10 August 2022
AperTO - Archivio Istituzionale Open Access dell'Università di Torino
Original Citation:
Treatment of autoinflammatory diseases: results from the Eurofever Registry and a literature
review
Published version:
DOI:10.1136/annrheumdis-2011-201268
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This is an author version of the contribution published on:
Ter Haar N, Lachmann H, Ozen S, Woo P, Uziel Y, Modesto C, Kone-Paut I,
Cantarini L, Insalaco A, Neven B, Hofer M, Rigante D, Al-Mayouf S,
Touitou I, Gallizzi R, Papadopoulou-Alataki E, Martino S,
Kuemmerle-Deschner J, Obici L, Iagaru N, Simon A, Nielsen S, Martini A,
Ruperto N, Gattorno M, Frenkel J; Paediatric Rheumatology International
Trials Organisation (PRINTO) and the Eurofever/Eurotraps Projects".
Treatment of autoinflammatory diseases: results from the Eurofever Registry
and a literature review.
ANNALS OF THE RHEUMATIC DISEASES (2013) 72
DOI: 10.1136/annrheumdis-2011-201268
The definitive version is available at:
http://ard.bmj.com/cgi/doi/10.1136/annrheumdis-2011-201268
1
Treatmentofautoinflammatorydiseases:resultsfromtheEurofeverRegistryandaliteraturereview.
Ter Haar N,Lachmann H,Özen S,Woo P,Uziel Y,Modesto C,Koné‐Paut I,Cantarini L,Insalaco A,Neven
B,Hofer M,Rigante D,Al‐Mayouf S,Touitou I,Gallizzi R,Papadopoulou‐Alata ki E,Martino
S,Kuemmerle‐
Deschner J,Obici L,Iagaru N,Simon A,Nielsen S,Martini A,Ruperto N,Gattorno M,Frenkel J;Paediatric
RheumatologyInternationalTrialsOrganisation(PRINTO)andtheEurofever/EurotrapsProjects.
Abstract
ObjectiveTo evaluate the response to treatment of autoinflammatory diseases from an international
registryandanup‐to‐dateliterature
review.
MethodsTheresponsetotreatmentwasstudiedin aweb‐basedregistry inwhich clinicalinformationon
anonymisedpatientswithautoinflammatorydiseaseswascollectedretrospectivelyaspartoftheEurofeve r
initiative.ParticipatinghospitalsincludedpaediatricrheumatologycentresofthePaediatric Rheumatology
International Trial Organisation network and adult centres with a
specific interest in autoinflammatory
diseases. The following diseases were included: familial Mediterranean fever (FMF), cryopyrin‐associated
periodicsyndromes(CAPS),tumour necrosisfactor (TNF)‐receptorassociatedperiodicsyndrome(TRAPS),
mevalonate kinase deficiency (MKD), pyogenic arthritis pustulosis acne (PAPA) syndrome, deficiency of
interleukin‐1 receptor antagonist (DIRA), NLRP12‐related periodic fever and
periodic fever aphthosis
pharyngitisadenitis(PFAPA)syndrome.Caseswereindependentlyvalidatedbyexpertsforeachdisease.A
literaturesearchregarding treatmentoftheabovementioneddiseaseswasalsoperformedusingMedline
andEmbase.
Results22monthsfromthebeginningof theenrolment, completeinformationon496 validatedpatients
was available. Data from
the registry in combination with evidence from the literature confirmed that
colchicine is the treatment of choice for FMF and IL‐1 blockade for DIRA and CAPS. Corticosteroids on
demandprobablyrepresentavalidtherapeuti cstrategyforPFAPA,butalsoforMKDandTRAPS.Patients
withpoorlycontrolledMKD,TRAPS,
PAPAorFMFmaybenefitfromIL‐1blockade;anti‐TNFtreatmentmay
representapossiblevaluablealternative.
ConclusionsIn the absence of high‐grade evidence, these results could serve as a basis for therapeutic
guidelinesandtoidentifycandidatedrugsforfuturetherapeutictrials.
Introduction
Autoinflammatorysyndromesaredisorderscharacterised
byrecurrentorchronicinflammationcausedby
dysregulationoftheinnateimmunesystem.
1
Sincemostofthesediseasesareveryrare,treatmentdataare
limited. Few randomised controlled trials (RCTs) have been conducted; for most autoinflammatory
diseases,clinicianshave relied oncasereports andpersonalexperience . The rarity of thesediseasesand
thefragmentaryclinicalexperiencehashamperedthedevelopmentofconsensusfor
treatmentguidelines.
