UBC Faculty Research and Publications

A survey of national and multi-national registries and cohort studies in juvenile idiopathic arthritis:… Beukelman, Timothy; Anink, Janneke; Berntson, Lillemor; Duffy, Ciaran; Ellis, Justine A; Glerup, Mia; Guzman, Jaime; Horneff, Gerd; Kearsley-Fleet, Lianne; Klein, Ariane; Klotsche, Jens; Magnusson, Bo; Minden, Kirsten; Munro, Jane E; Niewerth, Martina; Nordal, Ellen; Ruperto, Nicolino; Santos, Maria J; Schanberg, Laura E; Thomson, Wendy; van Suijlekom-Smit, Lisette; Wulffraat, Nico; Hyrich, Kimme Apr 19, 2017

Your browser doesn't seem to have a PDF viewer, please download the PDF to view this item.

Item Metadata

Download

Media
52383-12969_2017_Article_161.pdf [ 320.87kB ]
Metadata
JSON: 52383-1.0366874.json
JSON-LD: 52383-1.0366874-ld.json
RDF/XML (Pretty): 52383-1.0366874-rdf.xml
RDF/JSON: 52383-1.0366874-rdf.json
Turtle: 52383-1.0366874-turtle.txt
N-Triples: 52383-1.0366874-rdf-ntriples.txt
Original Record: 52383-1.0366874-source.json
Full Text
52383-1.0366874-fulltext.txt
Citation
52383-1.0366874.ris

Full Text

RESEARCH ARTICLE Open AccessA survey of national and multi-nationalregistries and cohort studies in juvenileidiopathic arthritis: challenges andopportunitiesTimothy Beukelman1,19*, Janneke Anink2, Lillemor Berntson3, Ciaran Duffy4, Justine A. Ellis5, Mia Glerup6,Jaime Guzman7, Gerd Horneff8, Lianne Kearsley-Fleet9, Ariane Klein8, Jens Klotsche10, Bo Magnusson11,Kirsten Minden10, Jane E. Munro12, Martina Niewerth10, Ellen Nordal13, Nicolino Ruperto14, Maria Jose Santos15,Laura E. Schanberg16, Wendy Thomson9, Lisette van Suijlekom-Smit2, Nico Wulffraat17 and Kimme Hyrich18AbstractBackground: To characterize the existing national and multi-national registries and cohort studies in juvenileidiopathic arthritis (JIA) and identify differences as well as areas of potential future collaboration.Methods: We surveyed investigators from North America, Europe, and Australia about existing JIA cohort studiesand registries. We excluded cross-sectional studies. We captured information about study design, duration, location,inclusion criteria, data elements and collection methods.Results: We received survey results from 18 studies, including 11 national and 7 multi-national studies representing 37countries in total. Study designs included inception cohorts, prevalent disease cohorts, and new treatment cohorts(several of which contribute to pharmacosurveillance activities). Despite numerous differences, the data elementscollected across the studies was quite similar, with most studies collecting at least 5 of the 6 American College ofRheumatology core set variables and the data needed to calculate the 3-variable clinical juvenile disease activity score.Most studies were collecting medication initiation and discontinuation dates and were attempting to capture seriousadverse events.Conclusion: There is a wide-range of large, ongoing JIA registries and cohort studies around the world. Oursurvey results indicate significant potential for future collaborative work using data from different studies andboth combined and comparative analyses.Keywords: Juvenile idiopathic arthritis, Registry, Observational study, Pharmacosurveillance, Pediatric rheumatologyBackgroundJuvenile idiopathic arthritis (JIA), a heterogeneous col-lection of inflammatory arthritides, is the most commonrheumatic condition of childhood [1]. Despite this, ourunderstanding of the long-term outcomes for many chil-dren with this condition, in terms of disease status,functional limitation, need for long-term immunosup-pression as well as the development of comorbidities,remains relatively limited. Similarly, we have an incom-plete understanding of the potential adverse effects ofnew therapeutic agents, especially effects that are rare orhave a long latency period.The epidemiological study of JIA is challenging.Compared to the 1% prevalence of rheumatoid arth-ritis (RA) in adults, JIA is rare. The approximateworldwide yearly incidence is 8 per 100,000 childrenand most prevalence estimates range from 15 to 150per 100,000 depending on geographic region and* Correspondence: tbeukelman@peds.uab.edu1University of Alabama at Birmingham, Birmingham, USA19Division of Pediatric Rheumatology, The University of Alabama atBirmingham, 1600 7th Avenue South, CPP 210, Birmingham, AL35233-1711, USAFull list of author information is available at the end of the article© The Author(s). 