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
Cryopyrin-associated
periodic
syndromes
(cryopyrinopathies
–
CAPS)
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
maSectorofPediatricRheumatology,DepartmentofPediatrics,UniversidadeFederaldeSãoPaulo(Unifesp),SãoPaulo,SP,Brazil
bCenterforDevelopmentofMedicalTeaching,MedicineSchool,UniversidadedeSãoPaulo(USP),SãoPaulo,SP,Brazil
cPediatricRheumatologyUnit,Children’sInstitute,MedicineSchool,UniversidadedeSãoPaulo(USP),SãoPaulo,SP,Brazil
dHospitaldaCrianc¸adeBrasíliaJoséAlencar(HCB),Brasília,DF,Brazil
eIrmandadedaSantaCasadeMisericórdiadeSãoPaulo,SãoPaulo,SP,Brazil
fServiceofImmunology,AllergyandPediatricRheumatology,DepartmentofPediatrics,FaculdadedeMedicinadeRibeirãoPreto,
UniversidadedeSãoPaulo(USP),RibeirãoPreto,SP,Brazil
gServiceofRheumatology,HospitaldasClínicas,UniversidadeFederaldePernambuco(UFPE),Recife,PE,Brazil
hUniversidadeFederaldoPará(UFPA),Belém,PA,Brazil
iServiceofRheumatology,NucleusAdolescents’HealthStudies,UniversidadedoEstadodoRiodeJaneiro(UERJ),RiodeJaneiro,RJ,Brazil
jInstitutodePuericulturaePediatriaMartagãoGesteira,ServiceofPediatricRheumatology,UniversidadeFederaldoRiodeJaneiro
(UFRJ),RiodeJaneiro,RJ,Brazil
kHospitalPequenoPríncipe,Curitiba,PR,Brazil
lServiceofRheumatology,HospitaldasClínicas,UniversidadeFederaldeMinasGerais(UFMG),BeloHorizonte,MG,Brazil
mPediatricRheumatologyUnit,FaculdadedeMedicinadeBotucatu,UniversidadeEstadualPaulista(Unesp),Botucatu,SP,Brazil
a
r
t
i
c
l
e
i
n
f
o
Articlehistory:
Received6July2015 Accepted30August2015 Availableonline20October2015
a
b
s
t
r
a
c
t
Objective:Toestablishguidelinesbasedoncientificevidencesforthemanagementof cry-opyrinassociatedperiodicsyndromes.
Descriptionoftheevidencecollectionmethod:TheGuidelinewaspreparedfrom4clinical ques-tionsthatwerestructuredthroughPICO(Patient,Interventionorindicator,Comparison
∗ Correspondingauthor.
E-mail:teterreri@terra.com.br(M.T.R.A.Terreri).
http://dx.doi.org/10.1016/j.rbre.2015.08.020
Keywords:
Familiarcoldautoinflammatory syndrome
Muckle-Wellssyndrome Chronicinfantileneurologic Cutaneousandarticular syndrome
Autoinflammatorysyndromes Guidelines
andOutcome),tosearchinkeyprimaryscientificinformationdatabases.Afterdefiningthe potentialstudiestosupporttherecommendations,theseweregraduatedconsideringtheir strengthofevidenceandgradeofrecommendation.
Results: 1215articleswereretrievedandevaluatedbytitleandabstract;fromthese,42 articleswereselectedtosupporttherecommendations.
Recommendations:1.ThediagnosisofCAPSisbasedonclinicalhistoryandclinical manifesta-tions,andlaterconfirmedbygeneticstudy.CAPSmaymanifestitselfinthreephenotypes: FCAS(mildform),MWS(intermediateform)andCINCA(severeform).Neurological, oph-thalmic,otorhinolaryngologicalandradiologicalassessmentsmaybehighlyvaluablein distinguishingbetweensyndromes;2.ThegeneticdiagnosiswithNLRP3geneanalysismust beconductedinsuspectedcasesofCAPS,i.e.,individualspresentingbefore20yearsofage, recurrentepisodesofinflammationexpressedbyamildfeverandurticaria;3.Laboratory abnormalitiesincludeleukocytosisandelevatedserumlevelsofinflammatoryproteins;and 4.Targetedtherapiesdirectedagainstinterleukin-1leadtorapidremissionofsymptomsin mostpatients.However,thereareimportantlimitationsonthelong-termsafety.Noneof thethreeanti-IL-1inhibitorspreventsprogressionofbonelesions.
