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Cryopyrinassociatedperiodicsyndrome(CAPS)includingfamilialcoldautoinflammatorysyndrome
(FCAS),MuckleWellssyndrome(MWS)andneonatalonsetmultisysteminflammatorydisease
(NOMID)/chronicinfantileneurologicalcutaneousandarticularsyndrome(CINCA).

FCAS,MWSandCINCA/NOMIDrefertothesamedominantlyinheritedAIDwithdifferentdegreesof
severity.

ClinicalManifestations.Thisgroupofrelateddiseasesisgenerallycharacterizedbyrecurrentfever,
urticariaandarthritis/arthralgia.FCASisthemildestofCAPS.[65]Conjunctivitisisafrequent
presentationofFCASaftercoldexposure.SensorineuralhearinglossisacommonfindingofMWS.
CINCA/NOMIDisthemostsevereformofthediseasecharacterizedbychronicmeningitis,uveitisand
deformingarthritisaswellasfever,sensorineuralhearinglossandurticaria

NumerouscasereportshaverecentlyshowedthatIL1ra(anakinra),seemseffectiveforCAPSvariants
includingFCAS[71],MWS[72]andCINCA/NOMID.

HyperIgDsyndrome(HIDs).Recurrenthighfeveroccursevery46weeksandlasts37days.Theattacks
offeverareaccompaniedbygeneralizedlymphadenopathyandabdominalsymptomssuchaspain,
vomitinganddiarrhoea.
HIDScutaneouspresentationincludeserythematousmaculesandpapules,urticariaandothertypesof
rash.[50]
Symmetricalpolyarthritis/arthralgiaispresentin66%patients,primarilyinvolvinglargejointssuchasthe
kneesandanklesbutwithoutjointdestruction.[50]Tendonitishasbeenreportedaswell.[51]Other
symptomsandsignsincludeheadache,oralandgenitalulcers.
Laboratoryfindingsincludeleucocytosisandraisedacutephasereactantproteins.PolyclonalIgDis
elevated>100U/ml.[49]
ThediseasedefininggeneistheMVKgene(mevalonicacidkinase),akeyenzymeinthebiosynthesisof
cholesterolandisoprenoid.[54]ThemutatedMVKgenecausesMVKdeficiency,resultinginanincrease
inurinarymevalonicacidexcretion.Ithasbeenassumedthattheincreasedmevalonicacidandlackof
isoprenoidcontributetotheinflammatorydiseasealthoughdirectevidenceislacking.
NoeffectivetherapyisavailableforHIDS.Simvastatin,asaninhibitorofhydroxy3methylglutaryl
coenzymeA(HMGCoA),reducesthedurationoftheattacks,perhapsbecauseHIDSisametabolic
diseaserelatingtoMVKdeficiency(involvedincholesterolsynthesis).Trialsofetanercepthaveproduced
mixedresults.Anakinra,asanIL1antagonist(IL1ra),wasrecentlyreportedtobemoreeffectivethan
etanercept.NSAIDs,colchicineandglucocorticoidshavebeenineffective.

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ClinicalManifestationsofTRAPS.Thisdiseaseischaracterizedbyrecurrentfeveratirregularintervalsof
weeksandmonths,accompaniedbyattacksofabdominalpain,pleurisy,localizedmyalgiainvolvinga
groupofmusclesandoverlyingerythematousmaculesandpatches,mostlyinthelimbs.[32]Thecellulitis
likesubcutaneousinflammationmovingdistallyontheupperlimbsandorbitaloedemaarethoughttobe
themostcharacteristic.[32,33]Arthralgiaoccursin2/3patients,involvingperipheraljointsina
monoarticularoroligoarticularfashion.Arthritisislesscommon.[34]Onecaseofmonocyticfasciitishas
beenreported.[35]TRAPSmaybeconfusedwithjuvenileidiopathicarthritis[36]anditmaybe
coexcistentwithmultiplesclerosis.[37]Thediseaseattacksbegininchildhoodandcanpersistforupto30
yrs.Asinglecaseofsmallvesselvasculitisandpanniculitishasbeenreported.[38]

Laboratoryfindings[32]includeleucocytosis,increasedacutephasereactantproteinsandpolyclonal
elevationofIg(IgA,inparticular).PositiveANAandcirculatingimmunecomplexescan,rarely,be
detected.
InTRAPS,glucocorticoidsareusuallyefficacious.[45]Colchicineisineffectiveinrelievingorpreventing
thediseaseattacks.[45]BasedonthemutationofTNFRSF1AinTRAPS,etanercepthasbeentriedbut
withmixedresults.

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Duringepisodicattacks,patientswithFMFpresentwithmoderatetohighfeverwhichtypicallysubsides
spontaneouslywithin13days.[4,5]Thefeverisaccompaniedbypainfulserositisinvolvingthe
peritoneum,pleuraand/orevenpericardium.[6]Patientsareasymptomaticbetweentheattacksalthough
subclinicalinflammationremainspresent.[7]

Arthritisoccurs,indecreasingfrequency,intheknees,anklesandhips.Thirtyonepercentofpatientswith
FMFhavearthritiswithmonoarticular,oligoarticularandpolyarticularinvolvement(70,26and4%,
respectively).[8]ThearthritisofFMFisusuallyacute,episodicandselflimitedwithnosequelae.

Erysipelaslikeerythemausuallyoccursbelowthekneesontheanteriorlegoronthedorsumofthefoot.

Laboratoryfindings[13]includeleucocytosisandelevatedacutephasereactantproteinssuchasESR,
CRP,fibrinogenandserumamyloidA(SAA)protein.

FMFgenerallyrespondstocolchicinetherapy.Thetherapeuticdoseisusually12mgp.o.daily[22]and
prophylacticuseofcolchicinemaypreventamyloidosis.[22,23]Approximately510%patientswithFMF
donotrespondtocolchicinetherapy.[24]Glucocorticoiduseisnoteffective.[25]Incolchicineresistant
patients,interferonhasbeenreportedtohavemodestdiseasemodifyingefficacy.[26]Thalidomide,
perhapsbecauseithassomeTNFinhibitingfeatures,hasbeenreportedtobebeneficialaswell.[27]TNF
blockadewithetanerceptorinfliximabhasbeenreportedtobeeffectiveforarticlularsymptomsin
particularandevenfortheamyloidosisofFMF.[2]Additionofanakinrahasbeenefficaciousin
colchicineresistantpatientsintwoseparateanecdotalcasereports.[28,29]