ww w . r e u m a t o l o g i a . c o m . b r
REVISTA
BRASILEIRA
DE
REUMATOLOGIA
Original
article
Recommendations
of
the
Brazilian
Society
of
Rheumatology
for
the
diagnosis
and
treatment
of
chikungunya
fever.
Part
2
–
Treatment
Claudia
Diniz
Lopes
Marques
a,b,∗,
Angela
Luzia
Branco
Pinto
Duarte
a,c,
Aline
Ranzolin
b,d,
Andrea
Tavares
Dantas
a,
Nara
Gualberto
Cavalcanti
b,
Rafaela
Silva
Guimarães
Gonc¸alves
b,
Laurindo
Ferreira
da
Rocha
Junior
b,d,
Lilian
David
de
Azevedo
Valadares
e,
Ana
Karla
Guedes
de
Melo
f,
Eutilia
Andrade
Medeiros
Freire
g,
Roberto
Teixeira
h,
Francisco
Alves
Bezerra
Neto
i,
Marta
Maria
das
Chagas
Medeiros
j,
Jozélio
Freire
de
Carvalho
k,
Mario
Sergio
F.
Santos
l,
Regina
Adalva
de
L.
Couto
Océa
m,
Roger
A.
Levy
n,
Carlos
Augusto
Ferreira
de
Andrade
o,
Geraldo
da
Rocha
Castelar
Pinheiro
n,
Mirhelen
Mendes
Abreu
p,
José
Fernando
Verztman
q,
Selma
Merenlender
r,
Sandra
Lucia
Euzebio
Ribeiro
s,
Izaias
Pereira
da
Costa
t,u,
Gecilmara
Pileggi
v,
Virginia
Fernandes
Moc¸a
Trevisani
w,x,
Max
Igor
Banks
Lopes
y,
Carlos
Brito
a,
Eduardo
Figueiredo
b,
Fabio
Queiroga
z,
Tiago
Feitosa
aa,
Angélica
da
Silva
Tenório
a,
Gisela
Rocha
de
Siqueira
a,
Renata
Paiva
ab,
José
Tupinambá
Sousa
Vasconcelos
ac,ad,
Georges
Christopoulos
ad,aeaUniversidadeFederaldePernambuco(UFPE),Recife,PE,Brazil
bUniversidadeFederaldePernambuco(UFPE),HospitaldasClínicas,Recife,PE,Brazil
cUniversidadeFederaldePernambuco(UFPE),HospitaldasClínicas,Servic¸odeReumatologia,Recife,PE,Brazil
dInstitutodeMedicinaIntegralProfessorFernandoFigueira(IMIP),Recife,PE,Brazil
eHospitalGetúlioVargas,AmbulatóriodeChikungunya,Recife,PE,Brazil
fUniversidadeFederaldaParaíba(UFPB),JoãoPessoa,PB,Brazil
gUniversidadeFederaldaParaíba(UFPB),HospitalUniversitárioLauroWanderley(HULW),Servic¸odeReumatologia,JoãoPessoa,PB,
Brazil
hUniversidadeEstadualdeCiênciasdaSaúdedeAlagoas(UNCISAL),Maceió,AL,Brazil
iUniversidadeFederaldoRioGrandedoNorte(UFRN),Natal,RN,Brazil
jUniversidadeFederaldoCeará(UFC),FaculdadedeMedicina,DepartamentodeMedicinaClínica,Fortaleza,CE,Brazil
kUniversidadeFederaldaBahia(UFBA),InstitutodeCiênciasdaSaúde,Salvador,BA,Brazil
lUniversidadeEstadualdoPiauí(UESPI),FaculdadedeMedicina,Teresina,PI,Brazil
mUniversidadeFederaldeSergipe(UFS),Aracaju,SE,Brazil
nUniversidadedoEstadodoRiodeJaneiro(UERJ),DisciplinadeReumatologia,RiodeJaneiro,RJ,Brazil
oFundac¸ãoOswaldoCruz(Fiocruz),EscolaNacionaldeSaúdePúblicaSérgioArouca(ENSP),RiodeJaneiro,RJ,Brazil
pUniversidadeFederaldoRiodeJaneiro(UFRJ),HospitalUniversitárioClementinoFragaFilho(HUCFF),RiodeJaneiro,RJ,Brazil
qHospitaldosServidoresdoEstadodoRiodeJaneiro,RiodeJaneiro,RJ,Brazil
∗ Correspondingauthor.
E-mail:[email protected](C.D.Marques). http://dx.doi.org/10.1016/j.rbre.2017.06.004
rHospitalEstadualEduardoRabello,Servic¸odeReumatologia,RiodeJaneiro,RJ,Brazil
sUniversidadeFederaldoAmazonas(UFAM),FaculdadedeMedicina,Manaus,AM,Brazil
tUniversidadeFederaldeMatoGrossodoSul(UFMS),CampoGrande,MS,Brazil
uUniversidadeFederaldeMatoGrossodoSul(UFMS),HospitalUniversitárioMariaAparecidaPedrossian(HUMAP),Servic¸ode
Reumatologia,CampoGrande,MS,Brazil
vUniversidadedeSãoPaulo(USP),HospitaldasClínicasdeRibeirãoPreto(HCRP),Servic¸odeReumatologiaeImunologiaPediátrica,
RibeirãoPreto,SP,Brazil
wUniversidadeFederaldeSãoPaulo(UNIFESP),SãoPaulo,SP,Brazil
xUniversidadedeSantoAmaro(UNISA),SãoPaulo,SP,Brazil
yUniversidadedeSãoPaulo(USP),HospitaldasClínicas,AmbulatóriodaDivisãodeMoléstiasInfecciosasdeParasitárias,SãoPaulo,SP,
Brazil
zInstitutodeMedicinaIntegralProfessorFernandoFigueira(IMIP),HospitalMiguelArraes,Paulista,PE,Brazil
aaUniversidadeFederaldePernambuco(UFPE),HospitaldasClínicas,DivisãodeGestãodoCuidado,Recife,PE,Brazil
abCRPFisioterapia,RiodeJaneiro,RJ,Brazil
acUniversidadeEstadualdoPiauí(UESPI),Teresina,PI,Brazil
adSociedadeBrasileiradeReumatologia,Brazil
aeSantaCasadeMisericórdiadeMaceió,Maceió,AL,Brazil
a
r
t
i
c
l
e
i
n
f
o
Articlehistory:
Received20December2016 Accepted24May2017 Availableonline22July2017
Keywords:
Chikungunyafever Treatment Consensus Brazil
a
b
s
t
r
a
c
t
Chikungunya feverhasbecomeanimportantpublichealth problemincountrieswhere epidemicsoccur becausehalfofthecasesprogresstochronic,persistentand debilitat-ing arthritis.Literaturedata onspecific therapiesatthe variousphases ofarthropathy causedbychikungunyavirus(CHIKV)infectionarelimited,lackingqualityrandomized tri-alsassessingtheefficaciesofdifferenttherapies.Thereareafewstudiesonthetreatment ofmusculoskeletalmanifestationsofchikungunyafever,butthesestudieshaveimportant methodologicallimitations.Thedatacurrentlyavailableprecludeconclusionsfavorableor contrarytospecifictherapies,oranadequatecomparisonbetweenthedifferentdrugsused. Theobjectiveofthisstudywastodeveloprecommendationsforthetreatmentof chikun-gunyafeverinBrazil.Aliteraturereviewwasperformedviaevidence-basedselectionof articlesinthedatabasesMedline,SciELO,PubMedandEmbaseandconferenceproceedings abstracts,inadditiontoexpertopinionstosupportdecision-makingindefining recommen-dations.TheDelphimethodwasusedtodefinethedegreesofagreementin2face-to-face meetingsandseveralonlinevotingrounds.Thisstudyispart2oftheRecommendationsof theBrazilianSocietyofRheumatology(SociedadeBrasileiradeReumatologia–SBR)forthe DiagnosisandTreatmentofchikungunyafeverandspecificallyaddressestreatment.
©2017PublishedbyElsevierEditoraLtda.ThisisanopenaccessarticleundertheCC BY-NC-NDlicense(http://creativecommons.org/licenses/by-nc-nd/4.0/).