©2015ElsevierEditoraLtda.Allrightsreserved.
Diretrizes
de
conduta
e
tratamento
de
síndromes
febris
periódicas
associadas
à
criopirina
(criopirinopatias
–
CAPS)
Palavras-chave:
Síndromeautoinflamatória familiarassociadaaofrio SíndromedeMuckle-Wells Síndromeneurológicacutâneae articularcrônicainfantil Síndromesautoinflamatórias Diretrizes
r
e
s
u
m
o
Objetivo: Estabelecerdiretrizesbaseadasemevidênciascientíficasparamanejodas Sín-dromesperiódicasassociadasàcriopirina(Criopirinopatias–CAPS).
Descric¸ãodométododecoletadeevidência: ADiretrizfoi elaboradaapartirde4questões clínicasqueforamestruturadaspormeiodoP.I.C.O.(Paciente,Intervenc¸ãoouIndicador, Comparac¸ãoeOutcome),combuscanasprincipaisbasesprimáriasdeinformac¸ãocientífica. Apósdefinirosestudospotenciaisparasustentodasrecomendac¸ões,estesforamgraduados pelaforc¸adaevidênciaegrauderecomendac¸ão.
Resultado: Foramrecuperados,eavaliadospelotítuloeresumo,1215artigos,tendosido selecionados42trabalhos,parasustentarasrecomendac¸ões.
Recomendac¸ões: 1.OdiagnósticodeCAPSébaseadonaanamneseemanifestac¸ões clíni-cas,sendoposteriormenteconfirmadoporestudogenético.Podesemanifestarsobtrês fenótipos:FCAS(formaleve),MWS(formaintermediária)eCINCA(formagrave).Avaliac¸ões neurológica,oftalmológica,otorrinolaringológicaeradiológicapodemserdegrandevaliana distinc¸ãoentreassíndromes;2.OdiagnósticogenéticocomanálisedogeneNLRP3deveser conduzidonoscasossuspeitosdeCAPS,istoé,indivíduosqueapresentam,antesdos20anos deidade, episódiosrecorrentesdeinflamac¸ãoexpressa porurticáriaefebremoderada; 3.Asalterac¸õeslaboratoriaisincluemleucocitoseeelevac¸ãonosníveisséricosdeproteínas inflamatórias;4.Terapiasalvodirigidascontraainterleucina1levamarápidaremissãodos sintomasnamaioriadospacientes.Contudo,existemlimitac¸õesimportantesemrelac¸ão àseguranc¸aemlongoprazo.Nenhumadastrêsmedicac¸õesanti-IL1evitaprogressãodas lesõesósseas.
©2015ElsevierEditoraLtda.Todososdireitosreservados.
Description
of
the
evidence
collection
method
ThisGuidelinewaspreparedfrom4relevantclinicalquestions relatedtothemanagementofcryopyrin-associatedperiodical syndromes (cryopyrinopathies). The questions were struc-turedbytheuse ofPICO(Patient,Intervention orindicator, ComparisonandOutcome),allowingthegenerationof strate-gies forsearchingevidence (described aftereach question, withthenumberofrecoveredarticles),inthemainprimary
atwww.cebm.net), including availableevidence ofgreatest strength.
Summary
of
grades
of
recommendation
and
strength
of
evidence
A. Experimental or observationalstudies of higher consis-tency
B. Experimentalorobservationalstudiesoflowerconsistency C. Casereports(non-controlledstudies).
D. Expertopinionwithoutexplicitcriticalappraisal,orbased onphysiologyorbenchresearch.
Objective
Toestablish guidelinesbased onscientificevidenceforthe management ofcryopyrin-associated periodical syndromes (cryopyrinopathies).