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, andreproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link tothe Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Beukelman et al. Pediatric Rheumatology  (2017) 15:31 DOI 10.1186/s12969-017-0161-5study methodology [2]. In contrast to the categorizationof the arthritis counterparts in adulthood, JIA encom-passes a wide range of inflammatory arthritides, from self-limited oligoarthritis to severe, persistent polyarthritis,and it also includes psoriatic arthritis, spondyloarthritis,and systemic arthritis (an autoinflammatory condition).Results from long-term follow-up studies of JIA may notbe broadly generalizable; they may exclude children withmilder forms of disease who are discharged from rhe-umatology care, and they may include too few children toadequately study the less common disease phenotypes.The long-term study of childhood-onset diseases iscomplicated when patients transition to the adulthealthcare setting, making the capture of health out-come data challenging. However, patients and parentsidentify long-term outcomes, such as physical abilityin adulthood, successful schooling and employment,and the consequences of long-term exposure to im-munosuppression in childhood, as some of their keypriorities for research [3, 4].With the advent of biological therapies and their in-creasing use, reliable outcome data in JIA has becomeeven more crucial. Little is known about the back-ground rates of serious outcomes, such as infectionsand malignancies, making it difficult to interpret thesafety of new medications. Extrapolation from studiesof these drugs in adults with RA has limited accuracybecause most children with JIA do not have RA (onlyapproximately 5% have rheumatoid factor positivepolyarthritis) and children have far fewer seriouscomorbid conditions compared to adults. Exposure toimmune modulating drugs in developing immune sys-tems may also result in different longer-term adversehealth outcomes compared to more mature immunesystems.Given the rarity of JIA and the now frequent use ofpotentially high risk treatments in the absence of ro-bust, large, long-term safety studies, the capture of datain longitudinal cohorts is essential. Appropriately com-bining data from various cohorts enables detection ofrare adverse events and more accurate assessment ofdisease outcomes. Comparing data from different co-untries may provide information about genotypicvariations in disease and geographic variation in envir-onmental risk factors. It may also allow for compari-sons of treatment differences that result largely fromlocal availability of therapeutic agents rather than dif-ferences in disease characteristics.The purpose of this study was to survey the inter-national landscape of prospective longitudinal registriesand cohort studies in JIA to assess the breadth anddepth of data being collected. This information willinform future international collaborative work in JIA,including data harmonization for future studies.MethodsA list of existing JIA registries and cohort studies wascompiled through known contacts of the authors, ongoingcollaborations, and a review of the recent literature. Thisincluded studies conducted in the United States of Amer-ica (USA), Canada, United Kingdom (UK), Germany, theNetherlands, Sweden, Norway, Portugal, and Australia, aswell as some multi-national studies. A survey developedin Microsoft Excel (2010) was emailed to the principal in-vestigators of each registry or cohort. The survey alsoasked for additional registries or cohorts known to the re-spondent. Surveys