Rev. Bras. Reumatol. vol.57 número3

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ww w . r e u m a t o l o g i a . c o m . b r

REVISTA

BRASILEIRA

DE

REUMATOLOGIA

Case

report

Clinical

course

of

Behcet’s

disease

in

a

patient

with

delayed

diagnosis

and

radiological

follow-up

of

the

thrombi

with

computed

tomography

angiography:

a

five-year

follow-up

under

immunosuppressive

treatment

Evoluc¸ão

clínica

da

doenc¸a

de

Behc¸et

em

paciente

com

atraso

do

diagnóstico

e

seguimento

radiológico

dos

trombos

com

angiotomografia

computadorizada:

seguimento

por

5 anos

durante

tratamento

imunossupressor

Muhammet

Cinar

a,∗

,

Sedat

Yilmaz

a

,

Sinan

Akay

b

,

Ugur

Bozlar

b

,

Ayhan

Dinc

a

a_Gulhane_Military_Medical_Academy_School_of_Medicine,_Division_of_{Rheumatology,}_Ankara,_Turkey

b_Gulhane_Military_Medical_Academy_School_of_Medicine,_Department_of_Radiology,_Ankara,_Turkey

a

r

t

i

c

l

e

i

n

f

o

Articlehistory:

Received23March2013

Accepted12August2013

Availableonline26November2014

Introduction

Behc¸et’s disease (BD) is achronic inflammatory disease of

unknownetiology.1_The_diagnosis_is_made_on_the_basis_of_the

combinationofclinicalfindings;thereforedelayinthe

diag-nosisisnotrare.Sometimes,cardiovascularandpulmonary

involvementisseenbeforemakingdiagnosisofBD.Such

man-ifestationscanbelife-threateningandfailuretodiagnoseBD

insuchapatientmay beveryserious.2–4 _In_this _paper, _we

describeaBDpatientdiagnosedlatewithintracardiac,

supe-riorvenacava,andbilateralpulmonaryarterythrombi.We

usedcomputedtomographyangiography(CTA)tostudythe

∗ _{Corresponding}_author.

E-mail:muhcinar@hotmail.com(M.Cinar).

timecourseofthrombusdevelopmentfromthetimeof

ini-tial diagnosis throughouttreatment. Inthis aspect, this is

the firstreporttouse CTAtoexplorethelong-termcourse

ofintracardiac,superiorvenacava,andbilateralpulmonary

arterythrombi.

Case

report

Ourpatientisawomanwhowas27yearsatthetimeof

diag-nosis,andherfirstcomplaintwasfever,whichcommenced

in January 2005.Prior to that time, shehad suffered from

aphthouslesions,butdidnotseekmedicalattention.InApril

http://dx.doi.org/10.1016/j.rbre.2013.08.004

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2005,investigationsrevealed elevatedlevelsofacutephase

reactantsincludingtheerythrocytesedimentationrate(ESR)

andC-reactiveprotein(CRP)level;thesewere 38mm/hand

149mg/L,respectively.Shewasadmittedtohospitalatthat

time.Onphysicalexamination,multipleoralaphthousulcers

were detected. AlthoughBDwas considered in differential

diagnosis,shewasnotdiagnosedwiththediseasebecause

othersignsofBDwereabsent.Infact,shedidhaveagenital

ulcerbut,unfortunately,itwasnotmentionedtothe

physi-cian,andthegenitaliawerenotexamined.Exhaustivetests

seekingtheetiologyofthefeverwereconducted;allof

infec-tious,autoimmune, and malignetiologieswere considered.

Echocardiographyrevealedacardiacmass24mm×13mmin

dimensionsonthelateralwalloftherightventricularcavity.