Introduction
Cryopyrin-associated periodic syndromes (CAPS) comprise a specific, rare group ofmonogenic autoinflammatory dis-easeswhichareincludedinthegroupofhereditaryperiodic fever syndromes caused by a defect in the regulation of inflammatory cytokines, particularly interleukin-1 (IL-1). Thesediseases includethe familialcold-associated autoin-flammatorysyndrome(FCAS);Muckle–Wellssyndrome(MWS) andchronicinfantileneurological,cutaneous,andarticular (CINCA)syndrome,alsoknownasneonatal-onset multisys-teminflammatorydisease(NOMID).
1. When should we suspect that an individual is a carrierofcryopyrin-associatedperiodicalsyndromes (cryopy-rinopathies)?
Strategy
(Cryopyrin-Associated Periodic Syndromes OR Urticarias, FamilialColdORFamilialColdAutoinflammatorySyndrome 1ORMuckle–WellsSyndromeORChronic Neurologic Cuta-neousandArticularSyndromeORNOMIDORPrieur–Griscelli Syndromes OR Cryopyrinopathy OR UDA Syndromes OR ChronicInfantileNeurological,Cutaneous,andArticular Syn-dromeORNeonatalOnsetMultisystemInflammatoryDisease) ANDSignsandSymptoms.n=543.
The cryopyrin-associated periodic syndromes (CAPS) are autoinflammatory diseases characterized by recurrent episodes of systemic inflammation, involving multiple tis-sues, including joints, skin, central nervous system (CNS), eyesandears.Contrarytowhathappenswithautoimmune diseases, CAPS are not associated with immune response throughautoantibodiesor antigen-specificTcells,but with the dysfunction of the innate immune system, which is notspecific, not requiring initialsensitization by antigen.1 (D)
Familial cold-associated autoinflammatory syndrome, Muckle–Wells syndromeand chronicinfantile neurological, cutaneousandarticularsyndromewereoriginallydescribed
asdistinctclinicalentities,despitetheoverlappingof symp-tomsand signs.2 (D) Patientsoftenare seen withrecurrent
episodesoffeverandpseudourticariformrash,aswellaswith inflammationoftissuessuchasjoints,brain,earsandeyes. Indeed,thesethreesyndromesexistinaprogressionof sever-ity,withfamilialcold-associatedautoinflammatorysyndrome beingtheleastsevereconditionandCINCAthemostsevereof them;MWShasanintermediatephenotypeofseverity.Skin rash,asignalpresentinallthreediseases,isusuallythefirst manifestationtodevelopafterbirthorinearlychildhood.This conditionhasamigratory,maculopapular,urticariformrash, andusuallyisassociatedwithpruritus.2,3(D)
Familial cold-associated autoinflammatory syndrome (FCAS), or cold-induced urticaria, is the mildest form of CAPS and hasan autosomal dominanttrait. FCAS is char-acterized by recurrent and self-limited episodes of mild fever, skinrashand arthralgia,precipitatedbyexposureto environmental changes characterizedby low temperatures (e.g.,windexposure,refrigeratordooropening).FCASdiffers from cold-induced hives,where contactwithcoldsurfaces is the triggering factor. Other related symptoms include conjunctivitis, myalgia, sweating, somnolence, headache, and nausea.4 (C) Symptomsusuallybeginafewhoursafter
exposuretolowtemperatures,usuallywithashortduration ofepisodes.5(C)Althoughlatecasesofrenalamyloidosishave
