全身型幼年特发性关节炎发病机制及治疗进展

全身型幼年特发性关节炎发病机制及治疗进展胡秀芬;高峰Systemicjuvenileidiopathicarthritis(sJIAisaspecialtypeofItisaninflammatoryconditioncharacterizedbyfever,lymphadenopathy,arthritis,rashandserositis.Itisthemostacuteandseveretype,whichhasadisproportionatelyhighmorbiditycomparedwithothersubtypes.InsJIA,systemicinflammationhasbeenassociatedwithdysregulationoftheinnateimmunesystem,suggestingthatitisanautoinflammatorydisorder.DysregulationoftheinnateimmunesysteminsJIAresultsinincreasedproductionofinflammatorycytokines,leadingtothedistinctiveclinicalfeaturesofthedisease.IL-1andIL-6playamajorroleinthepathogenesisofsJIAandtreatmentwithIL-1andIL-6inhibitorshasshowntobehighly

幼年特发性关节炎(

一种特殊的系统炎症与固有免疫IL-6sJIAIL-1IL-6sJIA取得了较好的疗效。《医药导报》2016(035)012【总页数】4页(P1287-1290)【关键词】关节炎,幼年特发性,全身型;发病机制;白细胞介素【作者】胡秀芬;高峰【作者单位】华中科技大学同济医学院附属同济医院儿科，武汉430030;华中科技大学同济医学院附属协和医院内分泌科，武汉430022【正文语种】中文【中图分类】R985;R684.3DOI10.3870/j.issn.1004-0781.2016.12.001(juvenileidiopathicarthrtIA湿性疾病，全身型幼年特发性关节炎(systemicjuvenileidiopathicarthitisJIA10%8%54%不等JIA，sJIAC与巨噬细胞活化综合征密切相关。其发病机制尚未完全明确，近期研究表明，固有sJIA发病的重要机制，sJIA是一种自身炎症性疾病。触发因素JIAHLA基因相关JIAsJIAHLA基因无关，其基因效应IL-6和巨噬细胞抑制因子(macrophageinhibitoryfactor,趋化因子基因启动子位置上的一个单核苷多态性sJIA有关[9-10]，IL-6sJIA的过度表达。此外，MIF5’sJIA相关，患儿血清和滑膜MIF可导致患儿长期功能损害IL-6MIF基因多态性的相关性提示sJIA是一个固有免疫异常所至的疾病。19sJIA发病和病情恶化有关1sJIA患儿接种减毒的水痘疫苗后病情加重的报道sJIA、、IL-18S100A8、S100A9、S100A12较其他炎症性疾病显著升高[13-15]，IL-6除外，所有这些分子都由所谓的替代分泌途径分泌，它完全不同于通过内质网和高尔基体进行的细胞内转运机制的多系统炎症。sJIA中吞噬细胞异常激活可致前炎症细胞因子、1(S100A8S100A9、S100A12)分泌。sJIAIL-1明显高于对照组IL-1IL-1受体可激活下丘脑体温调节中枢而致发热；IL-1sJIA的皮疹和IL-6产生IL-6sJIAIL-6[14,19-20]，IL-6还刺激肝脏介导急相蛋白的IL-18sJIAJIA前炎症S100S100蛋白包括S100A8、S100A9和S100A12，是由吞噬细胞特异性地分泌，又称骨髓相关蛋白(myeloid-relatedMRPs)，是钙结合蛋白sJIAS100蛋白与疾病活动度密切相关，而且在其他类型炎症性关节炎和其他自身免疫学疾病、感染疾病中都不会出现。因此，这些S100蛋白可作为sJIA最好的生物标记物，血清S100A8/S100A9 水平可以作为sJIA与感染、淋巴瘤等疾病进行鉴别诊断的指标。sJIAsJIAsJIA1～5sJIA240%sJIA患儿经过一个循环的病程后在数月内获得永久性缓解，少3～6经典2013ACR推荐指南作为第一线药的地位不确定，特别是对严重病例，而对发热和医生总体评分≥7sJIANSAIDs治疗超过2糖皮质激素治疗]；甲氨蝶呤(methotrexate,MTX)而对于有发热而无关节炎的患儿不推荐10～301g3～5d。IL-1治疗阿那白滞素(anakinraIL-1IL-1IL-1IL-1sJIA20042案治疗失败的病例sJIA3.2.2卡那单抗(anakinumab)卡那单抗为人源性的抗单克隆抗体，临床研究表明sJIA15d卡那单抗治疗，1/3的患儿可停用激素，半数以上的患儿糖皮质激素减量。3.2.3利纳西普IL-135%～40%sJIAACR儿童70sJIA3，ACR儿童30ACR50ACR儿童7078.3%，60.9%34.8%IL-6IL-6IL-6sJIA2005年10例sJIA患儿的疾病活动度获得明显减轻；TENDER研究中，112sJIA1，ACR儿童70ACR儿童9080%59%，48%的患儿无活动性关节炎，52%素TNF治疗TNF-JIARUSSO等[37]24%sJIATNF治疗有反应，13%TNF-sJIA的发病机制中仅发挥次要作用。