were completed between October andDecember 2014. Owing to delays in manuscript prepar-ation and in an effort to provide the most recent informa-tion possible, all respondents were given the opportunityto revise their responses in March 2016.The survey captured details about each registry or co-hort study, including study design, study duration, loca-tion, inclusion criteria and number of participants, anddata elements and collection method. Cross-sectionalstudies, defined as those with less than 12 months ofplanned follow-up per participant, were excluded.ResultsIn total, 20 investigators were contacted, and the repliesdescribed 20 studies. Two identified studies were not in-cluded (CLARITY from Australia [5] and EPOCA fromPRINTO [6]) due to cross-sectional design. Theremaining 18 studies contain more than 60,000 patientswith JIA (Table 1). These studies include 11 national and7 multi-national cohorts (covering more than 37 coun-tries in total), with data spanning from 1993 until 2016onwards. These included 5 JIA inception cohorts(recruiting exclusively from disease onset), 6 prevalentdisease cohorts (without strict requirements about dis-ease duration or treatment), and 7 treatment cohorts(restricted to children starting certain anti-rheumatictherapies, such as biologics). Data from treatment co-horts were often part of pharmacosurveillance regulatoryrequirements. A majority of studies had been establishedwithin the past 15 years. Despite the long duration ofsome studies, the number of total subjects recruited toeach study remained relatively low, with few nationalstudies exceeding 1500 children.Most studies are still recruiting and continuing to follow-up children previously recruited. The planned length offollow-up varied across studies and was generallydependent on the amount or nature of funding available(data not shown). A majority of studies were based in asingle country or a small number of countries within a geo-graphic area. One noted exception is the large multi-national Pharmacovigilance in Juvenile Idiopathic ArthritisPatients (Pharmachild) collaboration,which was initiatedwith a European Union grant from the FrameworkBeukelman et al. Pediatric Rheumatology  (2017) 15:31 Page 2 of 9Table1SummaryofJIAregistriesandcohortstudiesStudyNameandPublishedReferenceCountryStartYearApprox.numberofpatientsChildren/adultsenrolledMinimumFollow-up(Years)ActiveFollow-upafterTransitionofCareActiveRecruitmentActiveFollow-upInceptionCohortsCAPS[ChildhoodArthritisProspectiveStudy][19]UK20011500Children10yearsortransitionNo(patientquestionnaireatage18and21years)YesYesICON[InceptionCohortofNewlyDiagnosedChildrenwithJIA][35]Germany2010950Children10YesNoYesJACS[JuvenileArthritisCohortStudy]Australia201225ChildrenTotransitionNoYesYesNordicJIACohort[24]Sweden,Finland,Denmark,Norway,Iceland19971200Children15YesYesYesReACChOut[ResearchinArthritisinCanadianChildrenEmphasizingOutcomes][36]Canada20051500Children5NoNoYesPrevalentDiseaseCohortsCARRALegacy[ChildhoodArthritisandRheumatologyResearchAlliance][37]USA,Canada20106600ChildrenUntil2013NoNoNoCARRA(current)a[ChildhoodArthritisandRheumatologyResearchAlliance][14]USA,Canada2015994Children10Yes,viaCallcentreYesYesNPRD[NationalPediatricRheumatologyDatabase][38]Germany1997~29,000ChildrenUnlimitedNoYesYesPHARMACHILD(Retrospective)[PharmacovigilanceinJuvenileIdiopathicArthritisPatients]Multi-national20117000ChildrenRetrospectivedatacollectiononlyNoYesYesReuma.pt[9]Portugal/Brazil20091188/310BothUnlimitedYesYesYesSwedishJIARegisterSweden20091800ChildrenTotransitionNoYesYesTreatmentCohortsABC[ArthritisandBiologicalsinChildren][39]Netherlands1999425ChildrenTotransitionNoNoNoBiKeR[BiologicsinPediatricRheumatology][10,11]Germany,Austria20013743ChildrenTotransitionNoYesYesJuMBO[JuvenileArthritisMethotrexateBiologicsLong-TermObservation][8]Germany20071100Adults10Follow-uptoBIKERstudyYesYesBCRDbUK2010850Children10YesYesYesBeukelman et al. Pediatric Rheumatology  (2017) 15:31 Page 3 of 