beenreportedinfamilymembersaffectedbyFCAS,deafness andamyloidosisarenotusuallyobservedinthissyndrome, as opposed to what occurs inMWS and CINCA patients.6 (C)
Muckle–Wells Syndrome (MWS), is characterized by episodes ofurticariaand deafness, andrenal amyloidosis.7 (C)Recurrentepisodesoffeverandskinrashassociatedwith
jointandocularmanifestationsweredescribed,althoughnot alwayswithfever.8(C)Thecourseofthediseasevaries,from
recurrentattacks topermanent symptoms.9 (C) AsinFCAS,
conjunctivitis isoften present. Neurological impairment is oftennotdescribed,althoughinsomecasesheadache and papilledema have been reported. Amyloidosis is the most severe complication, developinginto adulthoodin approxi-mately 30% ofthe cases.8 (C) Sensorineural hearing lossis
observedin70%ofcases.10(D)
Chronic infantile neurological, cutaneous and articular (CINCA)syndrome,alsoknownasneonatal-onset multisys-tem inflammatory disease (NOMID),is associatedwith the mostseverephenotypeofthisspectrumofdiseases.11(C)The
firstsymptomsofCINCAoccuralreadyinthefirstweeksoflife orinearlychildhood.12(C)Fevercanbeanintermittentand
mildfinding;insomecasesthissignisevenabsent.Skinrash isvariableamongindividuals,dependingfromdisease activ-ity.Involvementofbonesandjointsalsovariesinseverity:in approximatelytwothirdsofthesepatients,joint manifesta-tions,mainlyinlargejoints,arelimitedtotransientarthralgia and edema. However, in one third of patients a crippling arthropathycanbeseen.12(C)PatientswithCINCA/NOMIDcan
alsoexhibitanexcessivegrowthofepimetaphysarycartilage, particularlyoflongbones,whicheventuallycauses deforma-tions leading toadiscrepancy inthe lengthoflimbs,joint contracturesanddegenerativearthropathy.13,14(C)CNS
(C)Headache,seizures, mentalretardation,spasticityofthe
lowerlimbsandpapilledemaareoftenobservedasa conse-quenceofanincreasedintracranialpressure.Eyeinvolvement withidentificationofuveitisoccursinapproximately50%of patients,withposterioruveitisinaround20%.Opticatrophy may also develop, and ocular manifestations can progress toblindness.15,16 (C) Sensorineural hearing losscanalso be
noted.
Recommendation
ThediagnosisofCAPSisbasedonclinicalhistoryandclinical manifestations,beinglaterconfirmedbygeneticstudies.CAPS maymanifestitselfinthreephenotypes,withnofixed demar-cationamongthem:FCAS (mild form),MWS(intermediate form)andCINCA(severeform).17(C)Thedistinctionbetween
thesecryopyrinopathies may bea difficulttask,since they havesymptomsincommon.Neurological,ophthalmic, otorhi-nolaryngologicalandradiologicalassessmentscanbecritical indistinguishingamongthesyndromes.
2.Howthegeneticdiagnosisofcryopyrin-associated peri-odicalsyndromeisestablished?
Strategy
(Cryopyrin-Associated Periodic Syndromes OR Urticarias, FamilialColdORFamilialColdAutoinflammatorySyndrome 1ORMuckle–Wells SyndromeORChronicNeurologic Cuta-neousandArticularSyndromeORIOMIDORPrieur–Griscelli Syndromes OR Cryopyrinopathy OR UDA Syndromes OR ChronicInfantileNeurological,Cutaneous,andArticular Syn-dromeORNeonatalOnsetMultisystemInflammatoryDisease) AND(MedicalGenetics[filter]).n=270.
