Utilityofhydroxyureainmastcellactivation syndrome LawrenceBAfrin Abstract MastcellactivationsyndromeMCASisarelativelyrecentlyrecognizedcauseofchronicmultisystempolymorbidity ofagenerallyinflammatory ID: 942664
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CASEREPORTOpenAccess Utilityofhydroxyureainmastcellactivation syndrome LawrenceBAfrin Abstract Mastcellactivationsyndrome(MCAS)isarelativelyrecentlyrecognizedcauseofchronicmultisystempolymorbidity ofagenerallyinflammatorytheme.PatientswithMCASoftenreportmigratorysofttissueand/orbonepainwhich frequentlyrespondspoorlytotypical(narcoticandnon-narcotic)analgesicsaswellasatypicalanalgesicssuchas antidepressantsandanticonvulsants.Hydroxyurea(HU)isanoralribonucleotidereductaseinhibitorcommonlyused inthetreatmentofchronicmyeloproliferativeneoplasmsandsicklecellanemia.HUhasbeenusedtotreat systemicmastocytosis,sometimeseffectingimprovementinMCactivationsymptomsbutnottumorburden, suggestingpotentialutilityofthedruginMCAS,too.Reportedherearefivecasesofsuccessfuluseofrelatively low-doseHUinMCAStoreducesymptomsincludingpreviouslyrefractorysofttissueand/orbonepain.HUmaybe usefulintreatingmediatorsymptomsinMCAS,butfurtherstudyisneededtodefineoptimaldosingstrategiesand Keywords: Mastcellactivationdisease,Mastcellactivationsyndrome,KITmutations,Pain,Hydroxyurea Introduction Mastcellactivationsyndrome(MCAS,amoreprevalent butonlyrecentlyrecognizedcousinoftherare,prolifer- ativemastcell(MC)diseasemastocytosis)typically causeschronicmultisystempolymorbidityofagenerally inflammatorytheme[1].TheMCactivationseenin eithermastocytosisorrelativelynon-proliferativeMCAS oftenresultsinmigratorysofttissueand/orbonepain whichfrequentlyrespondspoorlytotypical(narcotic andnon-narcotic)analgesicsaswellasatypicalanalge- sicssuchasantidepressantsandanticonvulsants. Hydroxyurea(HU)isanoralribonucleotidereductase inhibitorwithantimetabolicandantineoplasticproper- ties[2].Firstusedclinicallyinthe1960sforchronicmy- eloproliferativeneoplasms(MPNs)[3],HUwasshown toraisefetalhemoglobin(HbF, 2 2 )levelsinsicklecell disease(SCD)in1985[4],anditisnowapparentthatthe requisiteincreasein -globinexpressionoccursviamul- cytotoxicityleadingto stresserythropoiesis withincrea- sedHbFlevels,nitricoxideproduction,andthesoluble guanylylcyclaseandcGMP-dependentproteinkinase pathway[2].Continuedclinicalresearchculminatedina Phase3double-blindrandomizedcontrolledtrialpub- lishedin1995[5]clearlyestablishingtheutilityofthe druginreducingtheseverityofsicklecellanemia(SCA). Italsoinhibitsreplicationofhumanimmunodeficiency virus-1(HIV-1)[6]andhasbeenusedincyanoticcon- genitalheartdisease[7].TheefficacyofHUforthese variedclinicalconditionsappearstobedue,atamini- mum,toitspotentinhibitionofribonucleotidereductase, aubiquitousintracellularenzymethatconvertsribonu- DNAsynthesisandrepair[8]. Althoughconcernshavebeenexpressedforpotential tumorigenicity(especiallyleukemogenicity)ofHUinthe treatmentofMPNs,analysisoftheseconcernshasbeen confoundedbytheinherentleukemogenicityofthese diseases.Morerecentretrospectiveandprospectiveana- lysesoflong-termhydroxyureauseintheMPNshave beenmorereassuringregardingthedrug spreviously allegedpotentialforfomentingmalignanttransformation [9-11].Inthenon-malignantsettingofSCD,too,data onthesafetyoflong-termHUusehavebeensimilarly reassuring[12-16]. HUhasbeenusedinthetreatmentofmastocytosis, too,andhasbeenassociatedwithreductionsinMCload Correspondence: afrinl@musc.edu DivisionofHematology/Oncology,MedicalUniversityofSouthCarolina, Charleston,SouthCarolina,USA Experimental Hematology & Oncology ©2013Afrin;licenseeBioMedCentralLtd.ThisisanOpenAccessarticledistributedunderthetermsoftheCreative CommonsAttributionLicense(http://creativecommons.org/licenses/by/2.0),whichpermitsunrestricteduse,distribution,and reproductioninanymedium,providedtheoriginalworkisproperlycited.TheCreativeCommonsPublicDomainDedication waiver(http://creativecommons.org/publicdomain/zero/1.0/)appliestothedatamadeavailableinthisarticle,unlessotherwise stated. Afrin ExperimentalHematology&Oncology 2013, 2 :28 http://www.ehoonline.org/content/2/1/28 brought to you by CORE View metadata, citation and similar papers at core.ac.uk provided by