Rev. Bras. Reumatol. vol.56 número1

(1)

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

REVISTA

BRASILEIRA

DE

REUMATOLOGIA

Original

article

Guidelines

for

the

management

and

treatment

of

periodic

fever

syndromes

familial

Mediterranean

fever

Maria

Teresa

R.A.

Terreri

a,∗

,

Wanderley

Marques

Bernardo

b

,

Claudio

Arnaldo

Len

a

,

Clovis

Artur

Almeida

da

Silva

c

_,

_Cristina

_Medeiros

_Ribeiro

_de

_Magalhães

d

_,

Silvana

B. Sacchetti

e

_,

_Virgínia

_Paes

_Leme

_Ferriani

f

_,

_Daniela

_Gerent

_Petry

_Piotto

a

_,

André

de

Souza

Cavalcanti

g

_,

_Ana

_Júlia

_Pantoja

_de

_Moraes

h

_,

_Flavio

_Roberto

_Sztajnbok

i

_,

Sheila

Knupp

Feitosa

de

Oliveira

j

_,

_Lucia

_Maria

_Arruda

_Campos

c

_,

_Marcia

_Bandeira

k

_,

Flávia

Patricia

Sena

Teixeira

Santos

l

_,

_Claudia

_Saad

_Magalhães

m

a_Sector_of_Pediatric_{Rheumatology,}_Department_of_Pediatrics,_Universidade_Federal_de_São_Paulo_(Unifesp),_São_Paulo,_SP,_Brazil b_Center_for_Development_of_Medical_Teaching,_Medicine_School,_Universidade_de_São_Paulo_(USP),_São_Paulo,_SP,_Brazil c_Pediatric_Rheumatology_Unit,_Children’s_Institute,_Medicine_School,_Universidade_de_São_Paulo_(USP),_São_Paulo,_SP,_Brazil d_Hospital_da_Crianc¸a_de_Brasília_José_Alencar_(HCB),_Brasília,_DF,_Brazil

e_Irmandade_da_Santa_Casa_de_{Misericórdia}_de_São_Paulo,_São_Paulo,_SP,_Brazil

f_Service_of_Immunology,_Allergy_and_Pediatric_{Rheumatology,}_Department_of_Pediatrics,_Faculdade_de_Medicina_de_Ribeirão_Preto,

UniversidadedeSãoPaulo(USP),RibeirãoPreto,SP,Brazil

g_Service_of_{Rheumatology,}_Hospital_das_Clínicas,_Universidade_Federal_de_Pernambuco_(UFPE),_Recife,_PE,_Brazil h_Universidade_Federal_do_Pará_(UFPA),_Belém,_PA,_Brazil

i_Service_of_{Rheumatology,}_Nucleus_{Adolescents’}_Health_Studies,_Universidade_do_Estado_do_Rio_de_Janeiro_(UERJ),_Rio_de_Janeiro,_RJ,_Brazil j_Instituto_de_Puericultura_e_Pediatria_Martagão_Gesteira,_Service_of_Pediatric_{Rheumatology,}_Universidade_Federal_do_Rio_de_Janeiro

(UFRJ),RiodeJaneiro,RJ,Brazil

k_Hospital_Pequeno_Príncipe,_Curitiba,_PR,_Brazil

l_Service_of_{Rheumatology,}_Hospital_das_Clínicas,_Universidade_Federal_de_Minas_Gerais_(UFMG),_Belo_Horizonte,_MG,_Brazil m_Pediatric_Rheumatology_Unit,_Faculdade_de_Medicina_de_Botucatu,_Universidade_Estadual_Paulista_(Unesp),_Botucatu,_SP,_Brazil

a

r

t

i

c

l

e

i

n

f

o

Articlehistory:

Received6July2015

Accepted30August2015

Availableonline20October2015

Keywords:

FamilialMediterraneanfever

Guidelines Childhood

a

b

s

t

r

a

c

t

Objective:Toestablishguidelinesbasedonscientificevidenceforthemanagementof

famil-ialMediterraneanfever.

