重症肌无力英文版书-myasthenia gravis-lwx

Myastheniagravis

Obiectives

1.Tograsptheclinicalfeatures,diagnosisandtreatmentofmyastheniagravis(MG)

2.Tounderstandthepathogenesis,clinicalsubtypesofMGandsubtypeofmyastheniccrisisandtreatment.

3.ToknowthepathologicalchangeofMGandotherneuromuscularjunctiondiseases.

Keyconcepts

MGisadisorderoftheneuromusculartransmissionowingtoantibody-mediatedattackonacetylcholinereceptors(ACHR)oragainstthemuscle-specificreceptortyrosinekinase(MuSK)atneuromuscularjunctions.MuscleweaknessoccursInassociationwithcontinuouseffortandimprovementwithrestisanimportantfeatureofthedisease.Pharmacologictesting,electrophysiologicaltestingandtheconcentrationsofserumautoantibodiescanhelptoconfirmthediagnosis.TreatmentusedinpatientswithMGisindividualizedMyastheniccrisisisanexacerbationofmyasthenialeadingtoparalysisofrespiratorymusclesthatrequiresanurgentrespiratorysupport.

10.1.1Introduction

MyastheniaGravis(MG)isanacquiredautoimmunedisorderoftheneuromuscularjunction(NM))atthepostsynapticlevel.Thecauseofthedisorderisantibodiesdirectedattheacetylcholinereceptor(ACHR)oragainstthemuscle-specificreceptortyrosinekinase(MuSK).Theabnormalities(neoplasiaandhyperplasiaofthethymusgland)playapartroleinpatientswithanti-AChRantibodies.Themainclinicalmanifestationsarecharacterizedbyfluctuating,fatigableweaknessofmuscles,worseningbyphysicalexertionandimprovingbyrestandcholinesteraseinhibitors(CHEI)treatment.TheprevalencerateforMGisabout5to15/100,000.

10.1.2Pathogenesis

Transmittingelectricalimpulsefromthenerveterminaltotheunderlyingmusclecellsisthefunctionoftheneuromuscularjunction.Intheneuromuscularjunction,acetylcholine(Ach)issynthesizedinthemotornerveterminalandstoredinvesicles(quanta).Whenanactionpotentialtravelsdownamotornerveandreachesthenerveterminal.Achisreleasedfrom150to200vesicles,thenbindstoACHRofthepostsynapticmembrane,whereuponthecalciumchannelsinthereceptorstransientlyopen,generatinganendplatepotential.Ifthedepolarizationissufficientlylargeenough,itinitiatesanactionpotentialthatispropagated.

TheconditionofMGiscausedbysensitizedT-helpercellsandanimmunoglobulinantibodyG(IGG)-directedattackonthenicotinicacetylcholinereceptoroftheNMI.Avarietyofexperimentalstudiessupportthishypothesis:1.AcetylcholinereceptorantibodiesarepresentinmostpatientswithMG.2.AcetylcholinereceptorantibodiescanbetransferredpassivelytoanimalsproducingexperimentalautoimmuneMG.3.Removalofacetylcholinereceptorantibodiesleadstorecovery.4.Animalsimmunizedwithanacetylcholinereceptorbeginproducingacetylcholinereceptorantibodies,whichcanprovokeanautoimmunedisease(i,e.experimentalautoimmuneMG)closelyresemblingthenaturallyoccurringdisease.

InMG,bindingofantibodytotheACHRinitiatesautoimmuneattackontheendplateregion.Thenumberofacetylcholinereceptorsissubstantiallyreduced.Thereducednumberofacetylcholinereceptorsleadstodiminutionoftheendplatepotential,sothatnoactionpotentialscanbegeneratedintheaffectedfibers.Ifmanyfibersareaffected,themuscleisweak.Withrepeatedcontractionofamuscle,neuromusculartransmissionfailsataneverlargernumberofsynapses,andtheweaknessbecomesprogressivelymoresevere.