9Table1SummaryofJIAregistriesandcohortstudies(Continued)[BiologicsforChildrenwithRheumaticDiseases][13]BSPAR-ETNb[BritishSocietyforPediatricandAdolescentRheumatolgy-Etanercept][12]UK20031400ChildrenUnlimitedYesYesYesBSRBRc[BritishSocietyforRheumatologyBiologicsRegister][7]UK2001550AdultsUnlimitedN/AYesYesPHARMACHILD(Prospective)[PharmacovigilanceinJuvenileIdiopathicArthritisPatients]28countries20111450Children10Yes,viaJAMARquestionnaireYesYesa TheCARRARegistrypreferentiallyenrolschildrenwithsystemicarthritis,polyarticularJIA,newdiagnosisofJIA,orinitiationoftreatmentwithmethotrexateorbiologicagentsbBCRDandBSPAR-ETNpreferentiallyrecruitchildrenatpointofstartingMTXorabiologicdrugc BSRBRrecruitsadultsstartingabiologicdrug.TheprimaryfocusisRAbutincludesadultswithJIABeukelman et al. Pediatric Rheumatology  (2017) 15:31 Page 4 of 9Table2DataCaptureAcrossJIARegistriesandCohortStudiesStudyILARCategoryAJCLJCMDglobalParentglobalCHAQ/HAQESRCRPFullACRCoreSetJADAScJADASPainUveitisdataJIAMedicationStart/StopdatesSeriousAdverseEventsStoredBio-samplesImagingresultsLinktoexternaldatasourcesIndustrypharmaco-surveillancestudiesInceptionCohortsCAPSYYYYYYYYYYYYYYYYYYNICONYYYYYYYYYYYYYYYYLimitedNNJACSYYYYYYYYYYYYYYYYNYNNordicJIACohortYYYYYYYYYYYYYNNYNNNReACChOutYYYYYYYYYYYYYYNYNNNPrevalentCohortsCARRALegacyYYNYYYNNNNYYYNLimitedNYNNCARRA(current)YYYYYYYYYYYYYYYLimitedYPotentialYNPRDYYYYYYYYYYYYYStartonlyYLimitedNNNPHARMACHILD(retrospective)YNNNNNNNNNNNYYYNNNNReuma.ptYYYYYYYYYYYYYYYLimitedLimitedNNSwedishJIARegisterYYNYYYYYNYYYYYNLimitedNNYTreatmentCohortsABCYYYYYYYNYYYYYYYYLimitedNNBCRDYYYYYYYYYYYYYYYYNYNBIKERYYYYYYYYYYYYYYYYNNYBSPAR-ETNYYYYYYYYYYYYYYYYNYYPHARMACHILD(prospective)YYYYYNYYNYYYYYYLimitedYNYBSRBRNNaNNYYYYNNNNNYYLimitedNYYJuMBOYYYYYYYYYYYYYYYLimitedNNYILARInternationalLeagueofAssociationsforRheumatology,AJCactivejointcount,LJClimitedjointcount,MDphysician,(C)HAQ(Childhood)HealthAssessmentQuestionnaire,ESRerythrocytesedimentationrate,CRPC-reactiveprotein,ACRAmericanCollegeofRheumatology,JADASJuvenileArthritisDiseaseActivityScore,cJADASclinical(3-variable)JuvenileArthritisDiseaseActivityScore,Yyes,N-noa Captures28-swollenandtenderjointcountonlyBeukelman et al. Pediatric Rheumatology  (2017) 15:31 Page 5 of 9Programme 7, managed by the Pediatric RheumatologyInternational Trials Organization (PRINTO), and has re-cruited children from 28 countries.The vast majority of studies recruited children,although 2 studies (The British Society for Rheumatol-ogy Biologics Register (BSRBR) [7] and The GermanJuvenile Arthritis - Methotrexate/Biologics Long-termObservation Study (JUMBO) [8], specifically recruitadult patients with JIA receiving biologic therapies. Moststudies stop follow-up after children leave paediatriccare; however, there are several exceptions. The Portu-guese register, Reuma.pt, is built into routine care andcontinues to capture data from patients into adulthood[9]. JUMBO is a follow-on study that links adults whowere followed in the German BiKeR registry [10, 11] aschildren. Similarly, the UK BSPAR [12] and BCRD regis-ters [13] continue to capture outcome data about youngadults from their adult care providers. The CARRARegistry follows young adults after transition of care viaa structured survey conducted by a telephone call center[14]. Pharmachild has the option for adult rheumatologycenters to submit data and plans to collect data directlyfrom young adults after transition of care by use of theJAMAR questionnaire [15].Despite differences in geographic location, time sincestudy inception, and study designs, the data elementscollected across studies appears to be quite similar(Table 2). All studies but one capture the InternationalLeague of Associations for Rheumatology (ILAR) cat-egory of JIA [1]. More than two-thirds of studies capturethe full American College of Rheumatology JIA coreoutcome set (count of joints with active arthritis,count of joints with limited range of motion, phys-ician global assessment of overall disease activity,patient/parent global assessment of overall well-being,functional ability (Childhood