We set out to document current clinical practices and to compare these with published reports on
treatmentof autoinflammatorydiseases in orderto identifypromisingtreatmentapproaches.To analyse
current practice, we used the Eurofever Registry. This international web‐based registry was designed to
identify the clinical characteristics and
response to treatment in patients who had been treated for
autoinflammatorydiseases.
2
2
Methods
EurofeverRegistry
An international registry for autoinflammatory diseases was initiated by the Eurofever initiative (EAHC
Project No. 2007332).
2
A secured web‐based registry was hosted at the Paediatric Rheumatol ogy
International Trial Organisation website (PRINTO,http://www.printo.it). Participating hospitals included
paediatric rheumatology centres of the PRINTO network and adult centres with a specific interest in
autoinflammatory diseases.
3
Seventy‐seven centres from 33 countries participated in this effort. Local
attending physicians retrospectively provided anonymised demographic and clinical information on
patients with the following diseases: familial Mediterranean fever (FMF), cryopyrin‐associated periodic
syndromes (CAPS), tumour necrosis factor (TNF)‐receptor associated periodic syndrome (TRAPS),
mevalonatekinasedeficiency(MKD,alsoknown
ashyperIgDandperiodicfeversyndromeHIDS),pyogeni c
arthritispustulosisacne(PAPA)syndrome,deficiencyofinterleukin‐1receptorantagonist(DIRA),NLRP12‐
related periodic fever, and periodic fever aphthosis pharyngitis adenitis (PFAPA) syndrome. Inclusion
criteriafor each diseaseare given in the onlinesupplement.All completed cases were anonymously and
independently
validatedbyatleastoneexpertforthespecificdiseaseinordertoconfirmthediagnosis.All
casesvalidatedbefore1September2011forwhomtheresponsetotreatmenthadbeendocumentedwere
usedfortheanalysis.Alltreatmentsthathadbeentriedduringthelifetimeofthepatient
wereevaluated.
Local physicians reported per treatment the way it was prescribed (maintenance or during attacks), the
response and whether the drug was continued or discontinued. The response was graded as complete
remission,partialremission,failureorworsening.Weconsideredremissiontobecompletewhensignsof
active disease were absent
and reported inflammatory markers had no rmalised, allowing for the
persistenceofsequelae.
Literaturesearch
AliteraturesearchonthetreatmentofautoinflammatorydiseaseswasperformedusingMedline,Embase,
Cochranedatabasesandanadditionalsearchwithinthereferencesoftheretrievedpapers.Onlyarticlesin
EnglishpublishedbeforeFebruary2012were
included.Thereader isreferredtotheonlinesupplementfor
more information about the search and selection of papers. All the treatments that had been reported
wereincludedintheanalysisoftheliteratureandgradedforstrengthofevidenceaccordingtotheOxford
CEBM table.
4
When the response was not clearly described, the authors of the original papers were
contacted. For each disease, only papers with the highest grade of evidence were included on each
treatment(seesupplementaryfigure1).Ofthe175retrievedpapers,onlyprospectivetrialsorstudiesonat
leastfivepatients
wereincludedinthereferencelistoftheprintversionofthisarticle.Reportsonfewer
thanfivepatientscanbefoundinthesupplementaryreferencesintheonlinesupplement.
Results
EurofeverRegistry
By 31 August 2011, complete clinical information was available on 902 patients. Of these patients,
diagnosiswasvalidated
andconfirmedin684atthattime.In188patients,informationontreatmentwas
incomplete, so 496 patients were included in the study. Many patients had tried multiple drugs. The
characteristics of these patients are summarised intable 1. Information about reported side effects and
patients who received non‐steroidal
anti‐inflammatory drugs (NSAIDs) and/or corticosteroids as single
therapeuticstrategycanbefoundinsupplementarytables2and3,respectively.
3
FamilialMediterraneanfever(FMF)
EurofeverRegistry
In the Eurofever Registry, data on 121 patients with FMF are available. All received colchicine; 75 (62%)
experienced a complete response, 44 (36%) a partial response and two failed to respond. Side eff ects,
mainlydiarrhoea,werenotedinfivepatients(seesupplementary
table2).Nopatientwasreportedtohave
discontinuedcolchicine.Forty‐twopatientswereadditionallytreatedwithNSAIDand/orcorticosteroidon‐
demand with a variable response (figure 1). Three patients were treated with anakinra, with a complete
responseinallofthem,includingonepatientwhofailedtorespondtocolchicine.