ThoughMGpatientswithantibodiestoMuskexhibitclinicalweaknessandelectrophysiologicfindingsthatarequitesimilartoMGpatientswithACHRantibodies,MUSKinitiatesaggregationofAChRsatthemuscleendplateduringdevelopmentbutthefunctionofMUSKinmatureskeletalmuscleandthepathophysiologyofMGrelatedtoMuskantibodiesarecurrentlyunknown.

Howtheantibodiesactatthereceptorsurfaceoftheendplateisnotentirelyclear.Neuromusculartransmissioncanbeimpairedinseveralways:1.TheantibodiesmayblockthebindingofAChtotheAChreceptors.2.SerumIgGfrommyasthenicpatientshasbeenshowntoinduceatwotothreefoldincreaseinthedegradationrateofAchreceptors.Thismaybetheresultofthecapacityofantibodiestocross-linkthereceptors,whicharegatheredintoclustersinthemusclemembrane,internalizedbyaprocessofendocytosis,anddegraded.3.Antibodiesmaycauseacomplement-mediateddestructionofthepostsynapticfolds.ThelattertwomechanismswouldbeexpectedtoreducethenumberofAchreceptorsatthesynapse.

MostpatientswithMGhavethymicabnormalitiesandapositiveresponsetothymectomy,soitislogicaltoimplicatethisglandinthepathogenesisofthedisease.BothTandBcellsfromthemyasthenicthymusareparticularlyresponsivetotheAchreceptor.Moreover,thethymuscontains"myoidcells”(resemblingstriatedmuscle)thatbearsurfaceAchreceptors.However,thethymicmyoidcellsareunlikelythefociofimmunologicstimulationinMG.Themostimportantreasonisthatsuchcellsareevenmoreabundantinthenormalthaninthemyasthenicthymus.

1.3Pathology

Thethymusgland:About80%ofpatientswithMGhavethymichyperplasia,lymphoidfollicularhyperplasiaandincreasedgerminalcenter.Approximately10%-20%ofMGpatientshaveathymoma.

Nerve-musclejunction:InMG,thefoldsoftheJunctionarereducedorabsent.Complements(C3,C9andthemembraneattackcomplex)andimmunecomplexcanbedemonstratedonthepost-synapticmembrane.

Musclefibers:FewabnormalitiesareseenInmusclebiopsies,includingatrophyoftype2fibers,andsometimesatrophyoftype1fibers,whichmaybeaccompaniedbythepresenceofsmalldarkangulatedfibres.Lymphorrhageshavebeenreportedin

myastheniagravis,theyarenotaconsistentfeature.

10.1.4ClinicalFeatures

AlthoughMGmayappearatanyage,ithasabimodalpeakofageatonset.Inwomen,theonsetusuallyoccursbetween20and40yearsofage;amongmen,theonsetisusuallyat40to60yearsofage.TheincidenceofMGisslightlygreaterinwomenthaninmen.Thedisorderischaracterizedbyfluctuatingfatigableweaknessofspecificmusclegroupsratherthanwithgeneralizedfatigue.Theweaknessisgenerallyworselaterinthedayandimproveswithrest.

Thedistributionofmuscleweaknessoftenhasacharacteristicpattern.Accordingly,theearliestmanifestationsofthediseaseareoftenptosis,diplopianasalspeech,dysphagia,andweaknessofneckextension.Therearealsopurelyocularformsofthedisease.Themusclesofthetrunkandlimbsgenerallydonotbecomeweakuntillater.Ptosisisthemostcommoninitialpresentationandmaybeunilateralorbilateral,whichbecomesworseafterrepeatedforcefulclosingandopeningoftheeyes.Unlikethirdcranialnervepalsies,MGneveraffectspupillaryfunction.Difficultyofchewing,speaking,orswallowingmayalsobetheinitialpresentation.SomepatientsmayhaveseverefatigabilityandweaknessduringmasticationMyasthenicweaknessoflaryngealmusclesisassociatedwithahoarse,breathyvoice.Examinationmayrevealreducedorabsentpalateelevation.Tongueweaknessmaybedemonstratedwhenthepatientattemptstoprotrudeeithercheekwiththetongueagainsttheresistanceoftheexaminer’sfingerappliedtothecheek.JawclosuremusclesarefrequentlyaffectedinMG,butstrengthisusuallynormalinjawopeningmuscles.Patientsmaycomplainofdifficultyinchewinghardfood.Weaknessofthelarynxandpharynxcausesdysphoniaanddysphagia,occurringinasmanyasonethirdofpatients.NeckflexorandextensormusclesareoftenweakinMG.

