Rev. Bras. Reumatol. vol.54 número5

r e v b r a s r e u m a t o l . 2014;54(5):356–359

REVISTA

BRASILEIRA

DE

REUMATOLOGIA

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

Original

article

Evaluation

of

frequency

and

the

attacks

features

of

patients

with

colchicine

resistance

in

FMF

Gozde

Yildirim

Cetin

,

Ayse

Balkarli

,

Ali

Nuri

Öksüz

,

Gezmis¸

Kimyon

,

Yavuz

Pehlivan

_,

_Ozlem

_Orhan

_,

_Bunyamin

_Kisacik

_,

_Veli

_Cobankara

_,

Hayriye

Sayarlioglu

_,

_Ahmet

_Mesut

_Onat

_,

_Mehmet

_Sayarlioglu

a_{SutcuImamUniversity,SchoolofMedicine,DepartmentofInternalMedicine,DivisionofRheumatology,Kahramanmaras,Turkey}

b_{PamukkaleUniversity,SchoolofMedicine,DepartmentofInternalMedicine,DivisionofRheumatology,Denizli,Turkey}

c_{GaziantepUniversity,SchoolofMedicine,DepartmentofInternalMedicine,DivisionofRheumatology,Gaziantep,Turkey}

d_{OndokuzMayisUniversity,SchoolofMedicine,DepartmentofInternalMedicine,DivisionofNephrology,Samsun,Turkey}

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Articlehistory:

Received26August2013

Accepted17March2014

Availableonline20August2014

Keywords:

FamilialMediterraneanfever

Colchicineresistance

Treatment Depression

a

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s

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t

Introduction:Colchicine is the mainstay for the treatment of FMF, which is an

auto-inflammatorydiseasemainlywithrelapsingpolyserositis.Despitedailydosesof2mgor

moreeachday,approximately5%to10%ofthepatientscontinuetosufferfromitsattacks.

Inthisstudy,weaimedtoinvestigatethedepressionandattackfeaturesinpatientswith

FMFwhohavecolchicineresistance(CR).

PatientseMethods:CRwasdefinedforFMFpatientswith2ormoreattackswithinthelast

6monthsperiodwhileusing2mg/daycolchicine.Eighteenpatients(9Female/9Male)were

enrolledintotheCRgroupand41patientswereenrolledintothecontrolgroup(12Male/29

Female).Demographic,clinicalelaboratory findings,treatment adherence,andtheBeck

DepressionInventory(BDI)scoreswereevaluated.

Results:TheageofonsetofFMFwassignificantlylowerintheCRgroup(12.3yrsvs.16.9yrs,

P=0.03).DiseasedurationwaslongerintheCRgroup(P=0.01).Abdominalandlegpaindue

toexerciseweresignificantlymorefrequentintheCRgroupversuscontrols(83%vs.51%;

P=0.02e88%vs.60%;P=0.04,respectively).PatientswithBDIscoresover17pointswere

morefrequentintheCRgroupcomparedtocontrols(50%vs.34.1%;P<0.001).

Discussion:Wefoundthat:(1)theageofdiseaseonsetwaslowerand(2)thediseaseduration

waslongerinCRgroup.Pleuriticattacks,hematuriaeproteinuriaweremorefrequentinCR

patients.Weproposethatdepressionisanimportantfactortoconsiderinthesusceptibility

toCR.

©2014ElsevierEditoraLtda.Allrightsreserved.

DOIoforiginalarticle:http://dx.doi.org/10.1016/j.rbr.2014.03.022.

∗ _{Correspondingauthor.}

E-mail:[email protected](G.Y.Cetin).

http://dx.doi.org/10.1016/j.rbre.2014.03.022

rev bras reumatol.2014;54(5):356–359

357

Avaliac¸ão

da

frequência

e

aspectos

dos

ataques

de

pacientes

com

resistência

à

colchicina

em

febre

familiar

do

Mediterrâneo

(FFM)

Palavras-chave:

FebrefamiliardoMediterrâneo

ResistênciaàColchicina

Tratamento Depressão

r

e

s

u

m

o

Introduc¸ão: Colchicinaéaviga-mestraparaotratamentodeFFM,queéumadoenc¸a

autoin-flamatóriacompolisserositerecidivante comoprincipal manifestac¸ão.Apesarde doses

diáriasde2mgoumais/dia,aproximadamente5%-10%dospacientescontinuamasofrerde

seusataques.Nesteestudo,objetivamosinvestigarosaspectosdadepressãoedosataques

empacientescomFFMapresentandoresistênciaàcolchicina(RC).