【相关文献】KUNJIRV,VENUGOPALANA,CHOPRAA.ProfileofIndianpatientswithjuvenileonsetchronicinflammatoryjointdiseaseusingtheILARclassificationcriteriaforcommunity-basedcohortstudy[J].JRheumatol,2010,37(8):1756-1762.FUJIKAWAS,OKUNIM.Clinicalanalysisof570caseswithjuvenilerheumatoidarthritis:resultsofanationwideretrospectivesurveyinJapan[J].ActaPaediatr1997,39(2):245-249.SETHV,KABRASK,SEMWALOP,etal.Clinico-immunologicalprofileinjuvenilerheumatoidarthritis-anIndianexperience[J].IndianJPediatr,1996,63(3):293-300.GLASSDN,GIANNINIEH.Juvenilerheumatoidarthritisasacomplexgenetctrait[J].ArthritisRheum,1999,42(11):2261-2268.PRAHALADS.Geneticsofjuvenileidiopathicarthritis:anupdate[J].CurrRheumatol,2004,16(5):588-594.THOMSONW,DONNR.Juvenileidiopathicarthritis-what'snew?next?[J].ArthritisRes,2002,4(5):302-306.DEBENEDETTIF,MEAZZAC,VIVARELLIM,etal.Functionalandprognosticrelevanceofthe-173polymorphismofthemacrophagemigrationinhibitoryfactorgeneinsystemic-onsetjuvenileidiopathicarthritis[J].ArthritisRheum,2003,48(5):1398-1407.DONNR,ALOURFIZ,ZEGGINIE,etal.Afunctionalpromoterhaplotypeofmacrophagemigrationinhibitoryfactorislinkedandassociatedwithjuvenileidiopathicarthritis[J].ArthritisRheum,2004,50(5):1604-1610.FISHMAND,FAULDSG,JEFFERYR,etal.Theeffectofnovlepolymorphismsintheinterleukin-6(IL-6)geneonIL-6transcriptionandplasmaIL-6levels,andanassociationwithsystemic-onsetjuvenilechronicarthritis[J].JClinInvest,1998,102(7):1369-1376.OGILVIEEM,FIFEMS,THOMPSONSD,etal.The-174Galleleoftheinterleukin-6geneconferssusceptibilitytosystemicarthritisinchildren:amulticenterstudyusingsimplexandmultiplexjuvenileidiopathicarthritisfamilies[J].ArthritisRheum,2003,48(11):3202-3206.GONZALEZB,LARRANAGAC,LEONO,etal.ParvovirusB19mayhavearoleinthepathogenesisofjuvenileidiopathicarthritis[J].JRheumatol,2007,34(6):1336-1340.KOREMATSUS,MIYAHARAH,KAWANOT,etal.Arelapseofsystemictypejuvenileidiopathicarthritisafterarubellavaccinationinapatientduringalong-termremissionperiod[J].Vaccine,2009,27(37):5041-5042.DEJAGERW,HOPPENREIJSEP,WULFFRAATNM,etal.Bloodandsynovialfluidcytokinesignaturesinpatientswithjuvenileidiopathicarthritis:across-sectionalstudy[J].AnnRheumDis,2007,66(5):589-598.DEBENEDETTIF,MASSAM,ROBBIONIP,etal.Correlationofseruminterleukin-6withjointinvolvementandthrombocytosisinsystemicjuvenilerheumatoidarthritis[J].ArthritisRheum,1991,34(9):1158-1163.FROSCHM,VOGLT,SEELIGERS,etal.Expressionofmyeloid-relatedprotein8and14systemic-onsetjuvenilerheumatoidarthritis[J].ArthritisRheum,2003,48(9):2622-2626.RAMMESA,ROTHJ,GOEBELERM,etal.Myeloid-relatedprotein(MRP)8andMRP14,calcium-bindingproteinsofS100family,aresecretedbyactivatedmonocytesvianovel,tubulin-dependenpathway[J].JBiolChem,1997,272(14):9496-9502.PASCUALV,ALLANTAZF,ARCEE,etal.Roleofinterleukin-1(IL-1)inthepathogenesisofsystemic-oncetjuvenileidiopathicarthritisandclinicalresponsetoIL-1blockade[J].JExpMed,2005,201(9):1479-1486.DINARELLOCA.BlockingIL-1insystemicinflammation[J].JMed,2005:201(9):1355-1359.DEBENEDETTIF,PIGNATTIP,GENLONIV,etal.Differencesinsynovialfluidcytokinelevelsbetweenjuvenileandadultrheumatoidarthritis[J].JRheumatol,1997,24(7):1403-1409.FONSECAJE,SANTOSMJ,CANHAOH,etal.Interleukin-6asakeyplayerinsystemicinflammationandjointdestruction[J].AutoimmunRev,2009,8(7):538-542.FOELLD,WITTKOWSKIH,VOGLT,etal.S100proteinsexpressedinphagocytes:anovelgroupofdamage-associatedmolecularpatternmolecules[J].JLeukocBiol,2007,81(1):28-37.FOELLD,ROTHJ.ProinflammatoryS100proteinsinarthritisandautoimmunedisease[J].ArthritisRheum,2004,50(12):3762-3771.FOELLD,WITTKOWSKIH,HAMMERSCHMIDTI,etal.MonitoringneutrophilactivationinjuvenilerheumatoidarthritisbyS100A12serumconcentrations[J].ArthritisRheum,2004,50(4):1286-1295.BEHRENSEM,BEUKELMANT,GALLOL,etal.Evaluationofthepresentationofsystemiconsetjuvenilerheumatoidarthritis:datafromthePennsylvaniaSystemicOnsetJuvenileArthritisRegistry(PASOJAR)[J].JRheumatol,2008,35(2):343-348.RUSSORA,KATSICASMM.Patientswithveryearly-onsetsystemicjuvenileidiopathicarthritisexhibitmoreinflammatoryfeaturesandaworseoutcome[J].JRheumatol,2013,40(3):329-334.PETTYRE,SOUTHWOODTR,MANNERSP,etal.InternationalLeagueofAssociationsforRheumatologyclassificationofjuvenileidiopathicarthritis:Secondrevision,Edmonton2001[J].JRheumatol,2004,31(2):390-392.SPIEGELLR,SCHNEIDERR,LANGBA,etal.Earlypredictorsofpoorfunctionaloutcomeinsystemic-onsetjuvenilerheumatoidarthritis:amulticentercohortstudy[J].ArthritisRheum,2000,43(11):2402-2409.RINGOLDS,WEISSPF,BEUKELMANT,etal.2013updateofthe2011AmericanCollegeofRheumatologyrecommendationsforthetreatmentofjuvenileidiopathicarthritis:recommendationsforthemedicaltherapyofchildrenwithsystemicjuvenileidiopathicarthritisandtuberculosisscreeningamongchildrenreceivingbiologicmedications[J].ArthritisRheum,2013,65(10):2499-2512.BEUKELMANT,PATKARNM,SAAGKG,etal.2011AmericanCollegeofRheumatologyrecommendationsforthetreatmentofjuvenileidiopathicarthritis:initiationandmonitoringoftherapeuticagentsforthetreatmentofarthritisandsystemicfeatures[J].ArthritisCareRes,2011,63(4):465-482.WOOP,SOUTHWOODTR,PRIEURAM,etal.Randomized,placebo-controlled,crossovertrialoflow-doseoralmethotrexateinchildrenwithextendedoligoarticularorsystemicarthritis[J].ArthritisRheumatol,2000,43(8):1849-1857.VERBSKYJW,WHITEAJ.Effectiveuseoftherecombinantinterleukin1receptorantagonistanakinraintherapyresistantsystemiconsetjuvenilerheumatoidarthritis[J].JRheumatol,2004,31(10):2071-2075.QUARTIERP,ALLANTAZF,CIMAZR,etal.Amulticentre,randomised,double-blind,placebo-controlledtrialwiththeinterleukin-1receptorantagonistanakinrapatientswithsystemic-onsetjuvenileidiopathicarthritis(ANAJIStrial)[J].AnnDis,2011,70(5):747-754.VASTERTSJ,DEJAGERW,NOORDMANBJ,et