Myastheniccrisis:Myastheniccrisisisdefinedasanexacerbationofweaknesssufficienttoendangerlife;itusuallyconsistsofrespiratoryfailurecausedbydiaphragmaticandintercostalmuscleweakness.ThemostcommoncauseofcrisisisinfectionCrisisrarelyoccursinproperlymanagedpatients.Thepossibilitythatthedeteriorationcouldbeduetoexcessiveanticholinesterasemedication("cholinergiccrisis")isbestexcludedbytemporarilystoppinganticholinesterasedrugs.Thisshouldbetreatedimmediately,becausethemechanicalandimmunologicdefensesofthepatientcanbeassumedtobecompromised.Ifthelimbmusclesareinvolved,theproximalmusclesareusuallymoreseverelyaffectedthanthedistalones.Cholinesteraseinhibitorsofthetreatmentiseffective.thisisanothercharacteristicofMG.

Thecourseoftheillness.Thesignsandsymptomscanfluctuateinseverityfromdaytoday,fromweektoweek,andoverlongertimes.Intypicaluntreatedcases,themanifestationsofdiseasegraduallyspreadfromtheeyestothefacialandbulbarmusclesandthentothetrunkandlimbs.Thefirstmanifestationofthediseaseisintheeyesinhalfofallcasesandtheeyesareeventuallyinvolvedinmorethan90%.Generalizationofmanifestationspracticallyalwaysoccurswithin3yearsofonset.In16%ofuntreatedcases,however,thediseasemanifestationsremainpermanentlyconfinedtotheextraocularmuscles.

ClinicalSubtype

AdultpatientswithMGcanbeclassifiedaccordingtotheOsserman'sclassification.

Thisscaledividescasesofmyastheniaintofivevarieties,oneofwhichhastwosubtypes:

I:Ocularmyasthenia(15%-20%)-myastheniaconfinedtotheeyes.

IIa:Mildgeneralizedmyastheniawithslowprogression(30%).Nocrisis.Drugresponsive.

IIb:Moderatelysevereformofgeneralizedmyasthenia(20%-25%).Themusclesofrespirationarenotaffected.Skeletalandbulbarmusclesareinvolvedbutnocrisis,drugresponselessthansatisfactory.

Ill：Acuteandrapidlyprogressivemyasthenia(15%6).Abruptonsetandprogression,withinvolvementofthemusclesofrespirationwithin6monthsofonset.Respiratorycrisisandpoordrugresponse.

IV:Chronic,severemyasthenia(10%).ProgressionfromgroupsIorIIafterarelativelystablecourselasting2years.PatientsingroupsIllandIVmoreoftenhaveathymomathanthoseingroupsorII,andsufferahighermortality.

V:Muscleatrophy(notduetodisuse)inlategeneralizeddisease,restrictedtoskeletalmusclesandusuallyrelatedtothedurationofthediseaseanclinicalseverity(myasthenicmyopathy).

Neonatalmyastheniagravis

Neonatalmyastheniagravisresultsfrompassivetransferofmaternalanti-AChRantibodiesandisself-limiting.15ofbabiesborntomyasthenicmothershowsignsofmyasthenia(hypotonia,weakcryandsuck).Thisisatransitoryphenomenonwithshortdurationandrecoverisusuallycompletewithin2monthsofbirth,withoutlaterrelapse.

Congenitalmyasthenicsyndrome

theonsetmaybecongenitalorinearlyadulthood.Theaffectedinfantshadbeenborntonon-myasthenicmothers.