Springer - Publisher Connector andsymptoms[17]aswellasreductionsinsymptomswithoutclearreductioninMCload(e.g.,malaiseandpruritus[18];progressivedecreaseinclinicalsymptomsandtheneedforintensiveantimediatortherapy[19];weightloss,severenightsweats,abdominalpain,andpruritus[20];facialflushingandbonepain[21];andpruritus,flushing,ascites,andhepatosplenomegaly[22]).ThesereportssuggestHUmightbeabletomodulateMCmediatorexpressioninsomepatientsindependentofitsanti-proliferativeeffects.ReportedherearefivecasesofsuccessfuluseofHUinMCAStoreducesymptoms.EachpatientwasdiagnosedwithMCASafterpriorextensiveevaluationsfailedtofindanyevidentdiseasebetterexplainingthefullrangeoffindingsinthecaseanduponfindingsymptoms,physicalexamfindings,andlaboratoryevidenceconsist-entwithchronicaberrantMCmediatorexpression[1].Allf
ivepatientsrespondedtoassortedsetsofMCAS-directedtherapies.Ofnote,inallfivepatientsmodestdosesofHUpromptly,markedlyreducedtheirdiffuseaching,thoughcytopeniasrequiredstoppingthedruginonepatient,andreactionstooneformulationofthedruginanotherthreepatientsrequiredtrialsofanalternativeformulation.Case1A55yearoldwhitemaleairlinepilotwasreferredinJune2009forfurtherevaluationofnon-palpablespleno-megalydiscoveredintheevaluationofchronic,waxing/waningnauseaandleft-sidedabdominalpain,non-bloodyemesis,earlysatiety,andmildweightlossthathademergedinthewakeofanepisodeofallegedfoodpoisoningin2005.Hisflightprivilegeswererevokedupondiscoveryofthesplenomegaly,andhetookapart-timeretailsalesposition.Pasthistorywasnotableforpersistentproblemswithepisodicdiffuselymigratorymusculoskeletalpaincomplaintssinceunexplainedleftshoulderbursitisatage9;repeatedevaluationsoftheseepisodeswerenon-diagnostic.Inadditiontohisgastro-intestinal/abdominalsymptoms,reviewofsystemsalsorevealedasenseoffrequentvariationinbodytempera-ture,sometimesevenwithmildrigors;neardailynightsweats;episodicdiffuselymigratoryedema;pruriticerythematousrashabouttheinferiorneck;occasionalacutespellsofseverediffusepruritus;waxing/waningdysgeusiaanddysosmia;chronictinnitus;chronicfatiguetothepointofinabilitytogetoutofbedonsomemornings;unpredictable/unprovokedacute-onsetepisodeseveryfewdaystoeveryfewweeksoflight-headednessandflushing;frequentpalpitations;chro-nicallyirritatedeyes;markedgastroesophagealreflux(intolerantofesomeprazolebutimprovedwithrani-tidine);chronicbackpainanddiffuselymigratorypolyarthritis;alternatingdiarrheaandconstipation;poorhealing;andoccasionaldiffuselymigratorytin-gling/numbnessparesthesias.Examinationwasnotableonlyfortendernesstopalpa-tionacrosstheupperabdomen(worstintheepigas-trium)andtheabove-notedneckrashbutwithoutpruriticbehaviors.Smallcherryangiomataweresparselyscatteredabouthisskin.Moderatedermatographismwasnoted.Serumtryptasewasnormal.UponfindinganelevatedurinaryprostaglandinD)levelduringanplusincreased(butnon-aggregated,non-spindled)MCsbybrightCD117immunohistochemicalstaininginmul-tiplegastrointestinal(GI)tractmucosalbiopsies,MCASwasdiagnosed.Hegainedincrementalimprovementwithloratadineandfamotidineandthenaspirin,thenquicklyprovedintolerantofserialtrialsofclonazepam,lorazepam,doxepin,quercetin,ketotifen,cromolyn,montelukast,andlow-doseimatinib(200mgdaily),andthengainedfurtherimprovementwithlow-dosedasa-tinibat40mgdaily.Waxing/waning,diffuselymigra-torysofttissueandbonepain(typically7/10orworse)persistedwithoutimprovement,oftenwasdisabling,andprovedrefractorytoawidevarietyofanalgesicsprescribedbyhislocalphysicians.Hydrea-brandHUwasbeguninDecember2011,initiallyat500mgdaily,escalatingweekly.HereturnedinFebruary2012,havingreachedtheprescribedtargetdoseof1500mgdaily.Hereportedthedrughadinitiallyworsenedhisnausea,abdominaldis-comfort,diarrhea,headache,andmalaise,butafteraweekthesesymptomscompletelyresolvedandhisdif-fusesofttissuepaincompletelyresolved,too.Hewasabletostopaspirinandotheroccasionaluseofnon-steroidalanti-inflammatorydrugs(NSAIDs).Twoweekslaterhereportednewdyspnea.Thoroughcardiopulmonaryevaluationwasunrevealing.Dasatinibwasstopped.InMarch2012softtissuepainmildlyrelapsed,andHUhadtobereducedto500mgdailyduetoexcessivecytopenias.Fatigue,bonepain,headaches,palpitations,anddiarrheaquicklyrelapsed,buttherewasinsufficientimprovementincytopeniasandthedrugwasfullystoppedinApril2012.Dasatinibwasrestartedat40mgdaily.Twoweekslaterhereportedmoderateimprove-mentinmanysymptoms,butsoft-tissueandbonepaincontinued.ByAugust2012hewashavingsomuchtroubleattendingtohisworkduetohispainthathewasconsideringapplyingfordisability.Droxia-brandHUwastriedat200mgdaily,butitseemedtopersist-entlyexacerbatehisleftupperquadrantabdominalpainandwasstoppedafteramonth.Atrialoflorazepamcompoundedwithbabyricecerealprovedhelpfulforhissofttissueandbonepain.AsofAugust2013hewaswellmostofthetimeandcontrollingExperimentalHematology&OncologyPage2of8http://www.ehoonline.org/content/2/1/28 