JAKinhibitors类风湿关

doi:10./rheumatology/key

Rheumatology,Volume58,IssueSupplement_1,February

JAKs,namedafterthetwo-facedRomanGodJanus,formafamilyconsistingoffourmembers:JAK1,JAK2,JAK3andTYK2.Theyareallcytoplasmictyrosinekinasesabletophosphorylatetyrosineresidueseitheronthemselves(autophosphorylation)oronadjacentmolecules(transphosphorylation),includingtheSTATs.Thelatterisafamilyoftranscriptionfactors,actingdownstreamofJAKsandconsistingof7members[3].TheJAK/STATpathwayisanevolutionarilyconservedpathwaymediatingtheeffectofmanydifferentmolecules,includingILs,IFNs,colony-stimulatingfactors,growthfactorsandhormones(alsoknownashormone-likecytokines),whichexerttheirfunctionthroughtypeIandtypeIIreceptors[3](Fig.1).TypeIreceptorsareusedbyseveralILs,colony-stimulatingfactorsandhormones,whiletypeIIreceptorsareusedbyIFNsandIL-10–relatedcytokines(IL-10,IL-19,IL-20,IL-22,IL-22andIL-26)[3].Thesereceptorsconsistofvarioussubunits,eachofthemassociatedwithaJAKmolecule.Uponligationoftheeffectorproteinwithitsreceptor,thelatterisoligomerized,leadingtoactivationoftherelevantJAK,which,inturn,isautophosphorylatedandalsotransfersaphosphatetoatyrosineresidueinthereceptor’ssubunit,creatingadockingsiteforaSTATmolecule.TheSTATmoleculeisalsophopsphorylatedbytheJAK.Subsequently,STATsaredimerizedandtranslocatefromcytosoltothenucleus,therebyregulatinggeneexpression[2].

jak，以罗马双面神janus命名，组成一个家族，由四个成员组成:JAK1,JAK2,JAK3和TYK2。它们都是细胞质酪氨酸激酶，能够磷酸化自身（自磷酸化）或相邻分子（转磷酸化）上的酪氨酸残基，包括STATs。后者是一个转录因子家族，作用于JAKs的下游，由7个成员[3]组成。

JAK/STAT途径是一种进化上保守的通路，介导许多不同分子的作用，包括ILs、IFN、集落刺激因子、生长因子和激素（也称为激素样细胞因子），它们通过I型和II型受体发挥功能。

I型受体被几个白介素,集落刺激因子和激素，而II型受体被ifn和IL-10相关细胞因子(IL-10、IL-19、IL-20、IL-22、IL-22、IL-26)激活[3]。

这些受体由不同的亚基组成，每个亚基都与一个JAK分子相关联。当效应蛋白与其受体连接时，后者寡聚化，导致相关JAK的激活，进而被自磷酸化，并将磷酸盐转移到受体亚基的酪氨酸残基上，为STAT分子创建一个对接位点。STAT分子也被JAK磷酸化。随后，STATs二聚并从细胞质转移到细胞核，从而调节基因表达[2]。

ReceptorsubunitsareassociatedwithaspecificJAK;someofthemmaybeassociatedwithmorethanoneJAK.Also,astheJAKfamilyhasonlyfourmembers,manydifferentcytokinesmayactthroughthesameJAK.Consequently,inhibitingaJAKmoleculemayimpedemorethanonepathway,whichmayinpartexplainboththeefficacyobtainedandsomeoftheadverseeffectsobservedwithJAKinhibitortreatment[4].

受体亚单位与特定JAK相关；其中一些可能与多个JAK相关。此外，由于JAK家族只有四个成员，许多不同的细胞因子可能通过同一JAK发挥作用。因此，抑制JAK分子可能会阻碍不止一条途径，这可以部分解释JAK抑制剂治疗所获得的疗效和观察到的一些不良反应[4]

ManyJAKinibshavebeendevelopedoverrecentyears(Table1),oftensubcategorizedasfirst-generationandnewerJAKinibs.Thefirst-generationJAKinibsdonotdisplayhighspecificity,demonstratingactivityagainstthreeorevenallfouroftheJAKfamilymembers(alsotermedaspan-JAKinhibitors).SelectivityagainstspecificJAKsisadesirablefeatureofthenewerJAKinibs,primarilyintermsofmitigatingsideeffects.CurrentlyonlytwoJAKinibshaveapprovalforthetreatmentofRAandPsA.However,theseandotherJAKinhibitorsappeartoalsohaveapotentialpositioninthetreatmentofmanyotherautoimmunediseases,including:SpAs;psoriasisandotherskindiseasessuchasatopicdermatitis(AD)andalopeciaareata(AA);IBD;uveitis;GCA;andsingle-genedisorders,suchastheso-calledinterferonopathies.