10.1.5AncillaryTests

(1)Repetitivenervestimulation(RNS)

RNSperform1,3or5-HZrepetitivestimulationwiththepatientatrest.Normally,thereshouldbelessthana10%decrementfromthebaselinevalueAcetylcholinesteraseinhibitorsshouldnotbetakenforatleast12hourspriortotesting.Ingeneralproximalmusclesincludingfacialmuscles,deltoid,andbicepsbrachiiaremorelikelytoexhibitabnormalfindings.RNSstudiesmaydemonstrateimpairedneuromusculartransmission,buttheyarerelativelyinsensitiveinocularandinmildgeneralizedMG.

(2)Singlefiberelectromyography(SFEMG)

SFEMGisanevenmoresensitivetest.Inmyastheniagravis,thistestrevealsincreasedjitterandmorefrequentblockades.Ifanormaljitterisfoundinaclinicallyweakmuscle,thereasonofweaknessinthatmuscleisnotfromMG.

(3)ThetestingofAchR-Abtiters

It'sthemostsensitiveandspecifictestforMG.PositiveantibodystudiesconfirmMGinapatientwithappropriatesymptomsandclinicalfindings.ACHRbindingantibodiesarepresentinapproximately80%-90%ofpatientswithgeneralizedMGbutinonly55%ofpatientswithocularMG.Thedegreeof"positivityforthetestresultsdoesnotcorrelatewiththeseverityofdisease.MUSKantibodiestoMUSKhavebeendemonstratedinaboutonethirdofpatientswithgeneralizedAchr-abnegtiveMG.Ryanodineantibodiesareassociatedwithlate-onsetMG.Patientswithryanodineantibodiesmayexhibitsevere,treatment-resistantMGassociatedwithmalignantthymomas.

(4)Othertestings

ChestCTshouldbeperformedtodemonstrateorruleoutathymoma/thymichyperplasia.SinceMGoftencoexistswithotherautoimmunedisorders,particularlyautoimmunethyroiddisease,patientsshouldundergothyroidfunctiontestingalong

withtestingforotherautoimmunedisorderswhenclinicallyappropriate.

10.1.6DiagnosisandDifferentialDiagnosis

TherearenowidelyacceptedformaldiagnosticcriteriaforMGpatients.Themostimportantelementsofdiagnosisareclinicalhistoryandexaminationfindingsoffluctuatingandfatigableweakness,particularlyinvolvingextraocularandbulbarmuscles.ThelaboratoryteststhatareavailabletoconfirmtheclinicaldiagnosisofMGincludepharmacologictesting,electrophysiologicaltestingandteststomeasuretheconcentrationsofserumautoantibodies.NeostigminecanelicitsunequivocalImprovementinstrength.RNSstudiesand/orSFEMGdemonstrateaprimarypostsynapticneuromuscularjunctionaldisorder.AchR-AbtitersarethemostsensitiveandspecifictestforMG,approximately90%ofpatientswithgeneralizedMGhavepositiveantibodies.

Differentialdiagnosisincludes:

lambert-eatonmyasthenicsyndrome(LEMS)

LEMSisthesecondmostcommonNMdisorderfollowingMG.Itisanacquiredautoimmunediseaseinwhichpathogenicautoantibodiescauseadeficiencyofvoltage-sensitivecalciumchannelsatthemotornerveterminal.Thedeficiencyrestrictscalciumingresswhentheterminalisdepolarizedbynerveimpulsesandtherebyreducestheprobabilityofquantalrelease.Usually,LEMSisassociatedwitha

smallcellcarcinomaofthelung.Thesyndromemaypredatedetectionofthetumorbyupto3years.Patientshaveweaknessandfatigabilityofproximallimbandtorsomuscleswithrelativesparingofextraocularandbulbarmuscles.Thelowerlimbsare