Periodicsyndromesassociatedwithcryopyrinarecaused bymutations (withan autosomal dominant pattern, or de novomutations)inCIAS1gene–cold-induced autoinflamma-torysyndrome 1, alsoknown as NLRP3 or NALP3 (NACHT, nucleotide binding oligomerization domain, leucine rich-repeatfamily,pyrin domainscontainingprotein3), located onchromosome1q44.Themechanismbywhichmutations inthegeneCIAS1causeinflammatorydiseasesisnotfully understood,howeverinvitrostudiessuggestthatthese muta-tions present a functiongain effect, probably through loss of regulatory mechanisms associated with activation.18 (D)
Sofar, theonline database knownas Infevers, dedicated to autoinflammatoryhereditarydiseases,describesmorethan 170mutationsrelatedtoCAPS.19(D)
Thisgeneencodesthe proteincryopyrin,whichbelongs to a family of proteins called nucleotide binding domain andleucine-richrepeats (NLR),predominantly expressedin peripheral blood leukocytes.10,20 (D) Cryopyrin isrelated to
theregulationofcaspase-1,andchangesinitsconcentration causeoverexpressionofIL-1,andthisincreasedproduction triggersrecurrentepisodesofsystemicinflammation. Cryopy-rinisalsoinvolvedintheregulationoftheapoptosispathway and in the activation of nuclear factor kappa B, despite conflictingevidenceontheactivationofthisfactor.21,22(D)
Dif-ferentmutationsinCIAS1genehavebeenlinkedtoCAPS,and someofthesemutationsareexclusivelyrelatedtooneofthese
syndromes(FCAS,MWSand/orCINCA/NOMID).23(D)Itis
fur-therrecognizedthatinabout50%ofpatientswithadiagnosis ofCINCA/NOMIDandinaround25–33%ofpatientswithMWS, NLRP3mutationsarenotidentified.24(C)
Becausethisisageneticdiseasethatfollowsan autoso-maldominant pattern,individuals withCAPSusuallyhave one of their parents affected by the disease, with a 50% probability of havingtheir offspring affected.25 (D) Patients
withCINCA/NOMIDareusuallyaffectedbymutationsdenovo, withnofamilyhistoryofCAPS.
Recommendation
ThegeneticdiagnosiswithananalysisofNLRP3genemust beobtainedinsuspectedcasesofCAPS,i.e.,individuals pre-senting,recurrentepisodesofinflammationexpressedbymild fever and urticaria before the age of 20. It should be left clear, however,thatinfactasignificantnumber of individ-ualsclinicallydiagnosedascarriersofcryopyrinopathyhave nomutationsassociatedwiththedisease.
3.Besidesgeneticstudies,whattestsshouldberequired fortheevaluationofpatientswithcryopyrin-associated peri-odicalsyndrome?
Strategy
(Cryopyrin-Associated Periodic Syndromes OR Urticarias, FamilialColdORFamilialColdAutoinflammatorySyndrome 1ORMuckle–Wells SyndromeORChronicNeurologic Cuta-neousandArticularSyndromeORIOMIDORPrieur–Griscelli Syndromes OR Cryopyrinopathy OR UDA Syndromes OR ChronicInfantileNeurological,Cutaneous,andArticular Syn-dromeORNeonatalOnsetMultisystemInflammatoryDisease) AND(Diagnosis/Broad[filter]).n=203.
Usually,acute-phaseproteins,suchasCreactiveprotein (CRP)andserumamyloidAprotein(SAA),exhibitincreased serum levels,despitetheabsenceofcutaneoussigns;thus, these indicators should be monitored.26,27 (D) Neutrophilia
mayalsooccur.Proteinuriaandrenalfunctiontestsshould be performed, since progression to nephrotic syndrome and renal failure reflects a late complication of systemic amyloidosis.
Cerebrospinal fluid examination can be conducted in suspectedcasesofCINCA/NOMIDandMWS.High polymor-phonuclearcellcounts,highconcentrationofproteinandan increaseinintracranialpressurecanbefound.27,28(D,C)
Imag-ingstudiessuchasCTscanorbrainMRIshouldbeobtained, confirmingthediagnosis.Thesestudiescanidentify ventricu-lardilatationwithaprominentsulcusandcentralatrophy.29 (C)Plainradiographscanidentifyboneandjointinvolvement
throughthe demonstrationofmetaphysealosteopathy and impairmentofgrowthplates.30(C)Audiometryisanimportant
test forthe establishment ofan early diagnosis and mon-itoring of sensorineural hearing loss; also importantis an ophthalmicevaluation.
Recommendation
serumlevelsofinflammatoryproteins;theseshouldbe moni-tored.Imagingstudiesmaybecriticalindistinguishingamong syndromes,aswellasfortheophthalmologistand otolaryn-gologistevaluation.