occasionalflareswithextraantihistaminesandlorazepam.Hewasattendingwelltohispart-timejobandwasreapplyingforflightprivileges.Case2A29yearolddisabledmalemanufacturingsupervisorpresentedinAugust2010forfurtherevaluationofawidespectrumofchronicidiopathicproblemsdomi-natedbydiffuselymigratorysoft-tissuepain.Otherthanneonatalpulmonicvalverepairandanumberofacci-dentaltraumasinchildhood,hisearlymedicalhistorywasunrevealing,butatage14migraineheadacheswithattendantcognitivedysfunction(brainfog)suddenlydevelopedandhadpersisted,waxingandwaning,eversince.Theheadacheshadoftenbeenattributedtochronicsinusitis,butthemanysinusitistreatmentshehadtriedhadbeenuniformlyunhelpful.Byage17hewassleepingthroughmanyclassesbecauseclassroomlightssometimestriggeredheadacheflares.Hesufferedf
ourmoremajoraccidentaltraumasatages1718,oncerequiringresuscitation.Heworkedforadecadeafterfinishinghighschoolbuthadbeenunemployedsinceage28duetochronicrightshoulderandbackpainaris-ingfromawork-relatedaccident.Healsonotedmarkedbilaterallowerextremitypainhademergedinthemonthsaftertheaccidentandwasalsoattributedtothisaccident,althoughtheonlyfindingonalumbosacralmagneticresonanceimaging(MRI)scanwasoldrightS1pedicletrauma.Hischiefcomplaintwasdiffuselymigratorypain,worstinthelegsasacrampy,achythrobbing.Lorazepamandclonazepamtendedtohelphispainnoticeablymorethantraditionalanalgesics,buthisphysicianswerereluctanttoregularlyprescribebenzodiazepines.Onreviewofsystemhealsonotedseveregastroesoph-agealrefluxforthepriordecade,withfrequentnon-bloodypost-prandialemesis.Esomeprazolehelpedonlymodestly.Spicyfoodsreliablytriggeredthereflux.Bidir-ectionalendoscopyin2004toinvestigateanunrepeatedepisodeofrectalbleedingwasnon-diagnostic.Episodicmigratoryswellingofhisbilateralfeet,ankles,andhandswasalsonoted.Otherproblemsincludedmanyyearsofintermittentsubjectiveandobjectiveidiopathicfevers,frequentnightsweats,occasionalchills,episodicdif-fuselymigratorypruritus,eyeandthroatirritation,intra-nasalsores,deterioratingdentition,proximaldysphagia,waxing/waningdyspnea,palpitations,panicattacks,presyncope,syncope,diarrheaalternatingwithconsti-pation,tinnitus,insomnia,poorhealing,anddiffuselymigratorytingling/numbnessparesthesias.Extensiveevaluationsbyavarietyofspecialistshadbeenunreveal-ing.Hedeniedmedicationallergies.Pastmedicalhistoryincludedhypertension.Hehadnotusedillegalsub-stancessinceadolescence.Examwasnotableforfatigue,cane-assistedambu-lation,andobviouswholebodydiscomfortwithanymotion.Hisskinwasdiffuselyfreckled.Thereweresmalllipomasscatteredabouthisbodywhichhenotedhadbeenprogressinginnumberforseveralyears.Therewasdiffusemildabdominaltendernesstodeeppalpationand4/5strengthinalldistalextremities;reflexeswereintact.Moderatedermatographismwasnoted.Heappeareddiffuselyinflamed,butnospecificinflam-matoryailmenthadbeenidentifiedinyearsofevaluation.Normalbonedensitometrywasnoted.Porphyrinscreen-ingwasnegative.Serumtryptasewasnormal.Inadditiontomildrelativeeosinophilia,elevationsinplasmaPGDandhistaminewerefound.MCASwasdiagnosed.Lo-ratadineandfamotidineimmediatelyprovidedmajorimprovementsinreflux,dyspnea,fevers,pruritus,andeyeandnasalirritation.Aone-monthtrialofcelecoxibwasmoderatelyhelpfulforpain,butaccesstothedrugcouldnotbemaintained.Serialtrialsofmontelukastandazathi-oprineprovidednoadditionalbenefit;trialsofdoxepinandlow-doseimatinibquicklyprovedintolerable.Loraze-pamprovedhelpfultovaryingdegreesforsleep,malaise,anxietyandpanicattacks,fevers,sweats,andpalpitationsbutonlymildlyhelpfulforhisdiffusepain.InAugust2012HUwasbegunat500mgdaily.Forhisfirstfour-weeksupply,hispharmacistprovidedhimtwo-weeksuppliesofformulationsfromPARandBarr.InthefirsttwoweeksusingtheBarrformulation,hislegpainwassignificantlyimproved,butthreedaysafterswitchingtothePARformulation,allofhissymptomsmarkedlyworsened.Emergencyroomevaluationwasunrevealing.HestoppedHUandsoonreturnedtohispriorbaseline.HUwasthentriedagainwithDroxia200mgcapsules,whichimmediatelyreducedhisdiffusepainfromapersistent10/10atbaselinetoasustained6/10.Nofurtherimprovementwasseenat200mgtwicedailydosing,butat400mgtwicedailydosing,painwassubstantiallyfurtherreducedto3/10.Therewasnohematologictoxicity.AsofJuly2013hereportedfeelingcomfortableanddidnotneedfurtheradjustmentstohisregimen.Case3InFebruary2011a55yearolddisabledmalebusiness-manwasreferredforfurtherevaluationofanemiaandthrombocytopenia.Hereportedalifelonghistoryofmultisystempolymorbidityofagenerallyinflammatorytheme,includingfrequentupperandlowerrespiratorytractinfectionsandlotsofdiarrheaeversinceinfancy.Hisparentswereoftenupsetwithhimabouthisillnessesandoftensuspectedtheywerefactitious.Healsohadbeenafflictedsincehis20sbychronicdiffuselymigra-toryboneandjointandbackpains.Chronicheadachesandfatigueemergedinhis30s,andbyhismid-40sExperimentalHematology&OncologyPage3of8http://www.ehoonline.org/content/2/1/28 severegastroesophogealrefluxhademergedthatprovedrefractorytoaggressivemedicalandsurgicaltherapies.Onreviewofsystemsheendorsedfevers,chills,soakingsweats,diffuselymigratorypruritus,spontaneousbruis-ing,irritationofhiseyes/nose/mouth/throat,hoarseness,coughoccasionallyproductiveofclearorcoloredsputum,dyspnea,chestpainrequiringfrequentemergencyroomevaluationswhichwerealwaysunrevealing,palpitations,proximaldysphagia,nausea,bloodyandnon-bloodyvomiting,alternatingdiarrheaandconstipation,urinaryhesitancyandfrequency,dysuria,diffuselymigratorymacularerythematousrash,diffuselymigratorytingling/numbnessparesthesias,diffuselymigratoryedema,poorhealing,cognitivedysfunction,depression,presyncope,syncope,andpanicattack
s.Inspiteofalloftheseprob-lemshehadrunabusinessformanyyearsbeforeprogres-siveailmentdisabledhimatage50.Pastmedicalhistoryincludedhypertension,hyperlipidemia,andpulmonarysarcoidosisin87treatedwitharightupperlobectomy;hehadbeendealingwithalow-gradeMycobacteriumaviumintracellulareinfectioneversinceandhadbeenalternatelytoldthatpossiblythisorchronicaspirationmightbecausingmanyofhisproblems.Thefamilyhistorywasrifewasassortedcancers.Hisonlyknownmedicationallergywasapenicillin-inducedrash.Examwasnotableforachronicallyill,mildlydiapho-reticgeneralappearance,diffuselyachymovement,andmildtendernesstopalpationacrosstheupperabdomen.Strongdermatographismwasnoted.Hehadhadamildnormocyticanemiaandmildthrombocytopeniaforonlytheprioryear;leukocytecountwasnormal,buteosino-philswere16%.Veryextensivepriorevaluationsbymul-tiplespecialistshadbeenunrevealing.ImmunoglobulinGandMlevelswerenormal,butIgAwasfoundseverelydeficient.Sputumstainsandcultureswerenegative,includingtestingforacid-fastbacilli.Serumtryptasewasnormal.ElevationsinserumandurinaryPGDfound.MCASandIgAdeficiency(morelikelysecondarytoMCASinviewofhispriortoleranceofredbloodcelltransfusions)werediagnosed.HistamineH1andH2blockerswereunhelpful.Atrialofanti-inflammatorieswasdesired,butaspirinandothertraditionalNSAIDswerefelttobecontraindicated.Celecoxiblessenedhisfatigue,flushing,bruising,irri-tability,andcough.Low-dosecromolynsignificantlyreducedhisabdominaldiscomfortandGIsymptoms.Doxepinwasunhelpful.Ketotifenfurtherimprovedhisenergy.Low-doselorazepam,too,furtherhelpedhismalaiseandGIsymptoms,butdiffuselymigratorysoft-tissue,bone,andjointpainremainedachiefcomplaint.InFebruary2013Hydrea-brandHUwasbegunat500mgdaily.InMarch2013hereportedhisbonepainwasreduced;HUwasincreasedto1000mgdaily.InApril2013hereportedhisbonepainhadbecometolerable.InMay2013hestoppedHUduetoconcernsitmightinterferewithhealingfromMohssurgery,andhisbonepainfullyrelapsedwithinafewdays.HewasunsurewhetherhewasfullytoleratingHydrea.Droxia-brandHUwasbegunat200mgdaily.Hisconstant8/10bonepainimmediatelydecreasedto2/10,andhiscoughandsputumproductionalmostcompletelyresolved,too.Therewasnohematologictoxicity.Hismusclepain,though,wasunimproved,andhewasplanningtotryincreasinghisDroxia.Case4InJanuary2012a30yearoldfemalelaboratorytech-nologistwasreferredforfurtherevaluationofsuspectedmastcelldisease.Shehadbeenhealthyuntilanemer-gencyCesareansectionwasrequiredatage19duetoinfection,afterwhichshedevelopedgeneralizedweak-nessandbilaterallowerextremityboneandjointpainswhichneverresolved.Atage24,shortlyafterherfatherdied,significantalopeciaandchronicfatigueemerged,andthechronicachingextendedtoinvolveherhands,too.In2008herfatiguewasassumedtobeduetoobstructivesleepapneaforwhichsheunderwentton-sillectomyandseptoplasty,theonlyapparentresultofwhichwasworseningoffatigueandjointpains.Multiplerheumatologicandneurologicevaluationswerenegativeexceptfortentativeconclusions(basedonmodesteleva-tionsinANA)oflupusforwhichtrialsofPlaquenilandmethotrexateneveryieldedanydiscernibleimprove-Cigarette-burn-likerashessometimeslikehivesandoftenleavingscars,togetherwithdiffuselymigratorypruritus,emergedatage29.Jointpainscametoinvolveherelbows,largelyincapacitatingheruseofherarms.Frequentnauseaanddiarrheaalternatingwithcons-tipationemerged,too,butextensivegastroenterologicevaluationwasnegative.Onreviewofsystems,shealsoendorsedwaxing/waningissuessubjectivefevers,chills,soakingsweats,flushing,diffuselymigratorymarkedach-ing,dysmenorrhea,headaches,irritatedeyes,frequentcor-yza,irritatedmouth,milddyspnea,proximaldysphagia,palpitations,refractorygastroesophagealreflux,diffuselymigratoryedema,diffuselymigratorytingling/numbnessparesthesias,spontaneousbruising,episodiccognitivedysfunction,anddailypresyncope.Thereweremultiplecancersinthefamilyhistory.Heronlyknownallergywasasulfa-inducedrash.Examfoundatired,overweight,achywomanwithasparsescatteringofsmallmaculardarkorlightlyery-thematouslesions,slighttendernessatallnodalstations,andanabdomennotablefordiffusemildtendernessanddiaphoresis,andtracedistaledema.Moderatelybrightdermatographismwasnoted.Serialcompletebloodcountswerenotableonlyforastableborderlinemicro-cytosis,chronicmildleukocytosis(withfrequentminimalExperimentalHematology&OncologyPage4of8http://www.ehoonline.org/content/2/1/28 monocytosisand/oreosinophilia).Alkalinephosphatasewaschronicallyminimallyelevated.Anti-nuclearanti-bodiesweremildlyelevated,C-reactiveproteinswerepersistentlysignificantlyelevated,anderythrocytesedi-mentationrateswerenormal.Extensivethyroidtestingwasnormal.Serumtryptasewasnormal,butplasmahistamineandurinaryPGDwerefoundelevated(thislastinspiteofongoing,ifineffective,useofibuprofen).MCASwasdiagnosed.Loratadineandfamotidineimmediatelyresolvedherrash.Aspirin,lorazepam,doxepin,quer-cetin,andcrom
olynwereunhelpful.Montelukast10mgtwicedaily(butnotoncedaily)improvedherfatigueandemotionallability.InApril2013,inviewofherdiffuselymigratorypainbeingherchiefcomplaint,Hydrea-brandHUwasiniti-atedat500mgdaily.Thisimmediatelybeganhelpingherpainandnausea.Shepreviouslyhadneededtooftenreclineandtakeweightoffherlegsduetothrobbingpainthroughoutherlegs(typically8/10orworse),butHUallowedhertostayuprightthroughouttheday.Theseimprovementswereamplifieduponincreasingthedoseto1000mgdailyandweresustainedasofJuly2013(painscore3/10).Therewasnohematologictoxicity.Case5InOctober2010a62yearoldretiredlawenforcementofficerwasreferredforfurtherevaluationofheterozy-gousalpha-1-antitrypsindeficiencydiscoveredwhilebeingevaluatedformysteriouschronicdebilitatingillness.Crohnsdiseasehadbeendiagnosedbycolonoscopicbiopsyin2003.Mesalaminewasunhelpfulforhisdiarrhea.Repeatendoscopyin2009ledtoachangeindiagnosistolymphocyticcolitis.Budesonideresolvedhisdiarrhea.Sev-eralmonthslater(onemonthafteratrip),aleftlowerextremitydeepvenousthrombosisandbilateralpulmon-aryembolideveloped.Chronicanticoagulationwasbegun.Hebeganrapidlylosingweight.Budesonidewasstopped.Diarrheadidnotimmediatelyrelapse.Pasthistoryinclu-dedchronicbackandbilaterallegpainsinceawork-relatedfallin1967.Onreviewofsystems,heendorsedchronicfatigue,anhedonia,depression,lethargy,feelingcoldallthetimesincestartingwarfarin,heatintolerance,diffuseachingsince2009,tinnitus,constantcoryza,throatirritation,drycough,constanthunger,constipation(pos-siblyfromchronicoxycodoneuse),urinaryfrequency,fre-quentconfusion,easyirritability,andfrequentpresyncope.Hewasanactivesmokerwitha100-pack-yearcigarettehistory.Examfoundathinning,worriedmanwithlivedoreticularisacrossthelowbackandmilddermato-graphism.Extensivepriorlaboratorytestingwasnotableonlyforstablemildelevationsinhepatictransaminases.Theserumferritinwastwicetheupperlimitofnormal.Liverbiopsyshowedhimtobeheterozygousforalpha-1-antitrypsindeficiencybutdidnotshowalpha-1-antitrypsinglobules.Serumtryptasewasnormal.PlasmaPGDwasdoubletheupperlimitofnormal.FactorVIIIwasmarkedlyelevatedat400%(normal50-150%).CD117immunohis-tochemicalstainingofendoscopicbiopsiesfrom2009showedsignificantlyincreased(thoughnon-aggregated,non-spindled)mastcells.MCASwasfeltlikely,possiblywithacomorbidFactorVIII-overexpressinghypercoa-gulablestate,thoughgiventhatFactorVIIIisaknownMCmediator,hishypercoagulablestatecouldhavebeensecondarytohisMCAS.Hestartedloratadineandfamotidineandsoonnotedmildtomoderateimprovementinalmostallsymptoms,butdiffuselymigratoryachingwasunimproved.Montelukastwasunhelpful.Aspirinfurtherhelpedmanyofhissymptomsbut,again,nottheaching.Low-doselorazepammildlyreducedhispain.Doxepinwasunhelp-ful.CromolynessentiallyresolvedhisGIsymptoms.Low-doseimatinib(200mgdaily)reducedhisfatigueandcognitivedysfunctionandfinallyprovidedhimmoregooddaysthanbad,butdiffuseachingwasun-improved,typically8/10orworse.InFebruary2013Hydrea-brandHUwasinitiatedat500mgdailybutimmediatelyprovedintolerable(nausea,vomiting,chills).InApril2013Droxia-brandHUwasinitiatedat200mgdaily.InJune2013hereportedsignifi-cantreductioninnotonlyfatiguebutalsodiffuseaching(3/10)andpresyncope.Therewasnohematologictoxicity.AsofJuly2013hewasplanningtotryescalatingtheDroxiadose.DiscussionOfhematopoieticorigin,mastcells(MCs)arefoundinallhumantissues,especiallyattheenvironmentalinter-facesandperivascular/perineuralsites[23].Theyservelargelyassentinelsofenvironmentalchangeandbodilyinsultsandrespondbyreleasinglargeandvariableassortmentsofmolecularmediatorswhichdirectlyandindirectlyinfluencebehaviorinother(localanddistant)cellsandtissuestorespondtochanges/insultssoastomaintain,orrestore,homeostasis.ThetransmembranetyrosinekinasereceptorKITisthedominantMCregu-latoryelement,showntobecriticalforkeyMCfunc-tionsincludingsurvival,differentiation,chemotaxis,andactivation[24].Traditionally,MCdiseasehasbeenthoughttobeprincipallyamatterofneoplasticburdensofMCs,withsymptomsresultingprincipallyfromanaccompanyinginappropriatereleaseofmediatorsfromtheseexcessivenumbersofMCs.Nearlyaquartercenturyago,though,thenotionwasfirstadvancedthattheremightbeformsExperimentalHematology&OncologyPage5of8http://www.ehoonline.org/content/2/1/28 ofMCdiseasemanifestinginappropriatemediatorre-leasewithlittletonoaccompanyingproliferationofMCs[25].ThistheoryappearedvalidatedwhenthefirstrecognizedcasesofwhatisnowcalledMCactivationsyndrome(MCAS)werepublishedin2007[26-28].Dif-ferentpatternsofaberrantexpressionofthelargeMCmediatorrepertoireindifferentMCASpatientsmakeformarkedlyheterogeneousandthusdiagnosticallychallengingpresentations[1].Thecauseofsuchhet-erogeneityisnotyetclear.Provocatively,though,Mold-etal.haverepeatedlyfoundawidearrayof(presumablymostlyconstitutivelyactivating)mutationsscatteredacrossalldomainsofKITi
nsmallcohortsofMCASpatients,withmostoftheirstudiedpatientsbear-ingmultiplemutationsinnoyet-apparentrecurringpat-terns[28,29].(Interestingly,theKITmutationsocommoninmastocytosisseemsrareinMCAS.)Thoughthesefindingshavenotyetbeenindependentlycon-firmed,itisnoteworthythatsimilarmutationalcom-plexity(inKITandothercellularcontrollers)hasbeenfound,too,acrossthespectrumofchronicmyelo-proliferativeneoplasms(MPNs)withinwhichtheMCdisordersreside[30],andinadvancedmastocytosisitself[31].Giventhesenewbiologicandclinicalinsights,pro-posalshaveemergedtoconsiderallMCdiseasesundertheumbrellatermofMCactivationdisease(MCAD)[32].Italsohasbeenproposedthattheassortedsys-temicMCADvariantsandclinicalphenotypesrepresentnotdistinctdiseaseentitiesbutinsteadvaryingpresenta-tionsofacommongenericrootprocessofmastcelldys-function[33].MastocytosismaybemerelythetipoftheproverbialMCADiceberg,fairlyreadilyrecognizable(inspiteofitsrarity)becauseofitsdistinctiveclinicopatho-logicpresentation,whilethebulkoftheiceberghiddenbelowthewaterlineofeasyclinicalrecognizabilitymaybeafarlarger,andfarmoreheterogeneous,collectionofvariantsofMCAS,someofwhicharealreadydiscretelyrecognized(e.g.,