This was confirmed by cardiac magnetic resonance

imag-ing (MRI); a soft tissue mass 25mm×40mm×40mm was

evident in the right ventricular cavity. The main features

of this soft tissue mass were its partially moving

charac-ter during systole and diastole, iso-hypointense according

to the myocardial tissue and without contrast

enhance-ment.Acardiacthrombuswasinitiallysuspected.Abiopsy

was performed, but it was non-diagnostic. Subsequently,

thepatientexperiencedherfirst episodesofpleuriticchest

painandhemoptysis.Lungventilation/perfusionscintigraphy

wasperformed;perfusionlossinmultiplesegmentsofboth

lungswasevident.Possiblefociofthrombosisandcausesof

thrombophiliaweresought.Shewasheterozygousforthe

pro-thrombinG-A20210mutation,butneithertheVLeidennor

theMTHFRgenewasmutated.Theactivatedpartial

thrombo-plastintime,andthelevelsoflupusanticoagulant,proteinC,

proteinS,anti-thrombinIII,anticardiolipinantibodies,

anti-beta2-glycoprotein1antibodies,andhomocysteinewereall

normal.

Onemonthlater,therightventricularmasswasbiopsied

oncemoreand foundtocontainonlynormalheartmuscle

fibersandadiposetissue.Hemoptysisre-occurredafterbiopsy

andpersistedforabout1week.PulmonaryCTAwasthen

per-formed, and ahypodense filling defect was evident inthe

rightventricleandrightpulmonaryartery(Fig.1A1andB1).

Therefore,anticoagulanttherapy(low-molecularweight

hep-arinfollowedbywarfarin)wascommenced.

InSeptember2005,whilestillonanticoagulanttherapy,the

patientwashospitalized withfever,cough,neckand facial

swelling,dyspnea,andpalpitations.Onphysicalexamination,

shehadfever(38.5◦_C),_bilateral_jugular_venous_distention,_face

and neck edema, osteofolliculitis, and erythema nodosum

onthe right pretibial region. Inaddition, two genital ulcer

scarsandoralaphthaewereobserved.Humanleukocyte

anti-gen B51 test was positive and pathergy test was negative,

sothediagnosisofBDwasmade.PulmonaryCTAwas

per-formedagain.Theintracardiacthrombus(ICT)notedearlier

remained,butnow,dilatationsof2cmoftheascendingand

2.5cm of the descending branches ofthe right pulmonary

arterywereevident,togetherwithadilatationof3cmofthe

descendingbranchoftheleftpulmonaryartery.Alldilatations

were associatedwiththe presenceofmuralthrombi. Also,

neithertherightbrachiocephalicveinnorthesuperiorvena

cavacouldbevisualizedbecauseofthrombosis.Theclinical

findingsthatdevelopedoverthe9-monthperiodpriorto

sub-sequenttreatmentareshowninchronologicalorder(Table1).

First, warfarin therapywasdiscontinuedbecause it was

possiblethatbothapulmonaryarterialaneurysmand

arteri-tiswerepresent.Methylprednisolone(1g/dayfor3days)was

administered,followedby1mg/kg/dayoforalprednisolone.

Acyclophosphamide(CYC)pulseof1gwasstartedand

con-tinuedmonthlythereafter.Prednisolonewastapered4weeks

later.Symptoms wererelieved,and boththeCRPlevel and

theESRfelltonormalranges.Hemoptysisgraduallydecreased

andthendisappeared.

In November2005, thepatient wasre-evaluatedby

pul-monaryCTA.Thrombipersistedintheintracardiacregion,the

superior venacava (Fig.1D2) and bothpulmonaryarteries.

Multiplecollateralintercostalveins,whichdraintheazygos

vein, were serving todrain theupper extremities.A filling

defectwasobservedinthedescendingbranchoftheleft

pul-monaryartery(Fig.1C2).Thiscreatedadilatationinthevessel

wall,whichwasassociatedwithminimalintraluminal

con-trastenhancement.However,thiswasnotconsideredtobe

ananeurysm.InSeptember2005,thereportofapulmonary

arteryaneurysmwasreviewedandre-classifiedaswall

dilata-tioncausedbyanintraluminalthrombus.