Descriptionoftheevidencecollectionmethod:TheGuidelinewaspreparedfrom5clinical

ques-tionsthatwerestructuredthroughPICO(Patient,Interventionorindicator,Comparison

andOutcome),tosearchkeyprimaryscientificinformationdatabases.Afterdefiningthe

potentialstudiestosupporttherecommendations,theseweregraduatedconsideringtheir

strengthofevidenceandgradeofrecommendation.

Results:10,341 articles were retrieved and evaluated by title and abstract; from these,

46articleswereselectedtosupporttherecommendations.

∗ _{Corresponding}_author_.

E-mail:teterreri@terra.com.br(M.T.R.A.Terreri).

http://dx.doi.org/10.1016/j.rbre.2015.08.019

(2)

Fever

Autoinflammatorysyndromes

Recommendations: 1.ThediagnosisofFMFisbasedonclinicalmanifestations,

character-izedbyrecurrentfebrileepisodesassociatedwithabdominalpain,chestorarthritisoflarge

joints.2.FMFisageneticdiseasepresentinganautosomalrecessivetrait,causedby

muta-tionintheMEFVgene.3.Laboratorytestsarenotspecific,demonstratinghighserumlevels

ofinflammatoryproteinsintheacutephaseofthedisease,butalsooftenshowinghigh

levelsevenbetweenattacks.SAAserumlevelsmaybeespeciallyusefulinmonitoringthe

effectivenessoftreatment.4.Thetherapyofchoiceiscolchicine;thisdrughasprovenits

effectivenessinpreventingacuteinflammatoryepisodesandprogressiontoward

amyloid-osisinadults.5.Basedontheavailableinformation,theuseofbiologicaldrugsappearsto

beanalternativeforpatientswithFMFwhodonotrespondorareintoleranttotherapywith

colchicine.

Diretrizes

de

conduta

e

tratamento

de

síndromes

febris

periódicas

associadas

a

febre

familiar

do

Mediterrâneo

Palavras-chave:

FebrefamiliardoMediterrâneo

Diretrizes Infância Febre

Síndromesautoinflamatórias

r

e

s

u

m

o

Objetivo: EstabelecerdiretrizesbaseadasemevidênciascientíficasparamanejodaFebre

FamiliardoMediterrâneo(FFM).

Descric¸ãodométododecoletadeevidência: ADiretrizfoielaboradaapartirde5questões

clínicasqueforamestruturadaspormeiodoP.I.C.O.(Paciente,Intervenc¸ãoouIndicador,

Comparac¸ãoeOutcome),combuscanasprincipaisbasesprimáriasdeinformac¸ãocientífica.

Apósdefinirosestudospotenciaisparasustentodasrecomendac¸ões,estesforamgraduados

pelaforc¸adaevidênciaegrauderecomendac¸ão.

Resultados: Foramrecuperados,eavaliadospelotítuloeresumo,10.341trabalhos,tendo

sidoselecionados46artigosparasustentarasrecomendac¸ões.

Recomendac¸ões:1.OdiagnósticodaFFMébaseadonasmanifestac¸õesclínicas,caracterizadas

porepisódiosfebrisrecorrentesassociadosadorabdominal,torácicaouartritedegrandes

articulações;2.AFFMéumadoençagenéticaapresentandotraçoautossômicorecessivo

ocasionadapormutac¸ãonogeneMEFV;3.Exameslaboratoriaissãoinespecíficos

demon-strandoníveisséricoselevadosdeproteínasinflamatóriasnafaseagudadadoenc¸a,mas

também,comfrequência,demonstrandoníveiselevadosmesmoentreosataques.Níveis

séricosdeSAApodemserespecialmenteúteisnomonitoramentodaeficáciadotratamento;

4.Acolchicinaéaterapiadeescolhatendodemonstradoeficácianaprevenc¸ãodosepisódios

inflamatóriosagudoseprogressãoparaamiloidoseemadultos;5.Combasenainformac¸ão

disponível,autilizac¸ãodemedicamentosbiológicospareceseralternativaparapacientes

comFFMquenãorespondemouquesãointolerantesàterapiacomcolchicina.