idiopathicanaphylaxis[27],cryopyrin-associatedperiodicsyndrome[34]),butmostnot.Withnopredictorsoftherapeuticresponseyetidenti-fied,MCADsheterogeneityposesnotonlydiagnosticbutalsotherapeuticchallenges(Table1).ThecasesinthepresentseriesextendearlierobservationsthatHUappearsabletomodulateMCmediatorexpressioninMCAD,includingMCAS,andmaybeparticularlyusefultotreatpaininpatientsrefractoryto,orintolerantof,othertypicalandatypicalanalgesics.Althoughallofthepatientsreportedherewerealreadyonsomeanti-mediatortherapyatthetimeHUwasbegun,thefactthatinitiationofHUwastheonlymedicationchangeprecedingtheobservedfurthersymptomaticimprove-mentsstronglysuggestsHUwassolelyresponsiblefortheseimprovements.ThreeofthepatientsinthisseriesquicklyshowedintoleranceofacommonlyusedformulationofHUbutthentolerated,andrespondedwellto,analternativeformulation,possiblyduetothepropensityofMCADpatientstomanifestoddandprolificmedicationsensiti-vitieswhichmayresultfromMCreactionstoeitheringredients.ItmaybeworthwhilewhendesigningtherapeutictrialsfortheMCADpopu-lationtoallowforswitchingtoalternativemedicationformulationswhenintoleranceofagivenformulationquicklybecomesapparent.Suchastrategymayreducethechanceofunderestimatingtolerabilityandefficacy. Table1TreatmentsusedinmastcellactivationdiseaseMechanismofactionTherapies/therapeuticclassesAnti-mediator(inhibitionofMCmediatorproductionoraction)HistamineHreceptorantagonistsHistamineHreceptorantagonistsNon-steroidalanti-inflammatorydrugsBenzodiazepinesCorticosteroidsLeukotrienereceptorantagonistsProtonpumpinhibitorsTricyclicantidepressants(antihistaminic)Phenothiazines(antihistaminic)HydroxyureaBisphosphonates,vitaminD,calcium5-hydroxytryptaminereceptorantagonistsAlphalipoicacidN-acetylcysteineAmphetaminesHypolipidemicsMastcellstabilizersCromolynTyrosinekinaseinhibitorsAlphainterferonVitaminCCytostatic/cytotoxicagentsCladribinePentostatinFludarabinePaclitaxelAlkylators(e.g.,cyclophosphamide)HydroxyureaImmunomodulationAllergydesensitizationtherapyAllogeneicstemcelltransplantationExperimentalHematology&OncologyPage6of8http://www.ehoonline.org/content/2/1/28 Theclinicalobservationsfromthepresentcaseseriesmaygainfurthersignificanceinlightoftherecentdis-coverybyVincentetal.thatinamurinemodelofsicklecellanemia(SCA),MCactivationwasfoundtounderliesicklepathophysiologyleadingtoinflammation,vasculardysfunction,pain,andrequirementforhighdosesofmorphine[35].HUisusedasadisease-modifyingagentinsicklecelldisease(SCD)andistheonlyapprovedsuchagent,thoughredbloodcelltransfusions,too,cangreatlydecreasediseaseseverityandhematopoieticstemcelltransplantationcancureSCD[36].DespiteuseofHUinthisfashionformorethan25years,thefullsetofmechanismsbywhichitreducesSCDseverityremainsunclear.TheefficacyofHUinthetreatmentofSCDisgenerallyattributedtoitsabilitytoincreaseHbF,butinarecentsystematicreviewoftheefficacyofHUinSCD,thesoleidentifiedrandomizedcontrolledtrialreportedthemeanincreaseinHbFfromtwoyearsofHUusewasonly3.2%[37],whileothersalutarybenefitsofHUinSCDnotclearlyrelatedtoincreasesinHbFhavebeenobserved,too,includingloweringofcirculatingleuko-cytecountsandlocalreleaseofnitricoxide[2].ItisunclearwhetherHUsestablishedactivityasaribonucle-otidereductaseinhibitoristhesolemolecularmecha-nismofactionthroughwhichallofthesebenefitsarise.Thus,giventherecentdatafromVincentetal.,theoverlapinthepatternsofpaininbothSCDandMCAS,estimatesofsignificant(14-17%)prevalenceofMCASinthegeneralpopulation[33,38],andtheobservationsfromthepresentcaseseriesoftheutilityofHUinthemanagementofotherwiserefractorypaininsomeMCASpatients,atleasttwoadditionalquestionsareraised:(1)mightunrecog
