、腮腺造影（）；,3,、唾液腺同位素检查（）,VI,、,自身抗体：抗SSA或抗SSB（）（双扩散法）,表,1,干燥综合征分类标准的项目,42,干燥综合征国际临床合作联盟（,SICCA,）建议的,SS,新分类标准（,2012,）,-,三项客观指标满足两项,Arthritis Care Res (Hoboken). 2012 , 64(4):475-87.,抗,SSA,和,/,或,抗,SSB,或,RF,和,ANA 1,：,320,灶性指数, 1,角结膜染色, 3,43,A R D 2016,2016,年,ACR/EULAR,原发性干燥综合征分类标准,44,符,合,1,2,3,45,Inclusion criteria,至少具有以下一个口干或眼干的症状：,(1),你每天都有持续干眼不适超过,3,月吗？,(2),你的眼睛有反复的磨砂感吗？,(3),你每天使用,3,次以上的泪液替代物吗,?,(4),你有持续每天口干超过,3,月吗？,(5),你进干食经常需要水送吗？,46,排除标准,include prior diagnosis of any of the following conditions, which would exclude diagnosis of SS and participation in SS studies or therapeutic trials because of overlapping clinical features or interference with criteria tests:,(1) history of head and neck radiation treatment,(2) active hepatitis C infection (with confirmation by PCR),(3) AIDS,(4) sarcoidosis,(5) amyloidosis,(6) graft-versus-host disease,(7) IgG4-related disease.,47,Development of the ClinESSDAI: a clinical score without biological domain. A tool for biological studies.,Ann Rheum Dis.,2016 Nov;75(11):1945-1950.,48,干燥综合征的治疗,对症治疗,免疫治疗,49,增加腺体分泌,唾液、泪液分泌,细胞因子,/,金属蛋白酶,胆碱脂酶,匹罗卡品是,M3,受体激动剂,羟,氯,喹,M3,受体（腺细胞表面）,副交感神经,乙酰胆碱,50,全身治疗,糖皮质激素 ：依病情决定是否使用及剂量,免疫抑制剂：,HCQ,：,MTX,、,LEF,、,CTX,、,MMF,、,AZA,、,Cys,、,FK506,、艾拉莫得,中药：雷公藤、白芍总苷,生物制剂,51,pSS,临床表现的治疗推荐,Nat. Rev. Rheumatol.,doi:10.1038/nrrheum. 2016. 100,52,pSS,临床表现的治疗推荐,53,根据,ESSDAI,脏器评分推荐治疗,Saraux, A.,et al.,(2016),Treatment of primary Sjgren syndrome,Nat. Rev. Rheumatol.,doi:10.1038/nrrheum.2016.100,54,根据,ESSDAI,脏器评分推荐治疗,55,pSS,合并,ILD,的治疗,糖皮质激素,(0.51 mg/kg/day),为一线药物；,治疗反应与病程和病理类型相关：,早期好，,NSIP, COP,和,LIP,较,UIP,疗效好；,免疫抑制剂：报道有效的：,CTX,、,AZA,、美罗华；,Interstitial lung disease in primary Sjgrens syndrome.,Autoimmun Rev.,2016. pii: S1568-9972(16)30212-9.,56,多中心、随机、双盲、安慰剂平行对照,研究,评价白芍总苷治疗,pSS,的有效性和安全性,The efficacy and safety of,t,otal glucosides of peony,o,n the treatment of primary,S,jogrens,S,yndrome,（,TOSS,研究,）,中日友好医院，等,10,家单位,57,治疗组在,第,4,周,、,8,周、,24,周与对照组,相比有显著差异,治疗组在用药第,4,周即开始起效，效果随用药时间有增加的趋势,眼干、口干,VAS, p0.05; p0.01; p0.001,；治疗组与对照组组间比较,%,（原始值,-,基线值）,/,基线值,治疗组（,n=,193,）,对照组（,n=,94,）,100,50,0,-50,-100,4,周,8,周,12,周,18,周,24,周,%,（原始值,-,基线值）,/,基线值,4,周,8,周,12,周,18,周,24,周,50,0,-50,-100, ,58,ESSDAI,59,IgG,20,治疗组（,n=,104,）,对照组（,n=,48,）,%,（原始值,-,基线值）,/,基线值,12,周,24,周,10,0,-10,-20,-30,-40,治疗组与对照组组间无显著性差异,时间（周）,60,At 24w, in TGP group, naive B cells decreased in while memory B cells increased.,The concentrations of TNF- and IFN- decreased in the TGP group at week 24,61,艾拉莫德结构式,艾拉莫德,-,小分子的抗风湿新药,分子式：,C,17,H,14,N,2,O,6,S,分子量：,374.37,62,药理作用,-,抑制免疫球蛋白,艾得辛显著抑制小鼠,RA,滑液组织的,IgG,和,IgM,的表达,【1】,并呈剂量依赖性。