Introduction

Periodicfever syndromesare autoinflammatorysyndromes

andareagroupofdiseasesclinicallycharacterizedby

recur-rentorcontinuousfeverandsystemicinflammation,lasting

from a few days to several weeks, with intervals without

symptomsthatmayvaryintheirduration.Thepresenceof

crisesofpredictabledevelopmentinassociationwitha

sim-ilar family history may suggest aperiodic feversyndrome.

Recent advances in the understanding of the molecular

basis of inflammation mechanisms allowed the

identifi-cation of genetic alterations involved in the pathogenesis

of these diseases. Currently, the following syndromes are

described: familialMediterraneanfever,

hyperimmunoglob-ulinemia D syndrome (HIDS), tumor necrosis factor (TNF)

alpha receptor-associated periodicsyndrome(TRAPS),

peri-odic fever, aphthous stomatitis, pharyngitis and adenitis

(PFAPA)syndrome,andcryopyrinopathieswhichincludethree

syndromes: Muckle–Wells syndrome (MWS), familial

cold-associatedurticaria(FCU)andchronicinfantileneurological,

cutaneousandarticular(CINCA)syndrome.Duetotheir

clin-ical relevance, the Pediatric Rheumatology Commission of

the BrazilianSociety ofRheumatology selected three

peri-odicfeversyndromesanddevelopedBrazilianGuidelinesfor

the conductand treatmentoffamilial Mediterraneanfever,

cryopyrinopathies, and periodicfever, aphthousstomatitis,

(3)

Familial

Mediterranean

fever

Descriptionofthemethodofevidencecollection

TheGuideline was preparedfrom 5relevant clinical

ques-tionsrelatedtothe managementoffamilialMediterranean

fever (FMF). The questions were structured by the use of

PICO(Patient,Interventionorindicator,Comparisonand

Out-come), allowing the generation of strategies for searching

evidence (described aftereach question, with the number

ofrecoveredarticles),inthemainprimarydatabasesof

sci-entificinformation(Medline/Pubmed,Embase,Lilacs/Scielo,

CochraneLibrary).Therecoveredevidencehasbeenselected

fromacritical evaluationusingdiscriminatory instruments

(scores):JADADandGRADEforRandomizedClinicalTrials,and

NewCastleOttawascaleforobservationalstudies.After

defin-ing thepotential studies tosupportthe recommendations,

thesearticleswereratedbasedonthestrengthofevidence

andgradeofrecommendation,accordingtotheclassification

ofOxford(availableatwww.cebm.net),includingavailable

evi-denceofgreateststrength.

Summaryofgradesofrecommendationandstrength

ofevidence

A: Experimentalor observational studies ofhigher

consis-tency

B: Experimentalorobservationalstudiesoflower

consis-tency

C: Casereports(noncontrolledstudies).

D: Expert opinion without explicit critical appraisal, or

basedonphysiologyorbenchresearch.

Objective

Toestablishguidelines based onscientificevidenceforthe

managementoffamilialMediterraneanfever(FMF).

1. Whenshould we suspectthatanindividual isacarrierof familialMediterraneanfever?

Strategy

(Familial Mediterranean Fever OR Familial Mediterranean

Fever, Autosomal Recessive OR Familial Paroxysmal

Poly-serositis OR Familial Paroxysmal Polyserositides OR

Parox-ysmalPolyserositides, FamilialORParoxysmalPolyserositis,

FamilialORPolyserositides,FamilialParoxysmalOR

Mediter-ranean Fever, Familial OR Periodic Disease OR Periodic

DiseasesORWolff’sPeriodicDiseaseORPeriodicPeritonitisOR

PeriodicPeritonitidesORPeritonitis,PeriodicORPolyserositis,

FamilialParoxysmalORPolyserositis,Recurrent)AND Signs

andSymptoms.n=2518.

ThediagnosticsuspicionoffamilialMediterraneanfever

(FMF)isbasedonclinicalmanifestations,whichare

character-izedbyrecurrentfebrileepisodesassociatedwithabdominal

and/orchestpaincausedbyserositis(peritonitis,pericarditis

orpleurisy)andarthritis/synovitisoflargejoints,

accompa-nied by erysipeloid erythema, whose emergence, in most

patients,occursbeforetheageof30(60and90%before10and

20yearsold,respectively)1,2₍_D_)._The_episodes_have_short

dura-tion(1–3days)withresolutionoccurringevenintheabsence

oftreatment;theperiodicityisirregular,varyingfromoncea

weektoonceayear.Betweenattacks,patientsremain

asymp-tomatic.Mediterraneanregionancestryisafrequentfinding.