Elevenmonthslater,whilestillundergoingmonthlyCYC

treatment,feverwithchillsre-occurredassociatedwithan

ele-vatedESRandCRPlevel(37mm/hand51mg/L,respectively).

Therefore,interferon-alpha(5MUthreetimesperweek)was

addedtotherapyandthedoseofprednisolonewasincreased

to 1mg/kg/day. The patientreceived atotal of15g ofCYC

overan18-monthperiod.Interferontherapywascontinuedfor

approximately11months.Next,azathioprine150mg/dayand

acetylsalicylicacid100mg/daywerecommenced.Atthetime

ofwriting,thepatientremainsonthistreatment,andthesigns

andsymptomspreviouslyreportedhavenotre-appeared.

PulmonaryCTAwasusedtofollow-upthethrombiinthe

intracardiacregion,thepulmonaryarteries,andthesuperior

venacava.Thethrombusintherightventriclehaddecreased

insizeby2008(Fig.1A2).In2010,thus5yearsafterinitialCTA,

thesizeoftherightventricularthrombus(andthecalcificpart

thereof)hadbecomefurtherreduced(Fig.1A3).Thethrombus

inthepulmonaryarteryremainedvisibleontheCTAimagesin

2008and2010.Incomparisonwiththescanperformedin2005,

CTArevealedthatthethrombiintherightintermediatelobar

pulmonaryartery(Fig.1B1–B3)andintheleftinferiorlobar

pulmonaryartery(Fig.1C1–C3)decreasedinsizeovertime.In

theCTAscanscarriedoutin2008and2010,thrombosisinthe

superiorvenacavapersistedunchangedinthecranialsection

oftheazygosdrainage(Fig.1D2–D4). Nonewthrombiwere

notedonfollow-uppulmonaryCTA.Currently,noclinicalor

laboratoryevidenceindicatesthepresenceofactivedisease.

Discussion

WereportaBDpatientwithseriouscomplicationsincluding

cardiacandvascularinvolvement.Wedescribeclinical

find-ingspriortoclinicaldiagnosis(thusbeforetreatment)anduse

ofCTAtofollow-upthrombiover5yearsoftreatment.

TheclinicalcourseofBDisnotablymoresevereinmales.

Severecomplicationssuchasvascular,neurologicaland

pul-monaryinvolvementaswellasmortalityaremostlyrelated

(3)

Fig.1–Five-yearcomputedtomographyangiography(CTA)follow-upofthrombiintheintracardiacregion,thesuperior venacava,andbothpulmonaryarteries.

In2005(A1),aCTAscanrevealedalargehypodensethrombusintherightventricle(arrow).In2008(A2),thethrombus decreasedinsizeandwaspartlycalcified,andsuchshrinkagecontinuedto2010(A3).

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Table1–ClinicalcourseofBehcet’sdiseaseinapatientwithdelayeddiagnosisandtreatment.

Clinicalfindings Dec.2004 Jan.2005 March2005 April2005 May2005 June2005 Sep.2005

Genitalulcer + − − − − − −

Oralaphthouslesiona ₊ ₊ ₊ ₊ ₊ ₊

Fever + + + + + +

Palpitation + + + + +

Intracardiacthrombus + + + +

Pleuriticchestpain + + +

Hemoptysis + + +

Cough + + +

Pulmonaryarterythrombus + +

Genitalulcerscarsb ₊

Erythemanodosum +

Acneiformandpseudofollicularskin lesions

+

Uveitis − −

Faceandneckedema +

Jugularvenousdistention +

Pathergytest − −

HLAB51 +

Superiorvenacavathrombus +

Treatment −

–Oralempiricalantibiotics +

–IVantibiotics +

–LMWH,followedbywarfarine + −

–Cyclophosphamideand corticosteroid

+

LMWH,lowmolecularweightheparin.

a _She_was_suffering_from_these_lesions_previously,_but_those_were_rare.

b _Not_examined_by_the_physician_previously.

