Table Of Contentd
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Angioedema
Congress Book
Edited by
Murat Bas
Thomas K. Hoffmann
Georg Kojda
19figures
3tables
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GeorgThiemeVerlag
Stuttgart·NewYork
IV
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V
Preface
Hereditary angioedema and other forms of non- Anotherimportantaimofthisbookistodraw
allergicangioedemaarelongknownandwerede- attention to bradykinin-induced angioedema
scribed firstbyQuinckein1882andbyOssler in whichiscausedbycertaindrugssuchasACE-in-
1888.Bothdescribeswellingsofthemucosaand/ hibitorsand/orsartans.Someoftheseangioedema
or submucosa of the skin which may impair arepresentinthelarynxandmaycausedeathas
breathing and are potentially life-threatening. In well. Currently, there is no published algorithm
particular,swellingsofthepharynxandthelarynx fordiagnosisandtreatment.Likewise,thereisno
often require emergency treatment and several evidence-based treatment at all. In more severe
daysofhospitalization.Thedifferentiationofbra- cases, such patients are usually hospitalized and
dykinin-induced angioedema to allergic angio- receiveglucocorticoidsandantihistamines.Fortu-
edemaiscrucialforsuccessfultherapy. nately,newdrugs havebeen developed in recent
Eventoday,manypatientswithhereditaryan- yearswhicharebasedonentirelynewmolecular
gioedema are notcorrectlydiagnosed in the first mechanisms and which are subcutaneously ap-
place.Furthermore,pharmacotherapyisoftenmis- plied. This appears to be a considerable advance.
directedifpatientsaretreatedinhospitalswhere Forthefirsttime,thesenewdrugsofferthepossi-
noorminorexperienceexistswithsuchpatients. bility of on-demand self-administration even in
Forexample,itstillhappensthatphysiciansrefuse children.
toprovide effectivebutexpensive antibradykinin
pharmacotherapyevenforpatientshavingacard Düsseldorf, GeorgKojda
identifying them as having hereditary angioede- September2009
ma.Thus, itis oneimportantaimof thisbookto
alertphysiciansandotherhealthcareprovidersto
the course of this disease, its diagnosis and its
pharmacotherapy.
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VI
Addresses
Prof.Dr.VolkerAdams PDDr.med.KarinHartmann
HerzzentrumLeipzigGmbH KlinikumderUniversitätzuKöln
Strümpellstraße39 KlinikundPoliklinikfürDermatologie
04289Leipzig undVenerologie
e-mail:[email protected] KerpenerStraße62
50937Köln
Dr.MuratBas e-mail:[email protected]
Hals-Nasen-OhrenklinikundPoliklinik
KlinikumrechtsderIsar PDDr.med.ThomasK.Hoffmann
derTechnischenUniversitätMünchen UniversitätsklinikumDüsseldorf
IsmaningerStraße22 Hals-Nasen-Ohren-Klinik
81675München Gebäude-Nr.:13.76
e-mail:[email protected] Moorenstraße5
40225Düsseldorf
Prof.Dr.KonradBork e-mail:Thomas.Hoffmann@
Universitäts-HautklinikMainz med.uni-duesseldorf.de
Johannes-Gutenberg-Universität
Langenbeckstraße1 PDDr.WolfhartKreuz
55101Mainz KlinikumJ.WolfgangGoethe-Universität
e-mail:[email protected] ZentrumfürKinderheilkundeIII
Hämostaseologie
Prof.Dr.IngridFleming Theodor-Stern-Kai7
KlinikumJ.WolfgangGoethe-Universität 60596Frankfurt
Theodor-Stern-Kai7
60596Frankfurt Dr.med.JanRamakers
e-mail:[email protected] UniversitätsklinikumDüsseldorf
Moorenstraße5
d Prof.Dr.PeterGohlke 40225Düsseldorf
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Gr Hospitalstraße4 Prof.Dr.BerndRosenkranz
sit?t 24105Kiel ViaDr.med.JensZimmermann
er e-mail:[email protected] JeriniAG
v
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VII
Table of Contents