近年来开发了许多jak药物(表1)，经常被细分为第一代和更新的jak药物。第一代JAKinibs不显示高特异性，对三个甚至全部四个JAK家族成员(也称为泛JAK抑制剂)显示活性。针对特定jak的选择性是较新的jakinib的理想特性，主要是在减轻副作用方面。目前，只有两种jakinib获批用于RA和PsA的治疗。然而，这些和其他JAK抑制剂似乎在许多其他自身免疫性疾病的治疗中也有潜在的地位，包括:spa;银屑病和其他皮肤病，如特应性皮炎(AD)和斑秃(AA);炎症性肠病;葡萄膜炎;GCA;以及单基因疾病，比如所谓的干扰素病。

2

PsAandSpAs

ThepotentialmodeofactionofJAKinibsinpsoriaticdiseaseisnotfullyunderstood.However,therearedatafromanimalmodelsandexvivoexperimentssuggestingthattheJAK/STATpathwayislinkedtotheIL-23/-17axis,whichinturnplaysacrucialroleintheunderlyingpathogenesisofPsAandspondyloarthropathies.AlthoughIL-17persedoesnotseemtoemploytheJAK/STATpathway[5],IL-23(whichisanupstreamdriverofIL-17Arelease)exertsit’sfunctionthroughtheJAK2-TYK2/STAT3-STAT4system[4,6,7].Additionally,IL-22(alsoakeyplayerinthepathogenesisofSpAsandanimportantmediatoroftheIL-23/-17axis)usestheJAK/STATpathway[4,6].Finally,typeIIFNsarealsoimplicatedinsomeelementsofthePsAarticularandcutaneousresponse.

JAKinibs在银屑病中的潜在作用模式尚不完全清楚。然而，来自动物模型和体内实验的数据表明，JAK/STAT通路与IL-23/-17轴相关，而IL-23/-17轴在PsA和脊椎关节病的潜在发病机制中发挥着关键作用。尽管IL-17似乎不使用JAK/STAT途径[5]，IL-23(IL-17A释放的上游驱动因素)通过JAK2-TYK2/STAT3-STAT4系统发挥其功能[4,6,7]。此外，IL-22(也是spa发病机制的关键角色和IL-23/-17轴的重要中介)使用JAK/STAT途径[4,6]。最后，I型ifn也与PsA关节和皮肤反应的某些因素有关。

Inanimalarthritismodels,JAKinibshavebeenfoundtoinhibit,dependentonthecytokineenvironment,theexpressionofTh17-relatedcytokines(IL-17A,IL-17F,IL-22),therebyblockingtheIL-23/-17axis[8].ExvivostudieshaveshownthatinsynovialfluidsamplesobtainedfrompatientswithPsA,proteinsinvolvedin(orfunctionallyrelatedto)theJAK/STATpathway[JAK1,Extracellularsignal-RegulatedKinase(ERK)1/2,STAT1,STAT3,STAT5]areincreased[9].ThecocultureofsynovialfibroblastsderivedfromPsApatientsorPsAsynovialexplantswithtofacitinib(afirst-generationJAK3/1inhibitorwithlessactivityforJAK2andpossiblyTYK2)ledtoreducedexpressionofphosphoproteinsinvolvedinthepathway,decreasedabilityoffibroblaststoformnetworksandmigrate,anddecreasedsecretionofinflammatorycytokinesandeffectorproteins,suchasmetalloproteinases[10].Additionally,arecentlypublishedstudydemonstratedthattofacitinibinhibitedphosphorylationofJAK2andSTAT3inducedbyIL-23inperipheralbloodmononuclearcellsfromPsApatients,andhinderedproliferationofCD4+CD11+CD45RO+IL-17+Tcells(alsoknownasIL-17+effectormemorycells)inperipheralbloodmononuclearcellsandmononuclearsynovialfluidcellsfromPsApatients[7,11].ThesefindingssuggestalinkbetweenJAKinibsandtheIL-23/-17axisandthereforepartiallyexplaintheeffectivenessofthisdrugclassinPsAandSpAs.

在动物关节炎模型中，已发现JAKinibs依赖于细胞因子环境抑制Th17相关细胞因子（IL-17A、IL-17F、IL-22）的表达，从而阻断IL-23/-17轴[8]。体外研究表明，在PsA患者的滑液样本中，参与（或功能相关）JAK/STAT通路[JAK1，细胞外信号调节激酶（ERK）1/2，STAT1，STAT3，STAT5]的蛋白质增加[9]。来自PsA患者或PsA滑膜外植体的滑膜成纤维细胞与托法替布（第一代JAK3/1抑制剂，对JAK2和可能的TYK2活性较低）共培养导致参与该通路的磷蛋白表达减少，成纤维细胞形成网络和迁移的能力降低，减少炎性细胞因子和效应蛋白的分泌，如金属蛋白酶[10]。此外，最近发表的一项研究表明，托法替尼可抑制PsA患者外周血单个核细胞中IL-23诱导的JAK2和STAT3磷酸化，并且阻碍PsA患者外周血单个核细胞和单核滑液细胞中CD4CD11CD45ROIL-17T细胞（也称为IL-17效应记忆细胞）的增殖[7,11]。这些发现表明雅克宁与IL-23/-17轴之间存在联系，因此部分解释了该类药物在PsA和SPA中的有效性。

ArecentclinicalresearchprogrammeledtotheFoodandDrugAdministrationapprovingtofacitinibforPsA.Theresultsfromlargephase3trialshaverecentlybeenpublished.Insummary,aplaceboandadalimumabcontrolled,12-month,double-blindstudydemonstratedthattofacitinibindosesof5mgbd(twiceaday)or10mgbdwassuperiortoplaceboinactivePsApatientswhowerenon-responderstoconventionalDMARDs.Significantlymorepatientstreatedwithtofacitinibachievedtheprimaryendpoints[ACR20andchangesinHAQscore]atweek12,

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