Recomendac¸ões
da
Sociedade
Brasileira
de
Reumatologia
para
diagnóstico
e
tratamento
da
febre
chikungunya.
Parte
2
–
Tratamento
Palavraschave: Febrechikungunya Tratamento Consenso Brasil
r
e
s
u
m
e
n
Afebrechikungunyatemsetornadoumimportanteproblemadesaúdepúblicanospaíses ondeocorremasepidemias,vistoquemetadedoscasosevoluicomartritecrônica, per-sistenteeincapacitante.Osdadosnaliteraturasobreterapêuticasespecíficasnasdiversas fasesdaartropatiaocasionadapelainfecc¸ãopelovíruschikungunya(CHIKV)são limita-dos,nãoexistemestudosrandomizadosdequalidadequeavaliemaeficáciadasdiferentes terapias.Háalgumaspoucaspublicac¸õessobreotratamentodasmanifestac¸ões muscu-loesqueléticasdafebrechikungunya,porémcomimportanteslimitac¸õesmetodológicas. Osdadosatualmentedisponíveisnãopermitemconclusõesfavoráveisoucontráriasa ter-apêuticasespecíficas,bemcomoumaadequadaavaliac¸ãoquantoàsuperioridadeentreas diferentesmedicac¸õesempregadas.
umametodologiaDelphi,emduasreuniõespresenciaiseváriasrodadasdevotac¸ãoonline. Esteartigorefere-seàparte2dasRecomendac¸õesdaSociedadeBrasileirade Reumatolo-giaparaDiagnósticoeTratamentodaFebreChikungunya,quetrataespecificamentedo tratamento.
©2017PublicadoporElsevierEditoraLtda.Este ´eumartigoOpenAccesssobuma licenc¸aCCBY-NC-ND(http://creativecommons.org/licenses/by-nc-nd/4.0/).
Introduction
The data on specific therapies in arthropathy following chikungunyafeverarelimitedbecausethestudiespublished have small samples, heterogeneous comparison groups, dosagevariability,shortfollow-uptimeandmethodological differences.Therearenoqualityrandomizedtrialsenabling robustconclusions on the different drugs used; onlyopen studies,caseseriesand reportsofexperiences inpainand arthritismanagementduringepidemicsareavailable.
InApril2016,themulticentercohortstudyCHIKBRASILwas started,aimedatassessingthebehaviorofchikungunyafever withchronicjointmanifestationsandcollectingdatato sup-portfuturetherapeuticdecisionsinBrazil.Thusfar,6centers inthestatesPernambuco(3),Paraíba(1),Ceará(1)andSergipe (1)havecollecteddatafrom431patients,whoseanalyseshave notyetbeenpublished.
Method
Threestudygroupswerecreatedtodevelopthe recommen-dations: a central group, a literature review group and a votingpanel.Thecentralgroupconsistedof5 rheumatolo-gistsandwasresponsiblefordefiningandsendingtheleading questionsusedasthebasisforpreparingthe recommenda-tions,coordinatingandsupervisingthemembersoftheother 2groups, conductingonline votingrounds andwriting the manuscript.Thegroupthatconductedtheliteraturereview consistedof20rheumatologistsand3physiotherapists.The search forevidence was conductedin the databases MED-LINE, SciELO, PubMed and EMBASE, and articles related to thediagnosisandtreatmentofchikungunyafever,alongwith conferenceproceedings abstracts, published in Portuguese, English,FrenchandSpanishuntilOctober2016wereselected. Thisgroupwasresponsibleforreviewingtheevidencefound, providingatheoreticalbasisforthefinalrecommendations.
Thecritical evaluation of the methodological quality of thestudies foundwasperformedusing theriskofbiasfor clinical trials.Weused theSTrengthening theReporting of OBservational studies inEpidemiology (STROBE)guidelines forthecriticalanalysisofobservationalstudiesregardingthe presenceor absence ofthe necessary itemsto conduct an observationalstudy1andtheNewcastle-OttawaScale(NOS) forthemethodologicalquality.2Becausethemethodological diversityofthestudiesfoundprecludedperformingthe meta-analysis, the evaluationwas performed based onthe level ofevidenceanddegreeofrecommendationaccordingtothe 2011Oxfordclassification(LevelsofEvidence),3 considering Grading ofRecommendations Assessment, Developing and
Evaluation(GRADE)4aspects,inwhichanevaluationis per-formed,foreachevidence,through 5domains: riskofbias, consistency,precision,indirectresultsandreportingbias.This evaluationresultsin4degreesofqualityofevidence(high, moderate,lowandverylow).
Duetothepoorqualityoftheevidencefound,andeventhe lackofevidenceinsomesituations,wealsousedtheresults fromthepreliminaryanalysesoftheCHIKBRASILcohortdata andtheexpertopinionofthegroupsupportingthe decision-makingindefiningtherecommendations.
Allmembersoftheother 2groups,inadditionto3 gen-eralpractitioners,1Infectiousdiseasespecialistand1public healthmanager,wereincludedinthevotingpanel.Two face-to-facemeetingswereheldinthecityofRecife,Pernambuco, (PE)tovoteontherecommendations(OctoberandNovember), withmorethan 90%attendance.Inadditiontoface-to-face voting, several rounds ofquestions,votingand corrections were conductedonline. Themembers ofthe votingpanels gavescoresfrom 0(totally disagree)to10 (totally agree)to definethedegreesofagreement.Themeanandstandard devi-ationofeachrecommendationwerecalculatedbasedonthose scores.
Twenty-five recommendations, split into 3 thematic groups, weregenerated:A.Clinical,laboratoryandimaging diagnosis;B.SpecialsituationsandC.Treatment.Thefirst2 themesarepublishedinpart1oftherecommendations.The treatment-relatedrecommendationsincludedinthepresent studyareoutlinedinTable1.
Recommendations
C.Treatment
C.1.Intheacutephaseofchikungunyafever,common
analgesicsand/orweakopioidsshouldbeused(incasesof
severeorrefractorypain),andnonsteroidal
anti-inflammatorydrugs(NSAIDs)andsalicylatesshouldbe
avoided.Corticosteroids(CS)arenotrecommendedfor
musculoskeletalmanifestationsinthisphase.Agreement:
9.31(SD± 0.8906).GRADE:verylowqualityofevidence
Intheacutephase,themaingoalisthereliefof musculoskele-talpain,whichisintenseanddisablinginmostcases.Averbal numericalorvisualanaloguescale(VAS)ofpainfrom0to10 canbeused.Intheserecommendations,weconsiderpainto beintensewhenVAS≥7.
Table1–Summaryofrecommendationsforthetreatmentofchikungunyafever.
C.Treatment
C.1.Intheacutephaseofchikungunyafever,commonanalgesicsand/orweakopioidsshouldbeused(incasesofsevereorrefractorypain), andNSAIDsandsalicylatesshouldbeavoided.Corticosteroids(CSs)arenotrecommendedformusculoskeletalmanifestationsinthis phase.Agreement:9.31(SD±0.8906).GRADE:verylowqualityofevidence.
C.2.Inthesubacutephaseofchikungunyafever,NSAIDsand/oradjuvantdrugsmaybeusedforpainmanagement(anticonvulsantsor antidepressants)incasesrefractorytoanalgesics/opioids.Inpatientswithmoderatetoseveremusculoskeletalpainorinthosewith contraindicationstotheuseofthesedrugs,theuseofprednisoneorprednisoloneatadoseofupto20mg/dayisrecommended,and withdrawalshouldbeperformedslowlyandgradually,accordingtopatientresponse.Agreement:9.24(SD±1.057).GRADE:lowtoverylow qualityofevidence.
C.3.Inthechronicphaseofchikungunyafever,theuseofanalgesicsisrecommendedforsymptomrelief.Weakopioids(codeineand tramadol)maybeusedforrefractoryorseverepainsymptoms(VAS≥7).Agreement:9.57(SD±0.741).GRADE:lowtoverylowqualityof evidence.
C.4.Inthechronicphaseofchikungunyafever,NSAIDsarerecommended,takingintoconsiderationtheclinicalcontext,contraindications andtherapeuticresponse.Agreement:8.97(SD±1.679).GRADE:lowtoverylowqualityofevidence.