1 TreatmentofAllergicAngioedema . . . . . .. . . . . . .. . . . . . .. . . . . . . .. . . . . . .. . . . . . . . 1
K.Hartmann
Introduction.. . . . . . .. . . . . . . .. . . . . . .. . . . 1 TherapyforChronicAngioedema. . . .. . . . . . . . 2
TherapyforAcuteAngioedema . .. . . . . . .. . . . 2
2 EmergencyTherapyforAngioedemaoftheUpperAirway . . . . . . . .. . . . . . .. . . . . . . . 4
T.K.Hoffmann,H.Bier,G.Kojda,M.Bas
Introduction.. . . . . . .. . . . . . . .. . . . . . .. . . . 4 Therapy . . . . . . .. . . . . . . .. . . . . . .. . . . . . . . 5
Symptoms . .. . . . . . .. . . . . . . .. . . . . . .. . . . 4 Conclusion . . . . .. . . . . . . .. . . . . . .. . . . . . . . 7
Diagnostics. .. . . . . . .. . . . . . . .. . . . . . .. . . . 4
3 HereditaryAngioedema:ClinicalManifestationandTherapy . . . . . .. . . . . . .. . . . . . . . 8
W.Kreuz,E.Aygören-Pürsün,I.MartinezSaguer,E.Rusicke
Introduction.. . . . . . .. . . . . . . .. . . . . . .. . . . 8 EpidemiologyandGenetics
BiologicalCharacteristicsofC1-INH. . . . . .. . . . 8 ofC1-INHDeficiency. . . . . .. . . . . . .. . . . . . . 9
DiagnosisandClassification ClinicalSymptomsofHereditaryAngioedema . 10
ofC1-INHDeficiency. .. . . . . . . .. . . . . . .. . . . 8 CurrentTreatmentofHereditaryAngioedema . 12
Conclusion . . . . .. . . . . . . .. . . . . . .. . . . . . . 13
d
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sit Introduction.. . . . . . .. . . . . . . .. . . . . . .. . . 15 DifferentialDiagnoses. . . . .. . . . . . .. . . . . . . 16
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v ClinicalPicture . . . . . .. . . . . . . .. . . . . . .. . . 15 Therapy . . . . . . .. . . . . . . .. . . . . . .. . . . . . . 16
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VIII TableofContents
5 AcutePhaseProteinsinKinin-InducedAngioedema . . . .. . . . . . . .. . . . . . .. . . . . . . . 19
M.Bas,H.Bier,M.Oppermann,T.K.Hoffmann,G.Kojda
Introduction . . . . . .. . . . . . . .. . . . . . .. . . . 19 AcutePhaseProteinsin
TheRoleofBradykininin Bradykinin-InducedAngioedema. .. . . . . . . . 21
Non-AllergicAngioedema . . . .. . . . . . .. . . . 20 Conclusion . . .. . . . . . . .. . . . . . .. . . . . . . . 22
6 BradykininandtheKallikrein-KininSystem:
Kallikreins,BradykininandVascularSignalTransduction . . . . . . . .. . . . . . .. . . . . . . . 23
V.Adams
TheKallikrein-KininSystem. . .. . . . . . .. . . . 23 AnimalModelswithParticipation
oftheKallikrein-KininSystems . . .. . . . . . . . 24
7 DrugsAffectingtheKallikrein-KininSystem . . . .. . . . . . .. . . . . . . .. . . . . . .. . . . . . . . 28
B.Rosenkranz,W.Fan,J.Zimmermann
TheKallikrein-KininSystem. . .. . . . . . .. . . . 28 AntagonistsoftheKallikrein-KininSystem. . . 28
8 RAASBlockerandBradykininMetabolism:
TheRoleofBradykininforClinicalEfficacy . . . . .. . . . . . .. . . . . . . .. . . . . . .. . . . . . . . 32
P.Gohlke
Introduction . . . . . .. . . . . . . .. . . . . . .. . . . 32 AT ReceptorAntagonists
1
TheKallikrein-KininSystem. . .. . . . . . .. . . . 33 andBradykinin . . . . . . . .. . . . . . .. . . . . . . . 36
ACEInhibitorandKinins . . . . .. . . . . . .. . . . 34 Conclusions. . .. . . . . . . .. . . . . . .. . . . . . . . 36
9 ANewLookattheTherapeuticEffectsofACEInhibitors:
d ACEasSignalTransductionMolecule . . .. . . . . . .. . . . . . .. . . . . . . .. . . . . . .. . . . . . . . 38
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?t AngiotensinConvertingEnzyme(ACE). .. . . . 38 Perspective:NewViewpoint
sit ACEInhibitorsandACESignalling . . . . .. . . . 39 withRegardtoRAS . . . . .. . . . . . .. . . . . . . . 40