PacienteseMétodos: EmpacientescomFFM,RCfoidefinidacomodoisoumaisataques

nosúltimosseismeses,quandoemmedicac¸ãocomcolchicina2mg/dia.Dezoitopacientes

(novemulheresenovehomens)foramrecrutadosnogrupoRCe41pacientesnogrupo

decontrole(29mulheres/12homens).Foramavaliadososachadosdemográficos,clínicose

laboratoriais,afidelidadeaotratamentoeosescoresdoBeckDepressionInventory(BDI).

Resultados: A idade de surgimento da FFM foi significativamentemenor no grupo RC

(12,3anosvs.16,9anos,P=0,03).Adurac¸ãodadoenc¸afoimaiornogrupoRC(p=0,01).

Doresabdominaisenaspernasemdecorrênciadoexercícioforamsignificativamentemais

frequentesnogrupoRCversuscontroles(83%vs.51%;p=0,02e88%vs.60%;p=0,04,

res-pectivamente).PacientescomescoresBDI>17pontosforammaisfrequentesnogrupoRC

versuscontroles(50%vs.34,1%;p<0,001).

Discussão:Verificamosque:(1)aidadedosurgimentodadoenc¸afoimaisbaixae(2)adurac¸ão

dadoenc¸afoimaiornogrupoRC.Ataquespleuríticos,hematúriaeproteinúriaforammais

frequentesempacientescomRC.Propomosqueadepressãoéfatorimportanteaserlevado

emconsiderac¸ãonasensibilidadeàRC.

©2014ElsevierEditoraLtda.Todososdireitosreservados.

Introduction

Familial Mediterranean fever (FMF) is a hereditary and an

auto-inflammatorydisease predominantly characterizedby

repeated attacks of fever, abdominal pain, pleuritic chest

pain,arthritis,and erysipelas-likeerythema.Thedisease is

most prevalent among non-Ashkenazi Jews, Arabs, Turks,

andArmenians.1 _{Thepathogenesisismainlybased onthe}

absence or insufficiency of pyrin production, which is a

peptideinvolvedin theinflammatorycascade thatinhibits

complement5a(C5a).ThemainmechanismsthattriggerFMF

attackshavenotbeenestablished.Colchicineisstillthe

main-stayinthetreatmentofthedisease.Itcompletelyorpartially

preventsFMF attacks and subsequent reactive amyloidosis

thatisregardedasthemostdangerouscomplicationofFMF.2

Interestingly, colchicine resistance (CR) is prevalent in

nearly10%oftheFMFpatients.Theattackfrequencyor

inten-sity may goon with similar or diminished frequency and

severity.TheCRpatientscouldbedividedinto completeor

partiallynon-responders.Manyfactorsmightbeinvolvedin

theCR,includinggeneticpredispositionaswellas

environ-mentalandpsychiatricconditions.Still,littleisknownabout

theabsoluteetiologyofCRinFMFpatients.Treatment

adher-enceandpotentialreasonsincludingdemographicalfactors,

socio-economic status, clinical and laboratory factors, and

psychiatricdynamicsarethoughttobecontributingfactors.

The Beck Depression Inventory (BDI) was developed by

Beckand colleagues(1979) and adaptedto TurkishbyHisli

(1988).TheBDIisaself-reportscaleof21itemsmeasuringthe

emotional, somatic, cognitive, and motivational symptoms

exhibited indepression. Thescale isnotdesignedto

diag-nosedepressionbuttoobjectivelydeterminetheseverityof

depressive symptoms. Correlation coefficients between the

EnglishandTurkishversionsofthescalewerecalculatedas

0.81and0.73(languagevalidity);splithalfreliabilitywas0.74,

and criterion-relatedvaliditywithMMPI-D(Minnesota

Mul-tiphasicPersonalityInventory)was0.63.TheBDIscores≥17

werereportedtodiscriminatedepressionthatmightrequire

treatmentwithmorethan90% accuracy.Thescoreofeach

itemrangesfrom0to3,andthedepressionscoreisobtained

byaddingthescoreofeachitem.Thehighestobtainablescore

is63.3,4

As a consequence, different therapeutic strategies are

ongoingtolimitCRinFMFpatients.Inthisstudy,weaimed

toinvestigatethedepressionandattackfeaturesinpatients

withFMFwhohavetheCR.