Thescarcityofperiodicsyndromes associatedwith cry-opyrinandthepresenceofoverlappingsymptomswithother conditions often result in a delay in the establishment of adiagnosis.Becauseofthedifferentphenotypesrelated to CAPS,areviewofclinicalsymptomsisinorder,aswellasa combinationofdiagnosticprocedures.
4.Whatistheroleofbiologicalagentsinthemanagement ofcryopyrin-associatedperiodicalsyndrome?
Strategy
(Cryopyrin-Associated Periodic Syndromes OR Urticarias, FamilialColdORFamilialColdAutoinflammatorySyndrome 1ORMuckle–WellsSyndromeORChronic Neurologic Cuta-neousandArticularSyndromeORIOMIDORPrieur–Griscelli Syndromes OR Cryopyrinopathy OR UDA Syndromes OR Chronic Infantile Neurological, Cutaneous, and Articular SyndromeORNeonatalOnsetMultisystemInflammatory Dis-ease) AND (Interleukin 1 Receptor Antagonist Protein OR Anakinra OR Urine-Derived IL1 Inhibitor OR IL1 Inhibitor, Urine-DerivedORUrineDerivedIL1InhibitorORIL1Febrile InhibitorORFebrileInhibitor,IL1ORinfliximabORetanercept ORadalimumabORgolimumabORcertolizumabORTumor NecrosisFactoralphaORCachectin-TumorNecrosisFactorOR CachectinTumorNecrosisFactorORTNFalphaORTNF-alpha ORTumorNecrosisFactorORTumorNecrosisFactorLigand SuperfamilyMember2).n=199.
IL-1receptorantagonist
The proposed use of drugs targeting the blockage of the inflammatorycytokine activation pathway isbased on the identificationofdefectsintheregulationofthesecytokines, wheresignificantlyelevatedserumlevelsareobserved.Three different types of IL-1 receptor antagonists are available: humanrecombinant non-glycosylatedanalogofIL-1 recep-torantagonist(rhIL-1Ra)(anakinra);fusionproteincomprising typeIreceptorofIL-1; andaccessoryproteinofIL-1 recep-torandtheFcportionofhumanIgG1(rilonacept)andhuman monoclonalantibodyagainstIL-1(canakinumab).31(D)
1.Anakinra(humanrecombinantnon-glycosylatedanalogofIL-1 receptorantagonist)
The mechanism of action of anakinra is a competitive inhibitionofbindingofIL-1␣andIL-1totheirreceptors.32 (D) Thefirst study on the use ofanakinra inpatients with
CAPSwasacasereportoftwopatientsdiagnosedwithMWS presenting,asclinicalfeatures,fever,skinrash, conjunctivi-tisand increasedserum levelsofserumamyloidA.33 (C)In
this study, treatment with anakinra (100mg/day) provided improvementofinflammatorysymptomshoursafter admin-istrationofthedrug,andbothpatientsshowedareduction inserumlevelsofamyloidA.Thisresponsewasfoundtobe maintainedthroughoutasix-monthfollow-upperiodinboth patients,withasubstantialreductionininflammatoryprotein levels.33(C)
In a prospective study, an analysis was conducted on 18 patients (age range, 4–32 years) diagnosedwith CINCA, where all ofthem should have atleast two ofthe follow-ingsymptoms:skinrash,centralnervoussystemimpairment (expressedbyhearinglossandpapilledema),andosteopathy identified bypatellaorepiphysisovergrowth.In thisstudy, it was found that the treatment with anakinra (1.0mg/kg) wasassociatedwithskinrashandconjunctivitisresolution threedaysafteradministrationofthedrug.34(C)Onemonth