C.5.Inthechronicphaseofchikungunyafever,oralcorticosteroidsmaybeusedformusculoskeletalandneuropathiccomplaints,andlow dosesarerecommended(5–20mg/dayprednisoneorprednisolone).Thetimeofusemayrangefromsixtoeightweeks,andwithdrawal shouldbeslowandgradualduetotheriskofrecurrenceofjointsymptoms.Agreement:9.24(SD±1.154).GRADE:lowtoverylowqualityof evidence.
C.6.Inthechronicphaseofchikungunyafever,antimalarials,preferablyhydroxychloroquine,maybeusedforthetreatmentofjoint symptoms,aloneorincombinationwithMTXorSSZ.Agreement:9.21(SD±1.166).GRADE:lowqualityofevidence.
C.7.Inpatientswithchikungunyafeverprogressingtothechronicphaseandwithinflammatoryjointdisease,withdifficultiesinCS withdrawal,wepreferentiallysuggestMTXatdosesof10–25mg/week.Agreement:9.43(SD±0.858).GRADE:lowtoverylowqualityofevidence. C.8.Inthechronicphaseofchikungunyafever,sulfasalazinemaybeusedatadoseof2to3g/day,aloneorincombination,especiallyin
patientswithcontraindicationtoorfailurewithMTX.Agreement:8.77(SD±1.794).GRADE:lowtoverylowqualityofevidence.
C.9.Biologicaltherapymaybeprescribedafterrheumatologistevaluationofpatientswithchronicinflammatoryjointdiseaseafterinfection withCHIKV,refractorytotheuseofCSandDMARDs,followingtherecommendationsusedtotreatRAorSpA.Agreement:8.97(SD±1.267). GRADE:lowtoverylowqualityofevidence.
C.10.Duringtheacutephase,inpatientsundergoingbiologicaltherapyfortheirunderlyingdisease,drugtherapydiscontinuationis recommended.However,treatmentcanbemaintainedinthesubacuteandchronicphases.Agreement:8.97(SD±1.884).GRADE:lowtovery lowqualityofevidence.
C.11.Rehabilitationinterventionsinallphasesofchikungunyafeverarerecommendedasacomplementarynon-pharmacologicalmeasure. Intheacutephase,analgesicandanti-inflammatorytherapiesareindicated,andtheuseofheatshouldbeavoided;furthermore,patient education,postureguidelinesandmanualtherapyshouldberecommended,inadditiontolight-intensityexercise.Inthesubacuteand chronicphases,thepreviousrecommendationsshouldbefollowed,whichmayalsoincludeheat,inadditiontofree,resisted,
proprioceptiveandactiveaerobicexercises,stretching,manualtherapyandaquaticphysicaltherapy.Agreement:9.43(SD±0.935).GRADE: verylowqualityofevidence.
theintensityofsymptomsandtheclinicalresponse.6,7Inthe casesofseverepainorpainrefractorytotheuseofcommon analgesics,weakopioidsmaybeused,includingtramadoland codeine6,7(Table2).
Given the difficulty of differential diagnosis between chikungunya fever and Dengue fever in the acute phase, NSAIDs should be avoided in the first weeks of the dis-easebecauseoftheriskofbleeding.Furthermore,salicylates shouldalsobeavoidedinthisphasebecausetheiruseinacute viralinfectionsmayleadtoReyesyndrome.6,7
When the pain has neuropathic characteristics (burn-ing and/or throbbing pain, pinching or feeling of shock, pins and needles, cold or tingling), tricyclic antidepres-sants (amitriptyline or nortriptyline) or anticonvulsants (gabapentin,pregabalinorcarbamazepine)maybeusedatthe recommendeddoses(Table2).8,9
It should be noted that the stratification into disease phases ismostly didactic. Decisions should be made on a case-by-casebasis.AlthoughNSAIDsarenotrecommended fortheacutephaseofchikungunyafeverduetotheriskof hemorrhagiccomplications,if necessary,theymay beused aftertheseventhday,aslongasthediagnosisofDengueis excluded.Inthesecases,thepresenceofcomorbiditiesand
possibleadverseeventsfromusingNSAIDsmustbe consid-ered,especiallyinthepopulationolderthan60years(expert opinion).
AlthoughinhibitionofCHIKVcellinfection with chloro-quine was shown in vitro,10 antimalarials were not able to improve the pain or to reduce the viral load in the acutephase11 and,therefore,are notrecommendedinthis phase.
TheuseofCSinthisphaseisnotrecommendedduetothe lackofevidenceoflong-termbenefits,inadditiontotherisk ofarthritisandtenosynovitisreboundafterwithdrawal.5
There is insufficient evidence on the safety or efficacy of the treatment of severe manifestations of chikungunya fever (neurological, cardiac,ocular or cutaneous vasculitis) in the acutephase. These casesmay benefit from the use ofCS athigher doses,albeitunder carefulevaluationbya specialist.
Table2–Drugsusedforthetreatmentofchikungunyafever:doses,monitoringandprecautions.
Drug Dose Monitoringandprecautions
Paracetamol 60mg/kg/day,withoutexceeding4g/day,
orally,4timesaday
Theincreasedriskofhepatitisresultingfromtheassociation ofviremia,druginteractionsandcomorbidities(liverorkidney diseaseoralcoholism)withhighdosesofparacetamolshould becarefullymonitored.
Dipyrone 1g,orally,4timesaday Evaluatekidneyandliverfunction,especiallyintheelderly.
Tramadol 50mgto100mg,orally,2–4timesaday Inpatientsover65yearsofage,startwiththelowestdose;in
patientsolderthan75years,donotexceed300mg/day.Riskof respiratorydepressionintheelderly.
Paracetamol+Codeine 500mg+30mg,orally,2–4timesaday Evaluatehepatotoxicity.
NSAIDs Dependingonthecompoundchosen Usethelowestdosefortheshortestpossibletime.
NeverusetwoNSAIDsincombination.
Evaluatetheriskfactors:age>65years,previoushistoryof ulcer,SAH,kidneydisease,useofCS,anticoagulants,asthma andsmoking.
Monitorbloodpressure,peripheraledemaandkidneyfunction.
Amitriptyline 25–50mg/day,orally Usewithcautioninpatientswithcardiovasculardisease,
diabetesmellitus,mania,kidneyorliverfailure,thyroid dysfunctionorepilepsy.Withdrawalshouldbegradual.
Gabapentin 300mg,2–3timesaday,orally Inchildrenaged3–12years,thereisariskofneuropsychiatric
adverseevents(emotionallability,hostility,thoughtdisorders andhyperkinesia).Withdrawalshouldbeinphases.
Pregabalin 50–150mg,2–4timesaday,orally Usewithcautioninpatientswithheartandkidneyfailure.
Monitorthrombocytopeniaandsymptomsofdependence. Withdrawalshouldbegradual.
Prednisone/Prednisolone 5–20mg/day,preferablyasingledoseinthe morning
Higherdosesmaybeusedinseverecases
Assessthepresenceofriskfactorsforosteoporosis,glaucoma (familyhistory)anddiabetesmellitus.
Monitorbloodpressureandfastingbloodglucose.
Antimalarials 5.0mg/kgHCQand3mg/kgchloroquine,
orally,1timeaday
Withriskfactorsforretinaltoxicitya:previousophthalmologic
evaluation;annualre-evaluation.
Withoutriskfactors:thereisnoneedforpriorevaluation; re-evaluationafter5yearsoftreatment.
Methotrexate 10–25mg/week,orallyorSC Hemogram,transaminases,andkidneyfunctionpriorto initiationoftreatmentandevery3months.Potentially teratogenic.Theuseoffolicacid(5mg,orally,weekly,theday afterMTX)reducestheriskofadverseevents.Riskof pulmonarytoxicity.
Sulfasalazine 1–2g/day,orally Hemogram,transaminasesandkidneyfunctionpriorto initiationoftreatmentandeverythreemonths.Maycause orangeurineorskin.