Theattackscanbetriggeredbyemotionalstress,intense

physical activity, temperature extremes, viral infection, or

evenmenstruation.Thediseaseusuallyoccursalongwiththe

symptomsofperitonitisandarthritis.However,itmay

man-ifestatypically,withonlyisolatedepisodesofsuddenonset

offeverwithspontaneousresolutionintheabsenceofsigns

of serositis3 ₍_B₎4,5 ₍_D_). _Patients _with _FMF _may _also _present

nonspecificsignsandsymptomsmimickinginfection,acute

appendicitis,cholecystitisandarthritis,whichmaydelaythe

establishmentofthedefinitivediagnosis.

AbdominalpainisthemostcommonfeatureofFMF,

occur-ringinaround95%ofpatients.Itmaybediffuseorlocalized,

beingmildtosevereintermsofintensity.Jointinvolvement

isthesecondmostcommonmanifestation.Inmostcasesthe

arthritishasanacuteonsetandaffectslargejointsoflower

limbsandcanlast longerthan theother manifestationsof

thedisease.Monoarthritismaybetheonlymanifestationofa

crisisin75%ofcases.6_Pain_and_swelling_in_the_scrotum_may

occur inpreschoolchildren.Themostimportantlong-term

complicationissecondaryamyloidosis(AAtype)4₍_D_).

Recommendation

The diagnosis of FMF is based on clinical manifestations,

characterizedby recurrentfebrile episodes associatedwith

abdominalandchestpain,orarthritisoflargejoints.

2. Howonedeterminesthegeneticdiagnosisoffamilial Mediter-raneanfever?

Strategy

Parox-ysmal Polyserositides,FamilialORParoxysmalPolyserositis,

FamilialParoxysmalORPolyserositis,Recurrent)AND

(Diag-nosis[filter]).n=705.

FMFisclassifiedasahereditaryperiodicfeversyndrome7

(D). It was first described in 1945, being known under the

nameof“benignparoxysmalperitonitis”8₍_D_)._This_is_a_genetic

autoinflammatorydiseasewithanautosomalrecessivetrait,

causedbyamutationintheMEFVgene(Mediterraneanfever

gene)locatedontheshortarmofchromosome16(16p13)and

encodingaproteincomposedof781aminoacidsnamedpyrin

ormarenostrin.Apparently,thisproteinplaysacriticalrolein

regulatingtheinflammatoryprocess(modulatinginterleukin

production)andapoptosis9,10₍_D_)._At_least₂₉₉_mutations_have

beendescribed,manyofwhichoccurinexon10(the

great-est in this gene),where onecan identifythe four primary

(4)

M680IandM694I11₍_D_)._The_mutation_p.Met694V_relates_to_the

moresevereformofthedisease,conferringahigh riskfor

occurrenceofamyloidosis12₍_C₎13₍_B_)._However,_there_is_no

lin-earityingenotype–phenotypecorrelation,withgreatdiversity

inclinicalexpressionofpatients’carriersofthesame

muta-tionintheMEFVgene14₍_C_).

Thepresenceoftwomutationsleadingtoahomozygous

stateisfoundin60%ofsubjects,andin10%amutationwas

notidentified3 ₍_B_). _However,_30% _of_patients_with _a_typical

clinicalpresentationofFMFshowonlyasinglemutation.An

evaluationofapopulationsampleidentifiedthatthe

num-berofindividualswiththedoublymutatedandnotexpressed

MEFVgeneexceedsthenumberofpatientswithadiagnosis

ofFMF.Thisfact,coupledwiththephenotypicvariabilityof

FMF,suggestsanimportantroleofenvironmentalfactorson

theclinicalexpressionofFMF15,16₍_B_).