developed during diagnostic evaluation were not fatal. It

remains poorlyknown why females withsevere

complica-tions suffer less mortality than males. As a mechanism,

estrogensmay suppress pro-inflammatory activities ofthe

vascularendotheliumandneutrophils.6_{Alternatively,}

testos-teronemay augment neutrophil functionality,especially in

males.7

Thrombophlebitisandmajorvesselthrombosisare

com-monmanifestationsofvascularinvolvementinBDpatients,

whereasICTisextremelyrare.1_As_in_our_case,_pulmonary_and

cardiaccomplicationsfrequentlyco-exist.1,8_Fever,

hemopty-sis,dyspneaandcougharecommonpresentingsymptoms.8

The frequencies of such complications may be

underesti-matedbecausetheclinicalpresentationofICTisnonspecific

inmostpatients.

In differential diagnosis of BD with venous

thrombo-sis and pulmonary involvement, Hughes–Stovin Syndrome

(HSS) should be considered. The clinical, radiological, and

histopathologicalfindingsofHSSandBDoverlapsignificantly.

HSSisaveryraredisordercharacterizedbythrombophlebitis

andbythepresenceofmultiplepulmonaryand/orbronchial

aneurysms. HSS patients usuallypresent with cough,

dys-pnea,fever,chestpainandhemoptysis;thesesymptomsare

also evidentinBD patients. Specifically, the extentof

pul-monaryinvolvementisoftenidenticalinpatientswiththese

diseases.Indeed,HSShasbeenconsideredtobeavariantof

BDoranincompleteformofthedisease.However,findings

associatedspecificallywithBDincluderecurrentgenital

ulcer-ation,eyelesions,skinlesions,iritis,arthralgiaandapositive

pathergytest;thesehelptodistinguishBDfromHSS.9

ThrombophilicfactorsareexpressedinsomeBDpatients

and maycontributetothrombus formation.Inour patient,

heterozygousmutationofprothrombinG-A20210genewas

detected.Importantly,ICThasbeenreportedtobeassociated

withdeepveinthrombosisandthrombosisofthevenacava

in50%and22%ofBDcases,respectively.10_We_found_no

evi-denceofdeepveinthrombosisonDopplerultrasonography.

In patientswithICT associatedwithBD, thepresenceofa

pulmonaryembolismand/orthrombusshouldbeinvestigated

evenifvenousthrombosiscannotbedetected.

In2005(C1),hypodensefillingdefectswereevidentintheleftinferiorlobarpulmonaryartery.In2008(C2)and2010(C3),a thrombuswasevidentinthisregionbutbecameprogressivelysmallerinsize.

In2005(D1,D2),thrombosiswasevidentinthesuperiorvenacava(thickwhitearrow),andtheupperextremitiesdrainedto theVCSvia_azygos_vein_(thin_white_arrow)._In₂₀₀₈_(D3),_coronal_CTA_imaging_revealed_thrombosis_in_the_superior_vena

cava(thickblackarrow).TheupperextremitiesdrainedtotheVCSvia_the_collateral_circulation_and_the_intercostal_veins

(5)

Associationofathromboticsuperiorvenacavasyndrome

withICTisnotcommon inBDpatients. However,the

inci-denceofpulmonaryembolismand/orthrombusishighinBD

patientswithICT.1,8 _The_presence_of_all _of_ICT, _thrombotic

superiorvenacavasyndrome,andapulmonaryartery

throm-bus/embolism,isextremelyrareinBDpatients;onlyfivecases

(includingthepresentcase)havebeendescribedinthe

litera-ture.Itissometimeshardtoechocardiographicallydistinguish

betweenICT,vegetationsandtumors.However,such

distinc-tionsare important,becausethe treatmentsand prognoses

differ.ComputedtomographyandMRImightbebetter

meth-odsforinvestigatingtheextensionoftheinvolvements,asin

ourcase.1,8 _Also,_although_biopsies_of_the_mass_in_the_right

ventricularcavitywerenotdiagnosticforourpatient,these

didallowustoexcludemyxoma,endomyocardialfibrosis,and

endocarditis.11

Hemoptysisandfeverarethemostcommonsymptomsof

pulmonaryartery involvementinBD.12 _Hemoptysis_can _be

causedbypulmonaryaneurysmsand/orpulmonaryarteritis.