moreseverelyinvolvedthantheupperlimbs.Onmaximalvoluntarycontraction,theforceproducedbyaweakmuscleincreasesforafewsecondsandthenagaindecreases.Cranialnervefindings,includingptosisoftheeyelidsanddiplopia,occurinupto70%ofpatientsandresemblefeaturesofMG.However,thetwoconditionsarereadilydistinguishedsincepatientswithLEMShavedepressedorabsentreflexes,showautonomicchangesandincrementalratherthandecrementalresponsesonrepetitivenervestimulation.Autonomicmanifestations(drymouth,impotence,decreasedsweating,orthostatichypotension,oralteredpupillaryreflexes)occurinabout50%ofpatients.Repetitivestimulationat2Hzinducesafurtherdecrement,butstimulationatfrequencieshigherthan10Hz.

(2)Botulism

Botulismisasevereneuroparalyticdiseasecausedbybotulinumtoxinproducedbyclostridialspecies.ThenetaffectofbotulinusneurotoxinintoxicationistheinhibitionofreleaseofACHRvesicles.Cranialnerveevaluationrevealsptosis,diminishedgagreflex,dysphagia,dysarthria,andweaknessoftheface,jawopeningandclosing,andtongue.Thepupilsareoftendilated,andrepetitivenervestimulationgivesanincrementalresponse.Theupperandlowerlimbsmaybeinvolvedtovaryingdegrees.TheupperlimbsaretypicallymoreaffectedthanthelowerlimbswithanoccasionalasymmetrynotedBotulismshouldbesuspectedinpatientswithacuteflaccidparalysis,especiallyinthepresenceofbilateralsixthcranialnervedysfunction,associatedneurologicfindings,recentingestionofpossiblycontaminatedfood,and/ortypicalsymptomsinotherpersonswhosharedthisfood.

(3)Exophthalmicophthalmoplegia

AsimilarsituationexistsinthisconditionWeaknessmaybeduetothyrotoxicmyopathyorfattyinfiltrationoftheorbitandextraocularmuscles.Neithertypeshowsanyresponsetoneostigmine.Patientswhoshowpartialimprovementprobablyhave

associatedMG.

(4)Hyperthyroidism

Itisreadilydiagnosedorexcludedbytestingthethyroidfunction,whichshouldbecarriedoutroutinelyinpatientswithsuspectedMG.Abnormalitiesofthyroidfunction(hyper-orhypothyroidism)mayIncreasemyasthenicweakness.

10.1.7Treatment

TreatmentmustbeindividualizedtoeachpatientwithMGaccordingtoclinicalpresentationorsub-type.Thetherapeuticgoalistorestorethenormalfunctionasrapidlyaspossiblewhileminimizingtheside-effectsoftherapy.Therearevarioustreatmentstrategiescommonlyusedfortreatmentofmyastheniagravis:acetylcholinesteraseinhibitors,plasmaexchange(PE),intravenousimmunoglobulintherapy(IVIG),thymectomy,corticosteroidsandotherimmunosuppressive/immunomodulatingagents.

(1)Acetylcholinesteraseinhibitors

AcetylcholinesteraseinhibitorsslowthehydrolysisofacetylcholineattheneuromuscularjunctionandprovidetemporaryimprovementofstrengthinmanypatientswithMG.Thisclassofmedicationremainsthefirstlineoftherapyinsymptomaticpatients.Themostcommonagentusedispyridostigminebromide.AcetylcholinesteraseinhibitorsareasymptomatictherapyforMGanddonotretardtheunderlyingautoimmuneattackontheneuromuscularjunction.IntreatingMG,therolesofacetylcholineteraseinhibitorsincludetreatmentofocularandmildgeneralizeddisease,treatmentinpatientswhocannotreceiveimmunesuppression,andadjunctivetreatmentforpatientsreceivingimmunotherapywithresidualorrefractorymyasthenicweakness.Thestartingdoseofpyridostigmineinadultsis30to60mgevery6hours.MostPatientsrequire60to120mgevery4to6hours.Thesideeffectsincludenauseavomiting,abdominalcramping,diarrhea,increasedoralandbronchialsecretions,bradycardia,andrarely,confusionorpsychosis,Anticholinergicshouldbeusedinpatientswithsignificantsideeffects.