,艾得辛通过,B,细胞抑制免疫球蛋白的表达，而不影响细胞增殖,【2】,。,-,免疫调节剂,Fang Du, Liang-jing L, T-614, a novel immunomodulator, attenuates joint inflammation and articular damage in collagen-induced arthritis. Arthritis Research & Therapy Vol 10 No 6 Du et al.,Tanaka K, Yamamoto T, Aikawa Y, et al. Inhibitory effects of an anti-rheumatic agent T-614 on immunoglobulin production by cultured B cells and rheumatoid synovial tissues engrafted into SCID mice. Rheumatology (Oxford) 2003;42:1365-71,Yamamoto T, Aikawa Y, Funaki J, et al. Immunopharmacological studies of a disease-modifying antirheumatic drug iguratimod (T-614); Its effect on immunoglo-blin production and lymphocyte proliferation. Jpn Pharmacol Ther 2007;35:561-9.,63,药理作用,-,抑制细胞因子,在多项的研究中，艾得辛对多种细胞因子,TNF,，,IL-6,、,IL-4,、,IL-17,都有显著的抑制作用。,Fang Du, Liang-jing L, T-614, a novel immunomodulator, attenuates joint inflammation and articular damage in collagen-induced arthritis. Arthritis Research & Therapy Vol 10 No 6 Du et al.,Tanaka K, Yamamoto T, Aikawa Y, et al. Inhibitory effects of an anti-rheumatic agent T-614 on immunoglobulin production by cultured B cells and rheumatoid synovial tissues engrafted into SCID mice. Rheumatology (Oxford) 2003;42:1365-71,Yamamoto T, Aikawa Y, Funaki J, et al. Immunopharmacological studies of a disease-modifying antirheumatic drug iguratimod (T-614); Its effect on immunoglo-blin production and lymphocyte proliferation. Jpn Pharmacol Ther 2007;35:561-9.,64,艾拉莫德有效治疗,pSS,65,Clin Exp Rheumatol 2016; 34 (Suppl. 98): S58-S62.,TNF and IL-1,：无效,B,细胞：抗,CD20,，抗,CD22,：研究有效,T-B,、,T-DC,相互作用的共刺激分子：,CTLA-4,、,ICOS,、,CD40L,：有望有效,生 物 制 剂,靶向：,66,Arthritis Rheum. 2009;60(11):3251-6.,Clinical and histologic evidence of salivary gland restoration supports the efficacy of,rituximab treatment in Sjgrens syndrome,.,5,例，利妥昔单抗,: 375 mg/m,2,X4,次；治疗前和治疗后,12,周分别腮腺活检。,结果：,4,例唾液流率升高，唾液中钠的浓度恢复正常。,唇腺淋巴细胞浸润减少，,B/T,比值下降，部分生发中心消失。,淋巴上皮样结构,3,例减少，,2,例消失。,因炎症反应而增生的腺泡间质所有患者均减轻。,67,Rituximab,therapy in primary Sjgrens syndrome with,interstitial lung disease,: a retrospective cohort study.,结果：治疗,6,月,肺功能改善：,DLCO,客观症状改善：整体情况、疲劳、眼干、口干、咳嗽、气短，等,；,HRCT,计分有下降趋势,(from 8.74.1 to 7.64.6, p=0.419).,结论,:,利妥昔单抗对,pSS,合并,ILD,的患者可改善临床症状和换气功能，稳定,HRCT,的计分。,Clin Exp Rheumatol.,2016 Aug 31, 台湾.,68,Ann Rheum Dis.,2016 Feb;75(2):348-55.,EULAR,干燥综合征疾病活动指数（,ESSDAI,）,69,the number of laboratory parameters,The entire cohort.,the maximum level of activity achieved in any of the 12 ESSDAI domains,the number of predictive parameters associated with mortality,70,Hope you have a rewarding, productive and joyful,2017,圣诞、 新年快乐！,71,