Anti-TNFs Infliximab,Etanercept,Adalimumab, Golimumab,Certolizumab
Screening–thesamerecommendationsasthecurrent protocolsforRAandSpA.Respiratorysymptomsmustbe carefullymonitored–riskofreactivationoflatenttuberculosis. NSAIDs,nonsteroidalanti-inflammatorydrugs;SC,subcutaneous;IV,intravenous;SAH,systemicarterialhypertension;AR,rheumatoid arthri-tis;SpA,spondyloarthritis.
a Dose>5mg/kg/day;treatmentlength;previousoculardisease;kidneydisease;liverdisease;useoftamoxifen;advancedage(riskofage-related
oculardiseasescomplicatingtoxicityassessment).
Inadditiontodrugtreatmentforpainrelief,properhydration andtheuseofcoldcompressestoreducejointpain(avoiding hotcompresses) should be recommended. At-risk patients (pregnantwomen,patientswithcomorbidities,elderlypeople andinfantsyoungerthan 2yearsofage,exceptnewborns) may also be followed-up atPCUs during the acute phase, but they require differentiated observation due tothe risk ofdeveloping severe formsof the disease; they should be followedupdailyuntiltheirtemperaturedropsandnosigns ofseverityaredetected.
Thecaseswithsignsofseverity(neurologicalimpairment, hemodynamic instability, dyspnea, chest pain, persistent
vomiting,mucosal bleedingand underlyingdisease decom-pensation)ormeetingadmissioncriteria(newborns)should befollowedupinwards.
Suspectedcasesmustbeadvisedtoadoptindividual anti-vectorial protection measures(mosquito netting,repellent, long-sleeved shirts and pants) to break the transmission chain,inadditiontomeasuresthatshouldbeimplemented athometopreventmosquitoproliferation.5
C.2.Inthesubacutephaseofchikungunyafever,NSAIDs
and/oradjuvantdrugsmaybeusedforpainmanagement
(anticonvulsantsorantidepressants)incasesrefractoryto
analgesics/opioids.Inpatientswithmoderatetosevere
musculoskeletalpainorinthosewithcontraindicationsto
theuseofthesedrugs,theuseofprednisoneorprednisolone
atadoseofupto20mg/dayisrecommended,and
withdrawalshouldbeperformedslowlyandgradually,
accordingtopatientresponse.Agreement:9.24(SD±1057).
GRADE:lowtoverylowqualityof
evidence
Inthesubacutephase,NSAIDsmaybeusedtotreatsymptoms refractorytoanalgesics,withnodifferencesineffectiveness betweenclasses,andthechoiceshouldbebasedonthe physi-cian’s experience and the patient’s clinical status. Rosario etal.12evaluated514patientswithameandiseasetimeof2.5 months,andmost(89%)showedagoodresponsetotheuse ofNSAIDs(naproxen,celecoxiboretoricoxib).The effective-nessofNSAIDtherapyshouldbereevaluatedafter7–10days ofuse.Incasesofinadequateresponsesafterthetenthdayof use,theNSAIDclassshouldbechanged.Ifwelltoleratedand effective,theNSAIDcanbemaintainedforseveralweeks,and thewithdrawalshouldbeslowandgradual,dependingonthe clinicalresponse.5
Althoughseveralstudies agreeon theefficacy ofCS for the treatment of pain in chikungunya fever after the fail-ure of analgesics and NSAIDs, there is still no consensus regarding the optimal dose and time of use. The French guidelinerecommendstheuseof10mg/dayprednisonefor 5daysandwithdrawalover10daysformoderatecasesand 0.5mg/kg/dayforseverecasesfor5daysanddosereduction in10days.5InBrazil,theMinistryofHealth(MH)recommends 0.5mg/kg/day(40mg/daymaximumdose)untilresolutionof symptoms,withgradualwithdrawal,butwithoutexceeding3 weeksoftreatment.6,7
PreliminaryresultsfromtheCHIKBRASILcohortshowthat theuseofCSinthesubacutephaseledtoconsiderable clini-calimprovement,whichwasmostsignificantatdoseshigher than 10mg/day; however, there was no additional benefit fromusingmorethan20mg/dayprednisone.Thus,we rec-ommendusing lower doses (5–20mg/day) ofprednisoneor prednisolone,withaslowandgradualreduction,according totheresolutionofjointsymptoms(unpublisheddata).Itis importanttohighlighttheneedtoadvisepatientsontherisks ofindiscriminateuseofCSforlongperiodsoftime,especially inthecasesofchronicdiseases,includingsystemicarterial hypertension (SAH), diabetes mellitus (DM), glaucoma and obesity(expertopinion).
Infiltrationsinjointandperiarticularconditionsand com-pressionsyndromescanbeperformedinthisphase.5
The evidence on the use of antimalarials in the suba-cute phase of symptoms refractoryto analgesics is scarce andindicates poorclinical response.AnIndianstudy com-paredagroupofpatientswithaminimumdisease timeof 30days(meantime:9weeks)usingchloroquine(250mg/day) with a group using meloxicam (7.5mg/day) for 24 weeks. Althoughtheresponsewasnumericallybetterinthe chloro-quine group, there was no significant difference in the improvementin the pain VAS score or number ofpainful joints.13
Another study, also conducted in India, compared 4 treatment groupsin patientsfollowed duringthe subacute phasefor6weeks:GroupA(200mg/dayaceclofenac);Group B (400mg/day aceclofenac+hydroxychloroquine); Group C (10mg/day aceclofenac+prednisolone) and Group D (ace-clofenac+hydroxychloroquine+prednisolone). All groups showedimprovementintheanaloguepainscale,butwitha greaterdifferencefavoringthegroupsthatusedCS(groupsC andD).14
Interestingly,althoughitwasnottheprimaryobjectiveof thestudy,theauthorsconcludedthatadding hydroxychloro-quine(HCQ)producednobenefittothetreatment,andboth groupsusingcorticoidshadbetterresultsinthefirstweeks. PreliminarydatafromtheCHIKBRASILcohortshowedsimilar resultsregardingtheuseofHCQinthesubacutephase,and itsresponsewasmoresatisfactoryinthegroupsthatusedCS incombination(unpublisheddata).
Althoughthe evidenceon HCQisinsufficientto recom-mend formaluse inthe subacutephase,the experienceof thespecialistsincludedintheBraziliangroupsuggeststhat abeneficialeffectmayoccur,particularlywhenitisusedasa corticoid-sparingdrug.Therefore,werecommendusing anti-malarialsinthisphase,accordingtoclinicalcriteria(expert opinion).
Tricyclicantidepressantsandanticonvulsantsareoptions forcaseswithneuropathicpaincharacteristics9andmaybe combinedwithcommonanalgesicsifmoreeffective analge-siaisrequired.Thetherapeuticregimenofchoiceshouldbe theonewiththelowestdoseandtheshortesttimepossibleto obtainthebestcost-benefitandtoreducetheriskofpossible adverseevents5(Table2).Therearenocontrolledstudies eval-uatingtheresponsestotheuseofthesedrugsinneuropathic painduringchikungunyafever.
C.3.Inthechronicphaseofchikungunyafever,theuseof
analgesicsisrecommendedforsymptomrelief
Weakopioids(codeineandtramadol)maybeusedinrefractoryor severepainsymptoms.Agreement:9.57(SD±0.741).GRADE:low toverylowqualityofevidence
C.4.Inthechronicphaseofchikungunyafever,NSAIDsare
recommended,takingintoconsiderationtheclinicalcontext,
contraindicationsandtherapeuticresponse.Agreement:8.97
(SD± 1.679).GRADE:lowtoverylowqualityofevidence
Inpatientswithpersistentlocalizedordiffuse musculoskele-talpain,without inflammatorysignsandwithmorethan3 monthsofillness,simpleanalgesicsorweakopioidsshould beused,dependingonthepainintensity,15atthesamedoses recommendedfortheacuteorsubacutephases.
Longitudinalstudieshaveshownhighuseofanalgesicsin the chronicphase: 72%after36months16and 93%after15 monthsofchikungunyafever.17 However,only34%patients were satisfied with this pharmacological approach.17 The treatment maybeoptimized bycombining analgesicswith NSAIDs, local anti-inflammatory therapies (joint or peri-tendinousinfiltration)andphysicaltherapy;thetherapeutic effectivenessismaintainedinthemedium-term(weeks).5
practice,NSAIDsmay beused inany patient with chikun-gunya fever showing refractory pain or intolerance to the use ofsimple analgesics and opioids, whether or not the symptomsarerelatedtoinflammatorymanifestations.
InthestudybyRosarioetal.,12although89%ofpatients reportedasatisfactoryresponseinpainimprovementusing anNSAID,72%ofthemsubsequentlyrequiredtheuseofCS.12 Sissokoetal.reportedthatonly1/3patientsusinga combina-tionofanalgesicsandNSAIDsafter15monthsoftreatmentof chikungunyafeverreportedsatisfactoryresponses.17
Cases progressing to the subacute and chronic forms requireamorecarefulevaluationfromthemusculoskeletal standpoint,whichmustbeperformedbytherheumatologist; thefollow-upmaybeperformedbythegeneralpractitioner. Thephysicalexaminationshouldbefocusedonthe articu-larandperiarticularinvolvement;tendoninvolvementshould bethoroughly researched. Other associated manifestations should beassessed:lack ofappetite, non-restorativesleep, impairmentofworkanddailyactivities,urinaryurgencyand incontinence,moodchangesanddepression.
C.5.Inthechronicphaseofchikungunyafever,oral
corticosteroidsmaybeusedformusculoskeletaland
neuropathiccomplaints,andlowdosesarerecommended
(5–20mg/dayprednisoneorprednisolone).Thetimeofuse
mayrangefrom6to8weeks,andwithdrawalshouldbe
slowandgradualduetotheriskofrecurrenceofjoint
symptoms.Agreement:9.24(SD± 1.154).GRADE:lowto
verylowqualityofevidence.
Mostpatients (approximately70%) withchronicsymptoms associatedwith chikungunya fever use oral CS, with good clinicalresponserates12,16–18andhighlevelsofsatisfaction.17 However,althoughthe efficacyofusingCSinthis phaseis wellestablished,theexisting evidenceonthe optimaldose andtimeofuseiscontroversial.
InacohortstudyfromtheDominicanRepublic,verylow dosesofprednisone/prednisolone (5–7.5mg/day)or deflaza-cort (6mg/day) were used, withexcellent clinical response after6–8weeks.12
TheFrenchguideline recommends usinga lowCS dose (10mg/day)forupto5daysandgraduallyreducingit until thetenthday;theCSshouldbeusedinmoderationafterthe failureoftheinitialtreatmentofmusculoskeletalsymptoms (tenosynovitis/distaledematouspolyarthralgiaand compres-siveneuropathy);NSAIDsshouldbeusedafterCSwithdrawal toavoidclinicalworsening.5,18
InBrazil,theMH’sclinicalmanagementprotocolof chikun-gunya fever recommends using 0.5mg/kg/day prednisone (40mg/daymaximumdose),foramaximumperiodof3weeks; longerthanthistime,intheabsenceofaresponse,and com-biningopioidswiththediscontinuationornotoftheCSshould beconsidered,dependingontheclinicalresponseandonthe absenceofadverseevents.6,7
ThepatientsparticipatingintheCHIKBRASILcohortstudy wereprescribedprednisonein64%cases,withameandose of15mg/day. At the first returnvisit (on average, 4weeks after the initial visit), patients treated with CS showed a more significant improvement in the overall assessment, number of painful and swollen joints; as observed in the subacutephase analysis, patients who used adose higher
thanorequalto10mg/dayshowedabetterresponse. How-ever, when the improvement of these same parameters was analyzed, comparing the dose of 10mg with higher doses,no significant difference wasobserved (unpublished data).
Animportantissueraisedinthediscussionwasthe recur-rence ofjoint symptomsinpatients forwhom theCS was withdrawn rapidlyafterclinicalimprovement(expert opin-ion). Thus, we recommend using doses ranging from 5to 20mg/day,for6–8weeks,withaslowandgradualwithdrawal, dependingontheclinicalresponse.Incasesprecluding with-drawingtheCSafterthisperiod,thepatientsshouldbemoved tothesecondstageoftreatmentofthechronicphase,with introductionofmethotrexateand/orHCQ(recommendations C6andC7).Animprovementinthesymptomsofneuropathic painwasalsoobservedbythespecialistswhenusingoralCS, whichmaybeusedaloneorincombinationwith antidepres-santsoranticonvulsants.
Therisk/benefitratioofusingCSshouldbeconsideredin patientswithDM,poorlycontrolledSAH,documentedhistory offractureduetoosteoporosis,bipolarmooddisorder,chronic renalfailureondialysis,Cushing’ssyndrome,gradeIII obe-sity, arrhythmiasandcoronarydiseases.When choosingto prescribeCS,thelowestdoseshouldbeusedfortheshortest timepossible,withstrictclinicalandlaboratorysurveillance (expertopinion).
Intra-articular or peritendinous infiltration can also be used as a therapeutic approach in this phase, with good results.5
C.6.Inthechronicphaseofchikungunyafever,
antimalarials,preferablyhydroxychloroquine,maybeused
forthetreatmentofjointsymptoms,aloneorincombination
withMTXorSSZ.Agreement:9.21(SD± 1.166).GRADE:
lowqualityofevidence
Similar tothe acute and subacute phases, treatment with antimalarials in the chronic phase lacks consistent evi-dence and may be the most controversial therapeutic issue.
Ravindranetal.19evaluatedpatientsusingHCQ200mg/day andwithactivedisease,definedbyatleast3swollenjoints, 6 painful joints and erythrocyte sedimentation rate (ESR) >28mm/1sthour.Thepatientswererandomizedinto2groups: 37patientscontinuedusingHCQinmonotherapy(dose opti-mized to400mg/day),and 35beganacombinedschemeof HCQ,methotrexate(MTX,15mg/week)andsulfasalazine(SSZ, 1g/day).After24weeks,thegroupusingthecombinedtherapy showed significant improvementsin all parameters of dis-easeactivity.Itshouldbenotedthatthesampleofthisstudy wassmallandthepatientswererandomizedtocomparethe useofHCQaloneandthecombinedHCQ-MTX-SSZtherapy inagroupthathadalreadyshowntherapeuticfailurewith HCQ.
higher in the chloroquine group, there was no significant difference in efficacy between the groups. These results suggestthatusingantimalarialsinpatientswith contraindi-cationsto the use ofNSAIDscould be aneffective option for the treatment of chronic joint pain in chikungunya fever.
Another randomized study20 assessed the efficacy of chloroquine (150mg/day) compared with paracetamol (500mg/day)inimproving painin86 patientswith chikun-gunyafever.Abenefitinpainrelief infavorofchloroquine wasobserved,withasignificantdifferenceforpainclassified asmildtomoderate.However,thefollow-upwaslimitedto8 days,andbothgroupsusedlowdoses.
Publishedcaseseriesreportcontroversialresults.Thefirst, publishedin1984,21evaluatedtenpatientswitharthritis fol-lowing chikungunya fever treated with chloroquine for 20 weeksand observed improvementsinthe Ritchiearticular index,morning stiffnessand generalphysicianandpatient assessments.InthecohortfromReunionIsland,only18%of patientsweretreatedwithHCQand failedtoshowan ade-quateresponsefordiffusejointsymptoms;noinformationon thetimeofusewasreported.18
Theexisting treatment protocols for chikungunya fever alsolackuniformityregardingtheuseofantimalarials.The World Health Organization (WHO) recommendsthe use of HCQ(200mg/day)orchloroquine(300mg/day)foraperiodof 4weeks,whenarthralgiaisrefractorytoothermedications.8 The French guideline did not validate the use of HCQ in patients with chikungunya fever and chronic symptoms, consideringitanindicationrestrictedtoisolatedcaseswhen theuseofMTXorSSZiscontraindicated.5TheBrazilianMH recommendsHCQinthechronicphaseofchikungunyafever, atthe maximum dose of600mg/day for a 6-week period, whichmaybecombinedwithanalgesicsincasesofpersistent mildtomoderatepain.6,7
In the CHIKBRASIL cohort, HCQ (400mg/day) was pre-scribed in 47.1% cases. In the first follow-up visit, after 4 weeks on average, a clearer improvement in the num-ber of painful and swollen joints was observed compared withpatientsnottreatedwithHCQ,althoughthedifference wasnotstatisticallysignificant(unpublisheddata).Thus,we recommend using antimalarials, particularly HCQ, for the treatmentofthechronicphaseofchikungunyafeverinmild tomoderatecases.Inaddition toits knowneffectsinpain controlandjoint inflammation22 andits potentialantiviral activity,23HCQisamoreeasilyuseddrugthanMTXforgeneral practitioners.