Health AssessmentQuestionnaire (CHAQ) score), inflammatory markers)[16]. Nearly all of the remaining studies capture 5 ofthe ACR core outcome variables. Fifteen studies(83%) collect the data needed to calculate the 10 or71-joint Juvenile Arthritis Disease Activity Score(JADAS-10 or JADAS-71) [17], and 16 can calculatethe 3-variable clinical JADAS (cJADAS) which omitsinflammatory markers [18]. All studies enrolling chil-dren captured data on the presence or absence ofuveitis. Most studies (83%) captured medication startand stop dates. Fourteen studies (78%) captured theoccurrence of serious adverse events (e.g., requiringhospitalisation), but only 28% had the ability to cap-ture these data additionally through external datasources (the majority based in the UK). Seven regis-tries were working with industry to perform pharma-cosurveillance studies and included monitoring ofdata and adjudication of adverse event reports.Biosample collection was performed in most of theregistries. Nine registries had relatively systematic collec-tion, and 7 had more limited collection on a subset ofpatients. Serum, plasma, and whole blood/DNA werethe most commonly collected samples. Synovial fluidwas collected less frequently.DiscussionThis is the first report to bring together informationabout the numerous existing JIA registries and longitu-dinal cohort studies, highlighting a wealth of JIA out-come data being collected around the world. Manyimportant questions surround the etiology, pathogenesis,optimal management, and long-term outcomes of JIA.No single registry can answer all questions. Registriesmust have a clearly defined purpose that determines theprocess of data collection and the specific data itemscollected.Three primary patient enrolment strategies are beingused: diagnosis inception cohorts, prevalence or con-venience cohorts, and treatment initiation cohorts.Although all studies aim to assess disease outcomes overtime, inception cohorts better identify predictors ofshort and long-term outcomes (e.g. social, clinical, psy-chological, laboratory and genetic) [19], whereas treat-ment initiation cohorts are superior to evaluatetreatment effectiveness and safety. Of course, with suffi-cient patient enrolment and procedures to collect dataat times when medications are newly started, treatmentcohort studies can be performed within a subset of pa-tients from any registry.Whilst one study started collecting data as early as1993, most initiated recruitment following the introduc-tion of biologic therapies for JIA around 2000. This waslikely a direct result of increased monitoring and safetyconcerns among investigators, sponsors, and patientswith JIA. The relatively recent increase of JIA cohortstudies coincided with a movement in the late 1990’s toclassify children with chronic arthritis into homogenousgroups to facilitate research using the ILAR classification[1], and this is reflected by all paediatric studies classify-ing children according to this system. Most studies con-tinue to actively recruit and follow previously recruitedpatients.Unfortunately, many studies cease to follow patientsafter they transition into adult care. The transition ofcare period presents many challenges. Patients not onlychange clinicians and often their place of residence, butalso may change medical systems and third-party payers.The most relevant outcome measures may also change,such as a change from active and limited joint counts inpaediatric clinics to counts of tender and swollen jointsin adult clinics, or change from JADAS to RA diseaseactivity measures (e.g., DAS28).Beukelman et al. Pediatric Rheumatology  (2017) 15:31 Page 6 of 9With the majority of JIA studies initiating in the2000’s only preliminary results on adult-aged patientsare currently available. Two studies specifically assess ef-fectiveness and safety of biologics in adult patients withJIA. The German JuMBO study has published outcomedata of 346 children (median age 21 years) who had re-ceived the biologic etanercept in