Patients

and

methods

Thestudygroupwascomposedof59 FMFpatientswith18

CR(9female/9male)and41(12male/29female)complete

colchicine responders.Patientshaving otheraccompanying

diseasesincludinginfections,malignancies,autoimmuneor

metabolic diseases and patients who were diagnosed for

depressionpreviouslyandunder-treatmentwith

antidepres-sants wereexcluded. Thediagnosiswascheckedonemore

timethroughthere-questioningofthepatientsinaccordance

withtheLivnehcriteriaofFMF.5

CRwasdefinedastwoormoreFMFattacksinasix-month

358

Table1–DemographicfeaturesofCRgroupandcontrolgroup.

CRGroup(n=18) ControlGroup(n=41) pvalues

Currentage(age ± SD) 30.1 ± 10,5 28.2± 9.3 0.5

Gender(F/M) 9/9 29/12 0.12

Monthlyincomeover1000TL 5(27.7%) 10(24.3%) 0.78

#ofmarriedsubjects 5(27.7%) 22(53.6%) 0.59

Educationalstatus(undergraduates) 5(27.7%) 9(21.9%) 0.62

#ofunemployedsubjects 2(11.1%) 8(19.5%)

#ofkids(number ± SD) 1± 1.5 0.9± 1.3 0.8

SubjectswithfamilyhistoryofFMF 13(72.2%) 27(65.8%) 0.6

AgeofFMFDiagnosis 20.6 ± 8.6 21.9± 10 0.6

Timebetweenonsetanddiagnosis(months) 92 59.3 0.2

Diseasesduration(months) 212 133 0.01

CR,Colchicumresistant;TL,TurkishLira.

with≤1FMF attackwithinthesixmonthsorwithoutany attacksoverthetwelvemonthswererandomizedintothe con-trolgroup. Patientsinthecolchicine resistancegroupwere using2mg/dayand higherdoses,and inthecontrolgroup patientswereusingcolchicinebelowthedosesof2mg/day. Thedemographicdata,adherencetotreatment,clinicaland attack features of the disease including the leg pain and amyloidosis,laboratoryfindings,andBDIscores,alcohol,and narcoticusagewererecorded.ABDIscore>17wasconsidered significantforseveredepressionthatrequirestreatment.

The age of disease onset as well as diagnosis and the time period from symptoms to diagnosis were carefully questioned.Thedemographicdataincludedsocio-economic featuressuchasmonthlyincome,educationandliteracy, mar-ital status, number of children, and employment. Patients were compared by the minimum wage in our country for their economic status. Concerning the educational status, post-graduatepatientswerecomparedwitheachother.Urine analyseswere assessedwith adipstick duringattacks and werecollectedfromfiles.

Thelocalethicalcommitteeapprovedthestudyprotocol and all the participant consentforms were collected. Stu-dent’sttestandone-wayANOVAwereusedforcomparison ofaverages.Pearson’scorrelationanalyseswereperformedto evaluateotherfactors.Pvalueof<0.05wasacceptedas statis-ticallysignificant.

Results

WhileCRpatientswereregularlyimplementingthetreatment protocolduringthe6-monthfollow-up, 40%ofthepatients incontrol group were misusingthe drugs. Baseline demo-graphicfeaturesofbothgroupsaredemonstratedinTable1.