Classically, the recommended daily dose of HCQ is 6.5mg/kg/day,consideringtheidealweightandnottheactual weightofthepatient, toreducethe riskoftoxicity.24 How-ever,amorerecent study,whichcalculatedthe doseusing theactualweight,showedthatdoseshigherthan5mg/kg/day increase the risk ofretinal toxicity by 10% after 10 years, reaching40%in20 years.25 Therefore, thenew recommen-dationsfromtheAmericanAcademyofOphthalmology(2016) indicatelowerdoses(5mg/kg/day,400mg/daymaximum)and usingtheactualweighttoreducetheriskofoculartoxicity (Table2).26
C.7.Inpatientswithchikungunyafeverprogressingtothe
chronicphaseandwithinflammatoryjointdisease,with
difficultiesinCSwithdrawal,wepreferentiallysuggestMTX
atdosesrangingfrom10to25mg/week.Agreement:9.43
(SD±0.858).GRADE:lowtoverylowqualityofevidence.
Manylongitudinalfollow-upstudiesofpatientsinthechronic phaseofchikungunyafeverincludeMTXinthemanagement ofjointsymptoms,althoughmostofthemareuncontrolled openstudiesorcaseseries.
Ravindranetal.19conductedanuncontrolled,openstudy thatincludedpatientswithmorethan1yearofarthritis post-infection with CHIKVwho failed torespond to the use of HCQalone.After24monthsoffollow-up,thegroupinwhich MTX(15mg/week)andSSZ(1g/day)werecombinedwithHCQ obtainedabetterclinical responsethan those who contin-uedusingHCQalone.Anotheruncontrolledstudyevaluated for16weeksthecombinationofMTX(15mg/week)withHCQ in 149 patients with more than 3 months of joint symp-tomspost-infectionwithCHIKV.Afterthis period,48.9%of patientsshowedimprovementsofatleast20%inthenumber ofpainfulandswollenjoints,combinedwithimprovementsin atleast3–5parameters:(1)patient’sevaluation,(2)physician’s evaluation,(3)painscale,(4)disabilityquestionnaireand(5) acute-phasereactants.27
In Reunion Island, of 159 patients who developed rheumaticdiseaseestablishedpost-infectionwithCHIKV,77% were treated withMTX (15mgweekly mean dose). Aftera mean periodof25months,75%ofcasesshowedapositive responsetoMTX.18
In the Dominican Republic cohort, 5 patients (0.97%) required the use of MTX (12.5–15mg/week), which was includedinthetreatmentwhenreducingtheCSwasdifficult andwasusedforamaximumof3months.12
InMartinique,27patientswithchronicarthropathycaused bychikungunyafever(withoutpreviousrheumatologic diag-nosis)weretreatedwithMTX(21mg/weekmeandose),with goodresponsesin21cases(77.7%)andameanfollow-uptime of6months.15
InBrazil,theMH’sprotocolrecommendsusingMTXonly aftertherapeuticfailurewithHCQandSSZ(2g/day),foratleast 6weeks,withpersistentmoderateandseverepain(VAS≥4).6,7 Conversely,theFrenchconsensusrecommendsMTX asthe first-choicedrugforthetreatmentofchronicinflammatory jointdisease(CIJD)post-infectionwithCHIKV,followingthe samerecommendationsusedforthetreatmentofrheumatoid arthritis(RA)orundifferentiatedarthritis.5,28
IntheCHIKBRASILcohort, 5.8%ofthe431patientswere prescribedMTXinthestudyinclusionvisitata13mg/week mean dose. In this group, all patients presented arthritis andarthralgiaafteranaverageof13weeksofdisease,with a VAS forpainranging from moderateto severein 88%of cases. It is interesting to note that MTX was initiated in 56% patientswho hadnotpreviouslyusedHCQorCS, and the decision was made based on the severity ofthe joint manifestations.
the follow-uptime ofthesepatients wasstill short,which precludes furtherconclusions on the long-term efficacy of MTXinpatientswithchikungunyafever.
Thus, werecommend initiating treatment withMTX in patientswithchikungunyafeverinthechronicphaseand per-sistenceofjointsymptomsorwhenfacingdifficultiesinCS withdrawal(after6–8weeksofuse),attheminimuminitial doseof10mg/week.Treatment shouldbereassessed every 4weeks,withagradualdoseincreaseuptoamaximumof 25mg/weekincasesofpartialresponse.Table2outlinesthe initialassessmentforprescriptionandmonitoringofadverse eventswithMTX.
Thevarious studies lacka consensusonthe idealtime whenMTXshouldbeusedinthe chronicphaseof chikun-gunya fever or when it should be discontinued. In our experience,weobservedthataminimumusetimeof3months mayleadtocompletesymptomremission,withoutrelapses afterwithdrawal(expertopinion).
Therearenostudiesinvolvingleflunomideforthe treat-ment of chronic arthropathy following chikungunya fever. The French guidelines indicate their use according to the recommendations for treatment of RA, after MTX treat-mentfailure;however, thereisnoevidencesupportingthis recommendation.5 There is only 1 case report describing improvementsinsubacuteandchronicjointsymptomswhen usingcolchicine0.6mg2xday(for6months)aftercelecoxib failure.29
Patientswithdiseasetimelongerthan6weeks,with per-sistentarthritis/tenosynovitissymptomsortheonsetofbone erosionsrequiringimmunosuppressivetreatmentshouldbe monitoredbytherheumatologist.
C.8.Inthechronicphaseofchikungunyafever,sulfasalazine
maybeusedatadoseof2–3g/day,aloneorincombination,
especiallyinpatientswithcontraindicationtoorfailurewith
MTX.Agreement:8.77(SD±1.794).GRADE:lowtovery
lowqualityofevidence.
TherearefewstudiesevaluatingtheuseofSSZinthechronic phaseofchikungunyafever,andtheywereallcaseseries with-outadetaileddescriptionofefficacy.
ThestudybyRavindranetal.19showedgoodresponsein only12.5%of16 patientswho usedSSZasmonotherapyin thechronicphaseofchikungunyafever.Whencombinedwith MTX,theresponseincreasedto71.4%.Itshouldbenotedthat all casesincluded had already used HCQ(200mg/day)and NSAIDs.
Bouquillard et al.30 reported the use of SSZ in 3 of 21 patientswho progressed toRA(accordingtothe American CollegeofRheumatology(ACR)criteria)afterinfection with CHIKV. Although no detailed description of the response was reported, radiographic progression was observed in most patients, despite the use of disease-modifying antirheumatic drugs (DMARDs), including HCQ, MTX and SSZ.
TheFrenchguidelinesuggestsusingSSZasasecond-line drugtreatmentforchikungunyafever.5Conversely,the Brazil-ianMHprotocolrecommendsusingSSZasafirst-lineDMARD, beforeMTX.6,7
IntheCHIKBRASILcohort, SSZwasprescribedtoonly4 patients(0.9%ofcases).Threeofthemshowedinflammatory
neck and low back pain, which may have influenced the choiceofSSZoverMTX,althoughwelacksufficientdatato statethat,inthesecases,SSZmaybethebestoption(expert opinion).
Ourrecommendation isthat SSZbeusedasan alterna-tiveincasesoftherapeuticfailureorcontraindicationtothe useofMTX,atdosesof1–2g/day,oraccordingtotheopinion andclinicalexperienceoftheprescribingphysician. Prescrip-tion precautions andmonitoring recommendationsforSSZ areoutlinedinTable2.