nizedMCASaccountforsomeofthecomorbiditieswhichhavelongbeenseeninsomeSCDpatients,andattributedtotheirSCD,butforwhichithasbeendifficultidentifyingspecificbiologicpathwayssupportingsuchattribution,and(2)mighttreatmentofunrecognizedMCASbeanothermechanismbywhichHUhelpsinSCD?ConclusionsMCASshouldbeconsideredinthedifferentialdiagnosisofdiffuselymigratorysofttissue,bone,and/orjointpain.HUappearsusefulintreatinganassortmentofmediator-drivensymptomsinsomepatientswithMCAS.Inparticular,HUmaybeusefulinaddressingotherwiserefractorysofttissueand/orbonepaininMCAS,butfurtherstudyisneededtodefineHUmechanismsofactioninMCAD/MCAS,optimaldosingstrategies,andwhichpatientsubpopulationsaremostlikelytobenefit.FurtherstudymayalsobewarrantedtocharacterizetheprevalenceandbehaviorofMCASinSCDpatients,particularlythosewithcomorbiditiesnoteasilyattributabletoerythrocytesickling.Writteninformedconsentwasobtainedfromeachpatientforinclusioninpublicationofthiscaseseries.CopiesofthewrittenconsentsareavailableforreviewbytheEditor-in-Chiefofthisjournal.Gastroesophagealrefluxdisease;IgA:ImmunoglobulinA;HU:Hydroxyurea;MC:Mastcell;MCAD:Mastcellactivationdisease;MCAS:Mastcellactivationsyndrome;MPN:Myeloproliferativeneoplasm;MSK:Musculoskeletal;pPGD:PlasmaprostaglandinD;uPGD:UrinaryprostaglandinD;SCD:Sicklecelldisease.CompetinginterestsDr.Afrinreportshehasnoconflictsofinterest,receivednosupportforthiswork,andhadfullaccesstoallofthedatainthestudyandtakesresponsibilityfortheintegrityofthedataandtheaccuracyofthedataanalysis.Thisworkhasnotbeenpresentedpreviouslyinanyotherformorvenue.sinformationLBAisanAssociateProfessorofMedicineintheDivisionofHematology/OncologyattheMedicalUniversityofSouthCarolinainCharleston,SC,USA.AcknowledgementsLBAreceivednofundingforthedevelopmentofthisarticle.PublicationissupportedbytheLindaB.SummerallFellowshipFundattheHollingsCancerCenter,MedicalUniversityofSouthCarolina,Charleston,SC,USA.Nofundingorothersupportwasreceivedforthisworkfromanysource.Received:26September2013Accepted:6October2013Published:9October20131.MolderingsGJ,BrettnerS,HomannJ,AfrinLB:Mastcellactivationdisease:aconcisepracticalguidefordiagnosticworkupandtherapeuticoptions.JHematolOncol10.http://www.jhoonline.org/content/4/1/10,accessedOctober5,2013.2.McGannPT,WareRE:Hydroyxureaforsicklecellanemia:whathavewelearnedandwhatquestionsremain?CurrOpinHematol3.KennedyBJ,YarbroJW:Metabolicandtherapeuticeffectsofhydroxyureainchronicmyeloidleukemia.JAmMedAssoc4.VeithR,GalanelloR,PapayannopoulouT,StamatoyannopoulosG:StimulationofF-cellproductioninpatientswithsicklecellanaemiatreatedwithcytarabineorhydroxyurea.NEnglJMed5.CharacheS,TerrinM,MooreRD,DoverGJ,BartonFB,EckertSV,McMahonRP,BondsDR:Effectofhydroxyureaonthefrequencyofpainfulcrisisinsicklecellanemia.NEnglJMed6.LoriF,MalykhA,CaraA,SunD,WeinsteinJN,LisziewiczJ,GalloRC:Hydroxyureaasaninhibitorofhumanimmunodeficiencyvirus-type1Science7.ReissUM,BensimhonP,ZimmermanSA,WareRE:HydroyxureatherapyformanagementofsecondaryerythrocytosisincyanoticcongenitalheartAmJHematol8.ElfordHL:Effectofhydroxyureaonribonucleotidereductase.BiophysResCommun9.PassamontiF,RumiE,PungolinoE,MalabarbaL,BertazzoniP,ValentiniM,OrlandiE,ArcainiL,BrusamolinoE,PascuttoC,CazzolaM,MorraE,LazzarinoM:Lifeexpectancyandprognosticfactorsforsurvivalinpatientswithpolycythemiaveraandessentialthrombocythemia.AmJ10.CortelazzoS,FinazziG,RuggeriM,VestriO,GalliM,RodeghieroF,BarbuiT:Hydroxyureaforpatientswithessentialthrombocythemiaandahighriskofthrombosis.NEnglJMed11.HarrisonCN,CampbellPJ,BuckG,WheatleyK,EastCL,BarefordD,WilkinsBS,vanderWaltJD,ReillyJT,GriggAP,RevellP,WoodcockBE,GreenAR:ExperimentalHematology&OncologyPage7of8http://www.ehoonline.org/content/2/1/28 Hydroxyureacomparedwithanagrelideinhigh-riskessential thrombocythemia. NEnglJMed 2005, 353: 33 45. 12.SteinbergMH,McCarthyWF,CastroO,BallasSK,ArmstrongFD,SmithW, AtagaK,SwerdlowP,KutlarA,DeCastroL,WaclawiwMA: Therisksand benefitsoflong-termuseofhydroxyureainsicklecellanemia:a17.5 yearfollow-up. AmJHematol 2010, 85: 403 408. 13.ZimmermanSA,SchultzWH,DavisJS,PickensCV,MortierNA,HowardTA, WareRE: Sustainedlong-termhematologicefficacyofhydroxyureaat maximumtolerateddoseinchildrenwithsicklecelldisease. Blood 2004, 103: 2039 2045. 14.FlanaganJM,HowardTA,MortierN,AvlasevichSL,SmeltzerMP,WuS, DertingerSD,WareRE: Assessmentofgenotoxicityassociatedwith hydroxyureatherapyinchildrenwithsicklecellanemia. MutatRes 2010, 698: 38 42. 15.McGannPT,HowardTA,FlanaganJM,LahtiJM,WareRE: Chromosome damageandrepairinchildrenwithsicklecellanemiaandlong-term hydroxyureaexposure. BrJHaematol 2011, 154: 134 140. 16.HankinsJS,AygunB,WangW,WynnL,ThornburgC,SchultzW,KimbleA, SmeltzerM,MortierN,WareR: Frominfancytoadolescence:overa decadeofcontinuoushydroxyureatherapyinsicklecellanemia [abs
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