(2)Plasmaexchange(PE)

PEisaneffectivemeansoftherapybutistransientinitsresponse.Thistechniqueisparticularlyusefulwhentreatingpatientsinmyasthenicexacerbationsorthoseinpreparationforsurgery.Plasma,whichcontainsthepathogenicantibodies,ismechanicallyseparatedfromthebloodcells,whicharereturnedtothepatient.PEtemporarilyreducestheconcentrationsofcirculatinganti-AChRantibodiesandproducesimprovementinamatterofdaysinmostpatientswithacquiredMG.Thetypicalcourseinvolvesexchangeof2to3Lofplasmathreetimesaweekuntilstrengthissigniticantlyimproved(atleastfivetosixtotalexchanges).Improvementisnoticeableaftertwotofourexchanges.PElowerstheserumconcentrationofanti-achrantibodies,butitmustberepeatedatrelativelyregularintervalsduetoitslimiteddurationofeffect.WithinaweekfollowingPE,theautoantibodiesbegintorebound.Thereforepatientswillneedtobealsostartedonanimmunosuppressiveagent.

(3)Intravenousimmunoglobulintherapy(IVIG)

IVIGhasbeenusedforthesameindicationsasplasmaexchange;rapidlyprogressivedisease,preparationofweakpatientsforsurgeryincludingthymectomy,andasanadjuvanttominimizelongtermside-effectsoforalimmunosuppressivetherapy.Theexactmechanismisnotwellunderstood.Intravenousimmunoglobulinisgivenasadoseof0.4g/(kg.d)for5daysandrepeatinfusionsatmonthlyintervalsforatleast3times.Thereaftertreatmentisindividualized.Somepatientsmayneedtreatment(0.4-2g/kg)everyweek,whileothersmaygoseveralmonthsbetweenIVIGcourses.IVIGisarelativelysafetreatmentmethodandhasfewadverseeffects,thoughheadache,chills,andfeverhavebeenreportedinsomepatients.Otherrareadverseeventsincludeasepticmeningitisandrenalfailure.

(4)Thymectomy

Nearly65%ofyoungpatientsACHR-MG,willhavethymichyperplasiaandabout15%ofallpatientsmayhavethymoma.Thymectomyisalwaysrecommendedinpatientswiththymoma.Mostexpertsalsoconsiderthymectomytobeatherapeutic

optioninanti-achr-positive,generalizedMGwithdiseaseonsetbeforetheageof50

Years.Becauseofincreasedsurgicalriskandreducedlifespan,thymectomyisrarelyperformedinpatientsatgreaterthanage60yearsfornon-thymomatousMG.Clinicalimprovementistypicallydelayedby6monthsto1yearaftersurgery.Theadvantageofthymectomyisthatitoffersthepossibilityoflong-termbenefit,insomecasesdiminishingoreliminatingtheneedforcontinuingmedicaltreatment.

(5)Corticosteroids

Asageneralrule,mostpatientswithMGrequiresteroidtherapyatsomepointduringtreatment.CorticosteroidsareoftenusedastheinitialimmunotherapyinpatientswithocularandgeneralizedMG,particularlyinpatientswithunsatisfactoryresponsestoacetylcholinesteraseinhibitors.TherearetwotreatmentstrategiesgenerallyusedwhenusingprednisoneinpatientswithMG:1.Aggressivehighdosedailysteroidsattheonsetoftreatmentapproach.2.Astartlowandgoslowapproach.

Themostreliableclinicalresponsestocorticosteroidsoccurwithahigh-dosedailyregimenthatisgraduallytaperedbasedonclinicalimprovementinstrength.Theinitialprednisonedoseistypically60-80mg/dor1.5-2.0mg/(kg.d),andthengraduallytaperedofforcontinuedatlowdosesformanyyears.Approximatelyathirdofpatientshaveatemporaryexacerbationafterstartingprednisone;thisusuallybeginswithinthefirst7-10dayswithhighprednisonedosesandlastsforseveraldays.Therefore,respiratoryfunctionshouldbecloselymonitored.