aftertheinitiationoftreatment,adecreaseininflammatory proteins (amyloid A and C-reactive protein), as well as in erythrocytesedimentationrate,wasnoted;andthesereduced levelsweremaintainedthroughthesix-monthevaluation.34 (C) Overall, eight patients had remission of inflammatory
symptomsinthe3rdmonthoffollow-up,whilethe remain-der (n=10) showed remission at6 months.With regard to adverseevents,themostcommonlyreportedoneswere reac-tions atthe siteofapplication, andupperrespiratory tract infection.34(C)
AretrospectivestudyanalyzingpatientswithCAPSfound that 15 patients treated with anakinra showed complete remission in disease activity within 12h after administra-tionofthedrug.35(C)Inthisstudyitwasalsoobservedthat
serumlevelsofC-reactiveproteinandofamyloidAreturned to normal oneweek after the initiation of treatment.35 (C)
Another studyonqualityoflifeofchildrendiagnosedwith CAPS showed that the use of anakinra for a mean period of37.5monthsproducedsignificantimprovementinoverall qualityoflife,analyzedbyCHQ(ChildHealth Questionnaire)-PF50.36(C)
2.Rilonacept(fusionproteincomprisingtypeIIL-1receptor,IL-1 receptoraccessoryprotein,andtheFcportionofhumanIgG1)
Rilonacept is adimeric fusion protein consistingof the extracellulardomainofinterleukin-1receptorandofhuman IgG1 Fc domain that binds and neutralizes IL-1. This was the firstdrugapprovedbytheFDA(FoodandDrug Admin-istration) forthetreatmentofCAPS,specificallyfocusedon FCASandMWS.In2008,ananalysisofresultsof47patients with FCAS and MWSenrolled intwo consecutive phaseIII studies was conducted. The first ofthese, a double-blind, randomizedstudywithasix-weekfollow-up,comparedthe administrationofweeklysubcutaneousinjectionsof rilona-cept160mg/weekversusplacebo.Thesecondstudyconsisted oftwoparts:PartA–nineweeksofanopen-phasetreatment withrilonacept;andPartB–Nine-weekofadouble-blind, ran-domized,placebo-controlledstudyofdrugdiscontinuation.In thisstudy,itwasshownthatrilonaceptadministrationwas associatedwithimprovementindiseaseactivitywithinafew daysoftheonsetoftherapy(animprovementof84%inthe symptom scorein thetreated groupversus 13% inplacebo group).37 (A) A decrease in serum levels of C-reactive
pro-tein and serum amyloid Aversus baselinevalues wasalso found.37 (A) An extension of this analysis with a 96-week
follow-upperiodshowedcontinuedimprovementinsignsand symptoms, as well asmaintenance oflow serum levelsof inflammatory proteins.38 (B) With regardto adverseevents,
reactionatthesiteofdrugapplication,upperrespiratorytract infection,headache,anddiarrheawerethemostfrequently reported.37,38(A,B)
Canakinumab,approvedin2009bytheFDA,isdirectedto thetreatmentofchildrenoverfouryearsandadultswitha diagnosisofFCASandMWS.Thisisahumanmonoclonal anti-bodyagainstIL-1withhighaffinitytobindinghumanIL-1, blockingitsinteractionwithreceptorsandtherefore neutral-izingitsactivity.