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Index. . . . . . .. . . . . . . .. . . . . . .. . . . . . . .. . . . . . .. . . . . . .. . . . . . . .. . . . . . .. . . . . . . . 46
1
1
Treatment of Allergic Angioedema
K.Hartmann
DepartmentofDermatology,UniversityofCologne,Cologne,Germany
Abstract
Angioedemasarecharacterizedbyasuddenonsetofswellinginthedeepdermisandsubcutis.Forsimplicity,
angioedemasareclassifiedintothosewithgeneticcausesandacquiredforms.Causesofacquiredangioedemas
includeallergicreactions,autoimmunemechanisms,infectionsandnon-allergic/pseudo-allergichypersensitiv-
ityreactions.Often,acquiredangioedemasareaccompaniedbyurticaria.Asinthecaseofspontaneousurtica-
ria,itisreasonabletodistinguishbetweenacuteacquiredangioedemawithacourseoflessthansixweeksand
chronicacquiredangioedemathatexistsformorethansixweeks.Forbothforms,possibletriggeringfactors
suchasdrugsandinfectionsshouldfirstbeexcluded.Acuteangioedemasaretreatedwithglucocorticoidsand
H1-antihistamines.Forchronicangioedemas,non-sedativeH1-antihistaminesarerecommendedasfirst-line
therapy.Insomecases,higherdosagesofantihistamines–uptofourtimestheapproveddose–arerequired.
Insevereforms,cyclosporinAcanbeconsidered,whereasglucocorticoidsarenotrecommendedforlonger
use.Somepatientswithautoimmuneangioedemamayalsorespondtodapsoneorhydroxychloroquine.
Introduction cretehistamineandmanyothermediatorsthat,for
example,leadtovasodilatationandedemaofthe
Angioedemas (synonyms: angioneurotic edema, tissues.Acuteangioedemasareoftentriggeredby
Quincke’sedema)arecharacterizedbysuddenon- IgE-mediated allergies, e.g., food allergies, viral
setofswellinginthedeepdermisorsubcutis.The infectionsanddrugs.Chronicangioedemas,incon-
variousformsofangioedemaincludeacquiredan- trast, are mostly caused by pseudo-allergic reac-
gioedemas, angioedemas due to ACE inhibitors, tions,chronicbacterialinfections,e.g.,Helicobacter
hereditary angioedemas, angioedemas with eosi- pylori, autoreactive processes and non-steroidal
nophilia(Gleichsyndrome)andotherrareangio- antirheumaticdrugs[3].
edemasinassociationwith,e.g.,alpha-1-antitryp- Morethanhalfofallpatientswithacquiredan-
sindeficiencyorcarcinoid[1].Therapydiffersfor gioedema suffer concomitantly from urticaria.
thevariousforms.Inthischapter,thetherapyfor Whileisolatedhiveslastforlessthan24hours,an-
d acquiredangioedemasofallergicandnon-allergic gioedemasexistforupto72hours.Asarule,an-
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eif gioedemas occur in combination with urticaria, are accompanied by pain or burning sensations.
Gr the therapy recommendations are comparable to Theyaffectabovealltheeyelids,lips,tongue,oral
sit?t the guidelines for the treatment of spontaneous and pharyngeal mucosa and the genital region
er urticaria [2]. Asin cases of spontaneous urticaria (Figs.1.1 and 1.2). Dangerous forms, especially of
v
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U
?r thatlastsforlessthansixweeksandchronican- phylacticreactions.Chronicangioedemaoftenex-
ert f gioedema that lastsfor morethan six weeks and istformanyyearsorevendecadesandareassoci-
si occuratleasttwotimesperweek. ated with decreased quality of life and working
n
e Causes and pathomechanisms of acquired an- ability[4].
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cesses,pseudo-allergichypersensitivityreactions, sisisplacedonthecasehistoryandspecificlabora-
autoimmune mechanisms or infections can lead torytestsaccordingtothehistory,e.g.,allergytests
toactivationofmastcells.Activatedmastcellsse- for angioedema after consumption of food or in-