C.9.Biologicaltherapymaybeprescribedafter
rheumatologistevaluationofpatientswithchronic
inflammatoryjointdiseasepost-infectionwithCHIKV,
refractorytotheuseofCSandDMARDs,followingthe
recommendationsusedtotreatrheumatoidarthritisor
spondyloarthritis.Agreement:8.97(SD±1.267).GRADE:
lowtoverylowqualityofevidence.
Biological therapy, also known as biological DMARDs (bDMARDs), is considered the breakthrough of the last decade inthe treatment ofchronicinflammatorydiseases, including RA, spondyloarthritis (SpAs) and inflamma-tory bowel disease (IBD). Tumor necrosis factor inhibitors (anti-TNF),thefirstclassofbDMARDstobeusedin rheuma-tologic clinical practice, has been a safe and effective therapeuticoptionforthecontrolofdiseaseactivity, radio-graphic progression and functional impairment in both RA and ankylosing spondylitis (AS) and psoriatic arthritis (PsA).31–33
Thereare somereportsofanti-TNFuse inpatientswith chronic joint symptoms of chikungunya fever. In the Mar-tiniquecohort, 6patients(23.3%)had touseanti-TNFafter failurewithMTX,HCQandCS,withgoodjointresponseandno adverseevents.Theefficacywasasexpectedaccordingtothe symptomsforwhichtheywereused.15IntheReunionIsland cohort,after6yearsoffollow-up,anti-TNFwasprescribedin 12 (12.8%)ofthe94patientswhodevelopedrheumatic dis-ease followingchikungunya fever after MTX failure.18 The French guideline recommends using biological therapy in casesthatprogresstoRAorSpA,aftertreatmentfailurewith DMARDs,andthesameprescriptionprecautionsand recom-mendations indicatedforeachparticulardiseaseshouldbe followed.5
It should be noted that although CHIKV infection has behavior similar to that of RA or AS, chikungunya fever is a different disease. The rationale for using immuno-biologicals for chikungunya fever was extrapolated from the experience in RA and SpAs, and similarly to MTX and SSZ, these drugs were not evaluated in clinical trials for use in patients with chronic infection with CHIKV.
Table3–Physicaltherapytreatmentmodalitiesrecommendedfortheacute,subacuteandchronicphasesof
chikungunyafever.
Objectives Acutephase Subacuteandchronicphases
Painandswellingreduction Cryotherapy TENS
Manualtherapy
Compressionbandages
Electrothermaltherapyandphototherapy (ultrasound,low-powerlaser)
Manualtherapy Aquaticphysicaltherapy Maintenanceofjoint
function
Light,activeexercise(caution) Orthoses
Manualtherapy
Therapeuticexercises:passiveandfreeandresisted activeexercises–progressive
Stretching
Proprioceptivetraining Aquaticphysicaltherapy Physicalfitness
improvement
Aerobicexercise
Posture Avoidpainfulpostures
Adoptionofdecubituspositionsfavoringvenous return
Stretching
Avoid Useofheat–mayworsentheinflammatory
response
Prolongedjointimmobilization
Patienteducation Adviceaboutthedisease
Strategiessupportingtreatment
Adjustmentofenvironmentalandindividualfactors thatmayaffectthecourseofthedisease
TENS,transcutaneouselectricalnervestimulation.
PRIMARY CARE ACUTE PHASE (up to 14 days)
Localized or diffuse MS pain
Paracetamol
Physical therapy
Neuropathic pain
Amitriptyline Gabapentin Pregabalin Carbamazepine
Subacute phase treatment
Without improvement after 14 days Persistent pain VAS ≥ 7
60 mg/kg/day, Maximum 4g/day
(4x dia), orally 4g/day (4x day), orally
Without improvement after 14 days
Tramadol
Dipyrone
Paracetamol/codeine
50 to 100 mg, 4x day, orally
50 a 100 mg, 4x day, orally or
Figure1–Treatmentflowchartoftheacutephaseofchikungunyafeveraccordingtotherecommendationsfromthe BrazilianSocietyofRheumatology(SociedadeBrasileiradeReumatologia–SBR).
MS,musculoskeletal;VAS,visualanaloguescale.
C.10.Duringtheacutephase,inpatientsusingDMARDsor biologicaltherapyforthetreatmentoftheirunderlying disease,themedicationshouldbediscontinued.However, thetreatmentmaybemaintainedinthesubacuteand chronicphases.Agreement:8.97(SD±1.884).GRADE:low toverylowqualityofevidence.
The existing data on chikungunya fever in patients with prior rheumatologic diseases are scarce and derived from caseseries published duringepidemics in other countries. However, all studies agree that there seems to be no risk of worsening of the viral condition or complica-tionsresultingfromtreatmentwithimmunosuppressantsor
immunomodulatorsinthisgroupofpatients,incontrastto othertypesofviralinfection.12,15,34,35
Localized or diffuse MS pain
Neuropathic pain SUBACUTE PHASE (15 days to 3 months) SECONDARY CARE
Arthritis/tenosynovitis
Antidepressants and/or anticonvulsants∗ Common analgesics∗
Weak opioids∗
NSAIDs∗∗
Physical therapy Persistent pain
or VAS ≥ 7
Without improvement with analgesics/opioids
No response after 7-10 days
No response after 7-10 days
No response after 7-10 days
Without improvement after 3 months or relapse
Oral corticoid 10 to 20 mg/day
Minimum 6 weeks
HCQ 5mg/kg/dia, maximum 400mg/day
Chronic phase treatment
Without improvement after 3
months or difficulties
in CS withdrawal
∗Refer to acute phase treatment
∗∗See text
Figure2–TreatmentflowchartforthesubacutephaseofchikungunyaFeveraccordingtotherecommendationsofthe
BrazilianSocietyofRheumatology.
MS,musculoskeletal;VAS,visualanaloguescale;NSAID,nonsteroidalanti-inflammatorydrug;HCQ,hydroxychloroquine.
Inthe epidemicinMartinique,36 22 patientswith infec-tionwithCHIKVusingbDMARDsandsyntheticDMARDsfor thetreatmentofpreviousrheumatologicdiseaseswere stud-ied:17patientsusedMTX(21.6mg/weekmeandose),3used HCQ, 2 used azathioprine, 1 used mycophenolate mofetil (MMF)and2usedcyclophosphamide.Ofthe22patients,11 usedcorticoids(8.6mg/daymeandose).Therewereno com-plicationsor hospitalizations due to infection with CHIKV. Treatmentperformedwithanalgesiaalone(4/22),combined withaNSAIDs(17/22)orprednisone(1/22)andrest,sufficed tocontrolthecrisis.Thebasictreatmentwasmaintainedfor allpatients(except1),withnocomplications(DMARDs, bio-logicsandimmunosuppressants)andwiththesameresultas thatobservedinotherstudies.15,35
Studiesconductedatothersitesofepidemicshaveshown that,althoughthereseemedtobenocomplicationsresulting fromtheuseofDMARDsorbDMARDs,ifthediseasebecame activeinsomepatientswithpreviousrheumatologicdisease, thesepatientsrequiredtreatmentintensification.InReunion Island,18of159studypatients,18hadpreviousrheumatologic disease(6RA,8SpA,2systemiclupuserythematosus(SLE)and 2chronichepatitiswithjointmanifestations),whoworsened immediatelyafterinfectionwithCHIKV.Mostofthesepatients requiredsystemicCStherapy(70%),andcompletewithdrawal was onlypossiblein half ofthe cases; 8patients required MTXinitiation,withtreatmentfailurein6,whowereswitched to biologics. Three patients with RA, previously controlled with MTX, required switching to biologics, and improve-mentswereobservedinthe3cases.Similarly,Bletteryetal.15 observeda reactivationofthe previous disease inpatients withSpAandseronegative RA,whichledtoan intensifica-tion or initiation oftreatmentwith DMARDsor bDMARDs. Tolerancewasgood,withoutanyviralinfectionrecurrenceor complications.
Another study conducted in Martinique37 described 56 patients with SLE and positive serology for CHIKV using immunosuppressants(33.9%),antimalarials(86.8%)and pred-nisone (64.8%); 3 patients used rituximab. Although the prognosisofSLEpatientsismoreseverethanthatobserved in RA, with the induction of disease activity and severe
manifestations,theuseofimmunosuppressivedrugsseems tohavenoeffectontheclinicalsymptomsofchikungunya fever.