Thefirstrandomizedcontrolledtrialexaminingtheuseof canakinumabinpatientswithCAPSwascompletedin2008 andconsistedofthreeparts.Inphase1,35patientsreceived canakinumab150mg.Thosewithcompleteresponseto treat-mententeredpart2ofthestudyandwererandomlyassigned totreatmentwithcanakinumabeveryeightweeksforupto 24weeksversusnon-treatment.Afterthecompletionofphase 2orinfaceoftheoccurrenceofrelapse,phase3was initi-ated,in whichthe participants receivedat leasttwo more doses ofcanakinumab.39 (A) In Phase 1,this study showed
(open-label)completeresponsewithrespecttoimprovement ofdiseasesymptomsin97%ofpatients(34/35).Duringphase 2(double-blind),all15patientsrandomizedtotreatmentwith canakinumabremainedinremissionofthedisease,in con-trastto81%(15/16)ofpatientsrandomizedtoplacebo,who showed active disease (including high serum levels of C-reactive proteinand serum amyloid A). Atthe end ofthis phase,52% ofpatients treatedwith canakinumabreported remissionofsymptoms,comparedtozeropatientsinplacebo group.Thisstudyalsoidentifiedthat75%ofuntreatedpatients remainedwithsymptomsofmildtomoderateintensity, com-paredtozeropatientstreatedwithcanakinumab.39(A)Inthis
study,theuseofcanakinumabwaswelltolerated,withonly two patients reporting serious adverse events, including a vertigoepisodefollowedbyclosed-angleglaucomarelatedto complicationsofCAPS,andlowerurinarytractinfectionand sepsis.Themostcommonlyreportedadverseeventsamong thosereceiving thedrugwere pharyngitis, rhinitis,nausea, diarrheaandvertigo.Mostpatientsreportednoreactionsat theinjectionsite.39(A)
Inagreementwiththefindingsdescribedabove,one mul-ticenterphaseIIIstudy(open-label)alsoassociatedtheuse ofcanakinumabtoimprovementofsymptomsand suppres-sionofsystemicinflammation,withnormalizationofserum C-reactiveproteinandamyloidA.40 (B) Thisstudy aimedto
examinetheeffects,inthelongrun,oftheuseofcanakinumab (150mgor2.0mg/kgeveryeightweeks,overmorethantwo years) inpatients with previouslyuntreated CAPS, or who had already been treated in previous studies.40 (B) A
com-pleteresponsewasachieved(accordingtoevaluationscores ofdiseaseactivity)by78%(85/109)ofthosetreatment-naive patients.Theadverseeventsnotedwereconsideredtobeof mildtomoderateintensity;mostpatients(92%)reported hav-ingsufferednoreactionattheinjectionsite.40(B)
Recommendation
Targetedtherapiesdirectedagainstcytokines(interleukin-1in thiscase)areassociatedwitharapidremissionofsymptoms inmostpatientsdiagnosedwithCAPS.Theuseofrilonacept forpatientswithFCASandMWSdemonstratedimprovement indiseaseactivityinafollow-upperiodof6–96weeks,with reduced serum levels of inflammatory proteins(C-reactive proteinandamyloidA).Theuse ofcanakinumabalso
pro-motedreductionofclinicalmanifestations.However,thereare significantlimitationsontheuseofthesedrugs,especiallyin relationtoshortfollow-ups,smallnumberofpatients eval-uated, intrinsicbias whenevaluating rare diseases,and in comparingtheefficacyoftreatmentwithplacebo,parameters thatpreventamorerobustassessmentoftheeffectiveness ofthesedrugs, aswellasinrelationtotheirsafety,taking intoaccounttheirpotentiallong-termrisks.Intheliterature, two studiesdemonstratingongoing efficacyusing anakinra were found.41,42 It is not yet clear whether rilonacept or
canakinumabofferatherapeuticoptionfortreatmentof asep-ticmeningitis,ocularimpairmentorhearingloss.Noneofthe threeanti-IL-1medicationspreventtheprogressionofbone lesions.41Worldwide,thehighcostofthesebiologicals,which
aredrugsofchronicuseinallpatients,isstillthemain limita-tiontoitsuseinclinicalpracticeofpediatricrheumatologists. Usuallyanincreaseofthedose,orevenachangeof immuno-biologicalagentduringthefollow-up,isneeded.Importantly, wedonotcountondirectcomparisonsofthethreedifferent typesofIL-1receptorantagonistscurrentlyavailable. Conse-quently,itbecomesimpossibletosuggestpreferentiallyone orotherofthesedrugsbasedonevidence.
Conflicts
of
interest
MariaTeresaR.A.TerreriandFlavioRobertoSztajnbokserve asspeakersforNovartis.ClovisArturAlmeidadaSilvahasa conflictofinterestswithConselhoNacionaldeDesenvolvimento Científico e Tecnológico (CNPq302724/2011-7), Federico Foun-dationand NúcleodeApoioàPesquisa“SaúdedaCrianc¸a edo Adolescente”,USP(NAP-CriAd).Theother authorsdeclareno conflictofinterests.
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