Thisinitialdoseismaintainedfortwotofourweeks,andstrengthisreassessed.Myasthenicrelapsesmaybedelayedforthreeweeksafterreductionsincorticosteroiddosing,andrapidtaperingmayprecipitatemyasthenicexacerbationsorcrises,Therefore,corticosteroidtaperingmustbeslow,judicious,andprecededbyclinicalreassessmentofstrength.Patientsarereassessedatfourtoeightweekintervals,andiftheyhavemaintainedorimprovedstrengthandnorecurrentsymptoms,theprednisonedoseistaperedby5mgevery2to3weeksdownto20mgeveryotherday.Subsequentprednisonedoseshouldbetaperedoverlongerinterval.

Theadverseeffectsofcorticosteroidsarenumerous,andusuallydose-dependent.Theseincludehypertension,fluidretention,weightgain,potassiumloss,hyperlipidemia,diabetesmellitus,osteoporosis,gastriculceration,cataracts,leucoma,moonfacies,obesity,acne,skinfriability,juvenilegrowthsuppression,andmood/personalitychanges.Individualsatparticularriskforsideeffectsincludethosewhoarediabeticorglucoseintolerant,obese,hypertensive,osteoporoticorpost-menopausal,andthosewithaffectiveorthoughtdisorders.

“Astartlowandgoslowapproach":Thedrugisusuallystartedat5mgdailyandmaybeincreasedby5mgevery4to7daysuntilaclinicalbenefitisachievedor1mg/kgisreached.Oncethepatientsconditionisstabilized,thedosagemaybeslowlytapereddownwardby5mgeverymonth.Ingeneralprednisoneshouldbecontinuedforatleastlor2years,thoughmanypatientsrequireitforalongertime,orevenforlifetime.

(6)Otherimmunosuppressive/immunomodulatingagents

1)Azathioprine

Azathioprinehasbeenthemostwidelyusedofthesedrugsbecauseofitsrelativesafetyinmostpatientsandlongtrackrecord.Itallowstaperingofsteroiddosageandreducessomeoftheadverseeffectsofsteroidtherapy.Commonly,thepatientwillnothaveclinicalbenefitfromazathioprineforabout4to6monthsandsometimeslonger.Thetypicalstartingdoseofazathioprineis50mgdailyforthefirstweek(testdose),andthenthedoseistitrateduptoamaximumof2to3mg/(kg.d)intwoorthreedivideddoses.Azathioprinecanbeusedaloneorasasteroid-sparingagentinMG,butwhenusedincombinationwithprednisoneitmightbemoreeffectiveandbettertoleratedthanprednisonealone.Hepatotoxicityandleukopeniaareimportantadverseeffects,butarereversibleifdetectedearlyandthedoseofazathioprineisreducedordiscontinued.So,completebloodcountsandliverfunctiontestsshouldbemonitoredeveryweekuntilthepatientisonastabledoseofazathioprine,thenevery3months.

2)Cyclophosphamide

Ingeneral,cyclophosphamideisusedonlywhenotheragentshavefailedorarenotwelltoleratedbythepatient.Cyclophosphamidetherapymaybestartedat25mgdailyandgraduallyincreaseduptoamaximumofapproximately2to5mg/(kg.d).An

increasedincidenceofhemorrhagiccystitisaccompaniestheuseofthismedicationinsomepatients.

3)Cyclosporine

ApowerfulimmunosuppressantthatinhibitsT-cellactivationiscyclosporine,Ciclosporinisusedmainlyinpatientsinwhomazathioprineiseitherineffectiveornottolerated.Therecommendedinitialdailydoseofciclosporinis4-6mg/kgintwodivideddoses,butmaintenancedailydosesof3-4mg/kgorlessareoftenadequatetomaintaintheeffect.Sideeffectsarecommonandincludehirsutism,tremorgumhyperplasia,andanaemi