Recommendation

FMFisageneticdiseasepresentinganautosomalrecessive

trait,and causedbyamutationinthe MEFVgene. Amore

severediseasewithhighriskforamyloidosiscanbeseenin

patientswithp.Met694Vmutation,revealingthepotentialof

agenotype–phenotypecorrelation. Mutationsand

polymor-phismsingenesotherthanMEFVmayhaveanimpactonthe

developmentofFMF,orevenontheseverityofthedisease.

3. Besidesgeneticstudies,whattestsshouldberequiredforthe evaluationofpatientswithfamilialMediterraneanfever?

Strategy

FamilialParoxysmalORPolyserositis,Recurrent)AND

(Diag-nosis/Broad[filter]).n=6126.

CrisesrelatedtoFMFarecharacterizedbyleukocytosisand

highlevelsofacutephaseproteins,forinstance,erythrocyte

sedimentation rate (ESR), C-reactive protein (CRP),

fibrino-gen,haptoglobulin,C3andC4fractionsofcomplement,and

serum amyloidA protein (SAA)17 ₍_C_). _These _inflammatory

markershelpthephysiciantodistinguishFMF-relatedcrises

fromotherdiseasessuchasviralinfection,fibromyalgiaand

irritable bowel syndrome.A persistentlyhigh SAAleads to

higherprobabilityofdevelopingamyloidosis.Proteinuria,as

anindicator ofrenal amyloidosis, developsyears afterthe

onsetofanuntreatedFMF,constitutingalatecomplication.

Inpatientswithsevereoruncontrolleddisease,thelevelsof

acutephaseproteinsmayremainhighintheintervalbetween

episodes18₍_C_).

Recommendation

Laboratorytestsare notspecific,withhigh serum levelsof

inflammatoryproteinsintheacutephaseofthisdisease,but

often,highlevelsarefoundevenbetweenattacks.SAAlevels

maybeparticularlyusefulinmonitoringtheeffectivenessof

treatment.

4. What is the role of colchicine in the treatment of familial Mediterraneanfever?

Strategy

Parox-ysmal Polyserositides,FamilialORParoxysmalPolyserositis,

PeriodicPeritonitidesORPeritonitis, PeriodicOR

Polyserosi-tis, Familial Paroxysmal OR Polyserositis, Recurrent) AND

ColchicineAND(Therapy/Broad[filter]).n=696.

Colchicine is a tricyclic alkaloid extracted from plants

belongingtoColchicumandGloriosagenera.Thiswasthefirst

microtubuledestabilizingagentidentified,showing

antipro-liferativeactivity19₍_D_)._Over_the_past₅₀_years,_colchicine_has

beenusedinanincreasingnumberofdiseases,includingFMF,

Behcet’ssyndrome,sclerodermaandamyloidosis.

Studies have demonstrated that colchicine inhibits the

synthesisofTNF␣,leukotrieneB4,cyclooxygenase2activity,

prostaglandin E2, and thromboxane A220,21 ₍_D_). _In

mono-cytes,colchicinereacheshigherconcentrationsthanthelevels

presentintheplasma,andtheirlevelsaredependenton

gly-coproteinP.Thisfeaturemakesitdifficulttopredict,basedon

plasmalevels,theconcentrationofcolchicinewhichcanbe

achievedininflammatorycells,andalsoexplainsthelackof

responsebysomepatientswithFMF,duetothepolymorphism

ofthegeneencodingP-glycoprotein.Studieshaveshownthat

dailyadministrationofcolchicinepreventsboththe

inflam-matoryattacksandtheoccurrenceofsecondaryamyloidosis,

a major long-term complication of FMF. While most

anti-inflammatoryeffectsofcolchicinearerelatedtothedisruption

ofmicrotubulefunction,withinhibitionofchemotaxisof

neu-trophilsandsuppressionofinflammation,effectsonNLRP3

inflammasomeactivity inmacrophagesand inthe

produc-tionandmaturationofcytokinesfromdendriticcellshavealso

beenobserved22₍_C₎23₍_D_).

The most effective results have been obtained using

colchicine forFMF prophylaxis;insuchpatients, thisagent

prevented the occurrence of episodes of acute

inflamma-tion andalsothe developmentofamyloidosis24–26 ₍_B₎27 ₍_C_).