Therewasnostatisticallysignificantdifferencebetweenthe

groupsconcerningthemonthlyincome,educationaland

mar-italstatus,numberofkids,andemployment.Distributionof

thepatientswithfamilyhistoryofFMFwassimilar.Disease

onsetagewassignificantlylowerinCRgroupincontrastto

thecontrols(12.3yearsand16.9years;p=0.03)anddisease

durationwassignificantlylongerinCRgroup(212monthsand

133months;p=0.01).Thereweresimilarresultsconcerning

thetimefromdiseaseonsettodiagnosis,andthedifference

wasnotsignificantbetweenthegroups.Whenwecompared

the accompanyingcomplaints duringthe attacks, pleuritic

chestpain,erysipelas-likeerythemaandeffortassociated,leg

pain wassignificantlymorefrequentinCRgroup(83%and

51% p=0.02;16.6%and 2.4%p=0.04;88%and 60% p=0.04;

respectively).Moreover,transientproteinuriaandhematuria

weresignificantlymorefrequentinCRgroup(p=0.006).There

wasnotavaluabledifferencebetweenthegroupsconcerning

abdominalpainandarthritis(Table2).Therewereno

alco-hol ornarcoticshistory amongthe groups. Thenumberof

patientswithamyloidosisinbothgroupswassimilar(Table2).

Therewasnorenalinsufficiencyinbothgroups.Patientswith

BDIscoresover17pointsweremorefrequentintheCRgroup

comparedtothecontrols(50%vs34.1%;p<0.001).

Discussion

Thisprospectivelydesignedstudy attemptstoevaluatethe

factorsthatmayleadtoCRamongtheFMFpatients.Disease

onsetagewassignificantlylowerinCRgroupincontrastto

thecontrol,anddiseasedurationwassignificantlylongerin

CRgroup.QuestionnaireresultsshowedthatpatientsinCR

group were receiving their drugs regularly under full drug

compliance. Patientswithinfrequent attacks forgottotake

thecolchicine.Additionally,therewerenoalcoholornarcotics

history amongthe CRpatients.Infact, themaintriggering

etiologicalfactorsbehindCRarenotknown.Intheprevious

study,Lidaretal.foundthatpatientswithsevereFMF

prog-nosishad moreCR.6 _{Thesefindingsare ingoodagreement}

withourstudy.Obviously, patientswithlong disease

dura-tion,highBDIscores,weresignificantlymorefrequentinthe

CR group.And attacksinCR groupwere moresevere than

controlgroup.Whenwecomparedtheaccompanying

com-plaintsduringtheattacks,pleuriticchestpain,erysipelas-like

erythema,andeffortassociatedlegpainweremorefrequent

inCRgroup.Moreover,proteinuriaandhematuriapresence

duringtheattacksweremorefrequentinCRgroup.AlsoLidar

etal.demonstratedthattheabdominalattack,chestpain,and

arthritisweremorefrequentandsevereinCRgroup,while

erysipelas-likeerythemaattacksweresimilarinbothgroups.

Thepresenceofdepressioncouldincreasethefrequencyof

FMFattacksorthecombinationoffrequentFMFattacksand

inflammatory painmight cause depression.The activityof

rev bras reumatol.2014;54(5):356–359

359

Table2–Symptomaticfeaturesofallpatients.

CRGroup(n=18) ControlGroup(n=41) pvalues

Abdominalattack 16(88.8%) 39(95.1%) 0.38

Jointattack 14(77.7%) 30(73.1%) 0.7

Chestattack 15(83.3%) 21(51.2%) 0.02

Erysipela-likeerythema 3(16.6%) 1(2.4%) 0.04

Effortassociatedlegpain 15(83.3%) 25(60.9%) 0.04

Presenceoftransienthematuriaandproteinuriaduringtheattacks 8(44.4%) 5(12.1%) 0.006

ofpatientswithamyloidosis 3(16.6%) 2(4.8%) 0.13

offamilymemberswithamyloidosis 2(11.1%) 1(2.4%) 0.16

provoketheFMF attacks.7 _{Itwasdemonstratedthat}

initiat-ing selectiveserotonin reuptakeinhibitors (SSRI) decreases

thefrequencyofFMF attackswithCR.8 _{Accordingly,itwas}

shownthatstressfactorsfacilitatedepressionandincrease

thesecretionofinflammatorycytokines.9 _{Therearestudies}

arguingtheroleofdepressionintheseverityofFMFandthat

depressiontreatmentalsodiminishesthenumberofattacks.