Inourcase,noaneurysmwasdetected,andwethusconsider

that the hemoptysis was caused by pulmonary arteritis.

Confirmationofthe causeofhemoptysis inaBDpatientis

essential to guide the choice of appropriate treatment.11

Hemoptysis caused us to discontinue anticoagulant

therapy.

RegardlessofthesiteoforganinvolvementinBD,theaimof

treatmentistopreventirreversibledamagethatoccurs

prin-cipallyatearlystagesofthedisease.Thus,earlydiagnosisis

important.11_In_our_case,_diagnosis_was_made_{approximately}

9 months after symptom onset; this delayed initiation of

immunosuppressivetherapy.Noconsensushasyetemerged

onthemanagementofmajorvesseldisease(withthrombi)

and ICT in BD patients.13 _Various _treatment _modalities

including surgery, immunosuppressiveand anticoagulation

medications,antiplatelettreatments,andthrombolytic

ther-apyhave been used.10 _However,_no _randomized _controlled

studyhasassessedtheefficacyofthevarioustherapeutic

regi-mens,andcurrentrecommendationsarebasedononlypartial

consensusorobservationalstudies.

Intravenousthrombolytictherapymightbeconsideredfor

BDpatientswithICTandwidespreadthrombibutwithout

pul-monaryarteryaneurysms.8_It_is_important_to_emphasize_that

ifapulmonaryembolisminsuspectedinaBDpatient,neither

anticoagulantnorthrombolytictreatmentshouldcommence

before CTA scanning confirms that aneurysms are absent;

suchtreatmentwouldbeassociatedwithahighriskof

hem-orrhageifaneurysmswerepresent.Theformofpulmonary

artery occlusion seen in BD patients differs from classic

pulmonaryembolismsbecausethe BDocclusionsrepresent

principallyinsituthrombicomplicatingunderlyingvasculitis,

whichmayalsoresultininfarction,hemorrhage,hemoptysis,

andformationofpulmonaryarteryaneurysms.8,14_As

hemop-tysiswasevident,andasitwaspossiblethatinsituthrombosis

waspresentinthepulmonaryarteries,weescheweduseof

thrombolytictherapy.

Aftersurgical removalof ICT, thrombus recursin some

BD patients despite prescription of heparin therapy. This

emphasizes the risk that BDcan be worsened bysurgery.

Therefore, to avoid surgery, immunosuppressive agents

shouldbegiven.10,13,15,16_High-dose_{methylprednisolone}_and

CYC should be the treatment of choice. Interferon alpha

shouldbegivenifsymptomsdonotresolvequickly.11,15,17

Weinitiallyusedpulsemethylprednisoloneandcontinued

withmonthlyCYC(15ginall),and1mg/kg/dayprednisolone.

Elevenmonthslater,interferonalphawasaddedbecauseof

recurrence of fever and hemoptysis; this was given for 11

months.Wethencontinuedwithazathioprine.

Anotablefeatureofthiscasereportisthatcomplications

did not completely disappear despite immunosuppressive

therapy(Fig.1A–D).Corticosteroidsandimmunosuppressive

drugsmaynonethelessbeverybeneficial,particularlyifgiven

atanearlystageofdevelopmentofcomplications,thusbefore

irreversibledamagedevelops.10,13

In conclusion,use ofthe non-invasiveCTAtechniqueis

valuableindiagnosisandfollow-upofBDpatientswith

intrac-ardiacandmajorvascularthrombi.WesuggestthatBDshould

bekeptinmindupondifferentialdiagnosisofpatientswith

ICT andfever.Familiarity withthe radiologicaland clinical

characteristicsofBDisessentialtoensureaccurateearly

diag-nosisandprompttreatment.

Conflicts

of

interest

Theauthorsdeclarenoconflictsofinterest.

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