Three crossover clinical trials have demonstrated efficacy

ofcolchicine bydecreasing therecurrence ofinflammatory

episodes. Onestudy identifiedthat,among43patients, the

numberofinflammatoryepisodesfellfrom178duringtheuse

ofplaceboto29withtheadministrationofcolchicine.Inthis

study,theirauthorsobservedasignificantfallintheseverity

ofattacks,since70%oftheepisodeswere consideredmild,

comparedtoonly25%withtheuseofplacebo26₍_B_).

However,thistreatmentdidnotshowefficacyinthe

con-trol of acute attacks, when administered early during the

(5)

Although colchicine cannot completely prevent febrile

episodes, its use may halt the progressionof amyloidosis,

reversingproteinuriaintheabsenceofirreversibleglomerular

damage29₍_C_)._One_study_showed_that_proteinuria_development

rateafteraperiodof9–11yearswas1.7%in960adultpatients

who have made a proper use of colchicine versus 49% in

54patientswhodidnotproperlyusethedrug24₍_B_)._Among

the86patientswithoutproteinuriaatnephroticlevelsbefore

theintroductionofcolchicine,thisdrugpromotedresolution

infivepatientsandstabilizationofproteinuriain6824₍_B_).

Recommendation

Colchicineisthetherapyofchoice;thisdrugshowedefficacy

inpreventingacuteinflammatoryepisodesandprogression

towardamyloidosisinadults.

5. Whatistheroleofbiologicalagentsinthetreatmentoffamilial Mediterraneanfever?

Strategy(FMFIL-1receptorantagonist)

PeriodicPeritonitidesORPeritonitis,PeriodicOR

(Interleukin1Receptor Antagonist ProteinORAnakinra OR

Urine-DerivedIL1InhibitorORIL1Inhibitor,Urine-DerivedOR

UrineDerivedIL1InhibitorORIL1FebrileInhibitorORFebrile

Inhibitor,IL1)AND(Therapy/Broad[filter]).n=113.

Strategy(FMFandanti-TNFagents)

PeriodicPeritonitidesORPeritonitis,PeriodicOR

(infliximabORetanerceptORadalimumabORgolimumabOR

certolizumabORTumorNecrosisFactoralphaOR

Cachectin-TumorNecrosisFactorORCachectinTumorNecrosisFactor

ORTNFalpha ORTNF-alphaORTumor NecrosisFactor OR

TumorNecrosis FactorLigand SuperfamilyMember2) AND

(Therapy/Broad[filter]).n=183.

IL-1receptorantagonists

CarriersofFMF showsignificantlyelevated levelsofserum

TNF␣,IL-1␤,IL-6and IL-830₍_B_)._Evidence_has_demonstrated

animportantroleofpyrinintheregulationofcaspase-1

acti-vationandsubsequentcleavageoftheinterleukinprecursor

initsbiologicallyactiveform(pyrinbindsprocaspase-1,

acti-vatingcaspase-1,whichcleavespro-IL-1␤toitsactiveform)31

(D).Thus,aselevatedlevelsofIL-1arerelatedto

inflamma-toryactivity,someauthorsproposedtheuseofdrugstargeting

interleukin1(IL-1),aproinflammatorycytokine.

The use of IL-1 receptor antagonists in patients with

FMF has been described in the following situations:

patientswithincompletecontrolofdisease activitydespite

treatment with colchicine (5–10% may be resistant to

colchicine);patientswithmaintenanceofhighserumlevels

ofSAA,inabilitytousecolchicinebecauseofseriousadverse

effects,andincasesofdiseaseassociatedtovasculitis32–35_(C)_.

ThreedifferenttypesofIL-1receptorantagonistsareavailable:

anakinraisahumanrecombinantunglycosylated analogof

theIL-1receptorantagonist(rhIL-1Ra);rilonaceptisafusion

proteinthatcontainstheextracellularportionsoftypeIIL-1

receptorandIL-1receptoraccessoryprotein.

Anakinraandrilonacept targetIL-1␣andIL-1␤;anakinra

actsbybindingtoIL-1receptortypeI,inhibitingitsbiological

effects,andrilonaceptneutralizesIL-1inbloodcirculation.On

theotherhand,canakinumab,afullyhumanizedmonoclonal

antibodyoftheclassIgG1,actsspecificallyagainstIL-1␤36(D).