Anactivesearchforsymptomsofchikungunyafeverwas performed inpatients includedin theBrazilian Registryof Biological Therapies (Registro Brasileiro de Medicamentos Biológicos–BIOBADABRASIL)38in4centersoftheBrazilian Northeast.Atthetimeofdatacollection(2016),358patients were included in the registry, and 112 patients were con-tacted by telephone. The other patients had outdated or deactivated telephone numbers. These contacted patients wereaskedaboutthepresenceoftypicalsymptomsofCHIKV infection.Patientswithcompatiblesymptomswereevaluated in person througha structured interview inwhich disease characteristics were identified, and the diagnosis was per-formedusingclinical-epidemiologicalcriteria.Amongthe112 patients interviewed, 30 cases of chikungunya fever (27%) wereidentified,accordingtotheMHclinical-epidemiological criteria.ThirteenofthesepatientswereusingbDMARDs,and 17wereusingDMARDs.Nosignificantdifferencesinclinical manifestationswereobservedwhencomparingthe groups. Interestingly,atthe onsetofchikungunyafever symptoms, 76%ofpatientswereinremission,andonly15%reportedthat theirjointmanifestationsweresimilartothoseoftheir under-lyingdisease.Theotherpatientsreportedmuchhigherpain intensity,anditslocationwasdifferentfromother exacerba-tionsoftheirpriordisease.Nocomplicationswereobserved inanyofthetreatmentgroups.
The experience gained with patients using bDMARDs treatedintheCHIKBRASILcohortidentifies3typesof chikun-gunyafeverprogression:(a)milderclinicalmanifestationsand withshorterprogressiontimethanthatofpatientswithout priordisease;(b)possibilityofdiseasereactivationrequiring changingtheDMARDsorbDMARDsand(c)patientswithout chikungunyafeversymptoms(possiblysubclinicalinfection), althoughallhouseholdcontactsshowedtypicalclinical symp-toms.
SECONDARY CARE RHEUMATOLOGY CHRONIC PHASE (> 3 months)
Arthritis/tenosynovitis MS symptoms
Localized Diffuse or neuropathic
Anticonvulsants and/or antidepressants
NSAIDs#
Oral corticoid
5 to 20 mg/day
Methotrexate
10 a 25mg/sem
Post-CHIK refractory CIJD
Biologic (anti-TNF)
HCQ 5mg/kg/day
Maximum 400mg/day
SSZ
1 to 2 g/day
∗Please refer to treatment of the acute phase
∗∗Please refer to text
#During CS withdrawal
Analgesics/ opioids∗
NSAID∗∗
Physical therapy
Infiltration with CS
Possibility of combination
Persistent pain ≥ 7 by EVA
6 to 8 weeks Possibility of combination
Contraindication Adverse event
At least 3 months
Possibility of combination/change
Figure3–Treatmentflowchartofthechronicphaseofchikungunyafeveraccordingtotherecommendationsofthe BrazilianSocietyofRheumatology.
MS,musculoskeletal;VAS,visualanaloguescale;NSAID,nonsteroidalanti-inflammatorydrug;CS,corticosteroid;HCQ, hydroxychloroquine;SSZ,sulfasalazine;CIJD,chronicinflammatoryjointdisease.
canbecontinued duringthe subacuteand chronicphases. Inthecaseofreactivationoftheunderlyingdisease,without responsetothetreatmentinuse,werecommendchanging thedrugtreatment,asrecommendedforeachdisease.
C.11.Rehabilitationinterventionsarerecommendedatall
phasesofchikungunyafeverasacomplementary
non-pharmacologicalmeasure.Intheacutephase,
analgesicsandanti-inflammatorytherapyareindicated,and
theuseofheatshouldbeavoided;furthermore,patient
education,postureguidelinesandmanualtherapyshouldbe
recommended,inadditiontolight-intensityexercise.Inthe
subacuteandchronicphases,thepreviousrecommendations
shouldbefollowed,whichmayincludeheatandactivefree,
resisted,proprioceptiveandaerobicexercises,stretching,
manualtherapyandaquaticphysicaltherapy.Agreement:
9.43(SD±0.935).GRADE:verylowqualityofevidence.
Intheacutephase,physicaltherapyincludestheresources indicated for pain relief and swelling reduction8 and may contribute to limiting the persistence of these symptoms andprogressiontothesubacuteandchronicphasesofthe disease(expert opinion).Amongtheresources,cryotherapy favors analgesia and helps reduce localswelling and joint inflammation.5,8,39Transcutaneous electricalnerve stimula-tion (TENS) is another useful resource for pain relief, as somestudieshaveshownsatisfactoryresultsinpatientswith RA.40–44TENSismainlyindicatedforpatientswithpersistent pain,evenwhenusinganalgesicandanti-inflammatorydrugs, andforcasesofneuropathicpain(Simonetal.,2015).5
Manualtherapymethodsmayalsobeappliedinthisphase, including manuallymphatic drainage, which may be com-binedwiththeuseofcompressionbandages.5Thismethod isindicatedbecauseitimproveslymphaticcirculation45,46in casesofextra-articularswelling,especiallyinthepresenceof lymphedema.Thiscomplicationhasbeenfrequentlyobserved incasesofCHIKVinfection.
Light-intensity, active exercise should be recommended to maintainjoint function, with caution not toexacerbate inflammatorysymptoms.5,8,39Relativerestmustbeindicated, avoidingpain-triggeringmovements8,39;accordingly,orthoses maybeused.5
Postureguidelinesarecrucialinthisphase.Theadoptionof antalgicposturesshouldbeavoided,anddecubituspositions favoring the return circulation should be recommended5 (expert opinion). In this phase, the use of heat should be avoided to prevent increasing the internal temperature of jointsorexacerbatingtheinflammatoryresponse.8
Patienteducationisakeyresourcetopromoteknowledge onthediseaseandstrategiesthatmighthelpthetreatment, inadditiontotheadjustmentofenvironmentaland individ-ualfactorsthatmayaffectthecourseofthedisease(expert opinion).
Several studies indicate the use of a physiotherapeutic approachinthesubacuteandchronicphasesofchikungunya fever.However,mostofthesestudiesdonotdescribewhich therapieswereusedintheirtreatmentprotocols.8,15,18,39,47,48 In these phases, when the initialinflammatory symptoms persist,thesameresourcesusedintheacutephasemaybe applied,andothertherapiesshouldbeincludedinthe treat-ment ofmusculoskeletal manifestations that occur as the diseaseprogresses.5
Electrothermalandphototherapeuticresources,including low-powerlaserandultrasound,mayhelptocontrol symp-toms in joint and tendon inflammatory processes, despite theirlowlevelsofevidenceforthetreatmentof musculoskele-taldiseases.40,41,43,44
maintainingorgainingjointrangeofmotion(ROM)and mus-clestrengthandendurance.5Stretchingexercisescontribute to maintaining muscle-tendon flexibility and preventing postural changes.49 Proprioceptive training also includes treatment, providing stimuli for movement reeducation and the recoveryoffunctional skills.Aerobic exercisesare indicated to improve the patient’s general physical fitness andtoreducefatigue.5
Manualtherapeuticresources, suchassoft tissue mobi-lizationandjointmobilizationtechniques,areindicatedfor muscle relaxation, reducing muscle tension and restoring painless ROM and are useful forrecovery from tendonitis, tenosynovitis,arthritisandarthralgia.5
Aquaticphysiotherapymayrelievepain,reduceswelling andimprovejointmobilityandfunctionalskillsindifferent phasesofchikungunyafever,asoccursinotherrheumatologic diseases50–55(Table3).
Figs.1–3summarizetherecommendationsforthe treat-mentofchikungunyafeverineachphase(acute,subacuteand chronic)basedonlevelofcarecomplexity.
Funding
TheBrazilianSocietyofRheumatologyprovidedallfinancial andlogisticalsupporttoconductthisstudy.
Conflicts
of
interest
Theauthorsdeclarenoconflictsofinterest.
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