ThesefindingsrevealtheroleofdepressioninCR.8

Increases in inflammation can affect the

pathophysi-ology of the depression.8 _{In cytokine based FMF studies,}

plasmaconcentrationsofinterleukin-2(IL),IL-12,IL-18and

tumor necrosis alpha (TNF-␣) were elevated in depressive

patients.10,11 _{Thepro-inflammatorycytokine,IL-12,was}

ele-vatedbothduringtheattacksandintheattackfreeperiod,

contrasting healthy control studies.12 _{In addition to IL-12}

secretion,cytotoxicTcellsIL-2,IFNgamma,andTNF-alpha

alsoincreasedinFMFpatients.Thesecytokineswereelevated

bothinFMFand depression.Ourstudyhasalimitationfor

theMEFVmutationsofthepatientsthatdidn’tholdforall

ofthepatientsenrolledintothestudy.Butouraimwasthe

investigationofotherfactorsaffectingCR.

Consequently,wecanarguethatdepressionisan

impor-tantreasonamongthefactorsthatmayleadtoCR.Consistent

withprevious studies,we havefoundout theCR patients’

depressionfindings are moresevere than thecontrols.

Cli-niciansshouldconsider theinitiation ofSSRI incolchicum

resistantpatients.Wefoundthatdiseaseonsetagewaslower

anddiseasedurationwaslonger.Inaddition,pleuritisattacks,

transientmicroscopichematuria,andproteinuriaweremore

frequentinCRpatientsduringattackepisodes.Further

large-scalescreeningisrequired.

Conflicts

of

interest

Theauthorsdeclarenoconflictsofinterest.

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1. LidarM,LivnehA.FamilialMediterraneanfever:clinical, molecularandmanagementadvancements.NethJMed. 2007;65:318–24.

2.OzturkMA,KanbayM,KasapogluB,OnatAM,GuzG,Furst DE,etal.TherapeuticapproachtofamilialMediterranean fever:areviewupdate.ClinExpRheumatol.2011;29: 77–86.

3.Savas¸ırI,SahinNH.Bilis¸sel-davranıs¸cıterapilerde

de ˘gerlendirme:Sıkkullanılanölc¸ekler[Cognitivebehavioral therapyevaluation:Commonscales.].AnkaraTürk PsikologlarDerne ˘giYayınları.1997:23–38.

4.OzerA,OrhanFÖ,Ekerbic¸erHC¸.Sociodemographicvariables anddepressioninTurkishwomenfrompolygamousversus monogamousfamilies.HealthCareWomenInt.

2013;34:1024–34,doi:10.1080/07399332.2012.692414.Epub 2013Feb27.

5.LivnehA,LangevitzP,ZemerD,ZaksN,KeesS,LidarT,etal. CriteriaforthediagnosisoffamilialMediterraneanfever. ArthritisRheum.1997;40:1879–85.

6.LidarM,ScherrmannJM,ShinarY,ChetritA,NielE, Gershoni-BaruchR,etal.Colchicinenon-responsivenessin familialMediterraneanfever:clinical,genetic,

pharmacokinetic,andsocioeconomiccharacterization. Semin.ArthritisRheum.2004;33:273–82.

7.Ozc¸akarL,OnatAM,KaymakSU,UretenK,AkinciA.Selective serotoninreuptakeinhibitorsinfamilialMediterraneanfever: arewetreatingdepressionorinflammation?RheumatolInt. 2005;25:319–20.

8.OnatAM,OztürkMA,Ozc¸akarL,UretenK,KaymakSU,Kiraz S,etal.Selectiveserotoninreuptakeinhibitorsreducethe attackfrequencyinfamilialmediterraneanFever.TohokuJ ExpMed.2007;211:9–14.

9.KuberaM,MaesM.Serotonininteractionsinmajor depression.In:PetersonCK,editor.Neuro-Immune InteractionsinNeurologicandPsychiatricDisorders.Berlin: Springer-Verlag;2000.p.79–87.

10.SutcigilL,OktenliC,MusabakU,BozkurtA,CanseverA,Uzun O,etal.Pro-andanti-inflammatorycytokinebalancein majordepression:effectofsertralinetherapy.ClinDev Immunol.2007;2007:76396.

11.MerendinoRA,DiRosaAE,DiPasqualeG,MinciulloPL, MangravitiC,CostantinoA,etal.Interleukin-18andCD30 serumlevelsinpatientswithmoderate-severedepression. MediatorsInflamm.2002;11:265–7.