A review conducted in MEDLINE primary database via

PubMedcouldonlyidentifycasereportsasevidenceavailable

toevaluatethe effectivenessofIL-1receptorantagonistsin

patientswithadiagnosisofFMF.Onehastoconsiderthat,in

thiskindofstudy,onlypositiveresultstendtobereported.

Inthesestudies,treatmentwithanakinra(children:1mg/kg

in children; adults; 100mg/day) or canakinumab (children

under40kg:2mg/kgeveryeightweeks;adults:150mgevery

eightweeks)showedbeneficialresults,indicatingthatdrugs

targeted to IL-1 receptor antagonism can be good choices

when oneseeks an additional oralternative treatmentfor

colchicine37–41₍_C_)._As_to_the_safety_of_these_drugs,_pain_and

signs of inflammation at the injection site were the only

adverseeventsreportedduringtheadministrationofanakinra

andcanakinumab.

Despite theuncertaintyrelated tothe useofIL-1

recep-torantagonistsinthetreatmentofpatientswithFMF,these

agentsappeartobeviabletherapeuticalternativesforpatients

intolerantorunresponsivetotheuseofcolchicine,aswellas

forthosewithrenalimpairmentorelevatedlevelsofSAA,even

whentakingcolchicine.

Anti-TNFagents

The role oftumor necrosis factor ␣ (TNF-␣) in the

patho-genesisofFMF isnotyetclearlydefined, butthereissome

evidence withrespecttoits clinical manifestations.Serum

levelsofTNF-␣are increasedduringrecurrencesofattacks;

anddecreasesinserumlevelsofTNF-␣havebeenobservedin

patientsunderregulartreatmentwithcolchicine42₍_D₎30,43₍_C_).

Thus,theuseofdrugsbindingtocirculatingTNF-␣molecules

orattachingtothesurfaceofeffectorcells,inhibitingbinding

totheirreceptor,thusobviatingthebiologicaleffectsofTNF-␣,

maybeanalternativeforpatientswithFMF44₍_C_).

Studiesontheuseofanti-TNFagentssuchasadalimumab,

infliximab,and etanerceptinpatients(mean age:30 years)

diagnosedwithFMFandwhopresentedchronicarthritiswith

(6)

resistanttotreatmentwithcolchicine,identified,afteramean

follow-upof28(±18)months,alowerfrequencyofrelapses45

(C).Recently,areviewstudyconductedinMEDLINEprimary

databaseviaPubMedfoundonlycasereportsandcaseseries

ofpatients diagnosedwithFMF under treatmentwith

bio-logicdrugs,making atotalof59patients, ofwhich 25had

beentreatedwithanti-TNFagents(etanercept,infliximab,or

adalimumab)46₍_B_)._Despite_the_clinical_improvement

identi-fiedamongpatients witharthritisand/orspondylitis,more

robustevidencearisingfrom well-designedclinicaltrials is

neededtoevaluatetheefficacyandsafetyofthesedrugs.

Recommendation

Currentdataontheuseofbiologicaldrugsinthetreatment

ofFMFarelimitedtocasereportsorcaseseries,andtherefore

itisahardtasktoobtainaquantitativeassessmentof

treat-mentresponses.Basedonavailableinformation,theuseof

biologicalsappearstobeanalternativeforpatientswithFMF

nonresponders or intolerant to colchicine. More controlled

studiesareneededtoevaluatetheefficacyandsafetyofthis

strategy.

Conflict

of

interests

MariaTeresaR.A.TerreriandFlavioRobertoSztajnbokserve

asspeakersforNovartis.ClovisArturAlmeidadaSilvahasa

conflictofinterestswithConselhoNacionaldeDesenvolvimento

Científico eTecnológico (CNPq 302724/2011-7), Federico

Foun-dationandNúcleode ApoioàPesquisa“SaúdedaCrianc¸aedo

Adolescente”,USP(NAP-CriAd).Theotherauthorsdeclareno

conflictofinterests.

r

e

f

e

r

e

n

c

e

s

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