childhood [8]. The UKBSRBR study has published data on outcomes of 225adults with JIA who started a biological therapy in child-hood [7]. In previous studies, outcomes of adults withJIA have been assessed cross-sectionally [20–22], retro-spectively [23], or by identifying adult patients diagnosedas children from medical records [24–27]. These studiesreported approximately 40 to 60% of children with JIAcontinue to have some level of active disease in adult-hood [22, 24, 25, 27–29]. Given the relative rarity of JIAand that not all children continue to have active diseasein adulthood, it will be important for registries to sharetheir experiences to develop robust methods to trackchildren through adulthood. Because few patients en-rolled in the current studies have reached adulthood,this may be an opportunity now to align the data to becollected in the future across studies.The studies included in our survey do not reflect theentirety of long-term outcomes studies in JIA. Severalrecent studies have used administrative data to investi-gate the risk of rare outcomes in JIA, such as malignancyor serious infection [30–32]. Administrative data sourcesprovide readily available data and often very large samplesizes, but provide scant clinical data compared to clinicalcohorts. Accordingly, administrative data are typicallymost useful for studies of adverse effects of medications,but are less useful for studies of medication effectivenessor long-term outcomes in JIA.Although there were many differences among thestudies, there was significant overlap in the data beingcollected. This may allow for the determination of aminimal data set that all existing and future prospectiveobservational studies could collect, enabling nearly iden-tical analysis plans to be conducted across all datasources.Our survey was able to summarize the extent of dataitems captured, but did not collect estimates of theamount of missing data for each variable. Missing dataare a common problem in observational research due toclinic non-attendance by patients, variable clinical needfor investigation (e.g. inflammatory marker and otherblood testing), and failure to report adverse events inbusy outpatient clinics, among others. This can result inbiases that require careful consideration of how to han-dle missing data and missing patients. This issue is com-pounded further in JIA due to the heterogeneity ofdisease, with many children who are well being dis-charged from secondary care and therefore no longercontributing to longer term outcome studies. Also, oursurvey did not enquire in detail about the timing of datacapture, particularly in relation to disease onset or startof therapies.In order to understand the risk of rare outcomes, largesample sizes and long term follow up are needed. Com-bining data from multiple studies increases statisticalpower, but must be done carefully. It is reassuring thatthere is significant commonality on the data itemscaptured across studies, which may permit the creationof a common data model to pool data. However, differ-ing methods of outcome ascertainment (e.g., assessingadverse events by patient report, physician report, orthrough an external data source) may produce importantdifferences in results. It will also be important to ensurethat no patients are double-counted if they have beensimultaneously enrolled in more than one registry effort;this is likely currently best addressed at the individualclinical site level, but assignment of a universal identifi-cation number allowing patients to contribute to variousdifferent registries over time (e.g., in response to changesin age or geographic location) would have potential add-itional benefits.This survey did not account for the differences inhealth care systems, clinical expertise in JIA, or fundingfor arthritis medications around the world. Because pa-tients are enrolled from pediatric rheumatology centers,differences in health care systems may influence enrol-ment into JIA registries through physician referral bias.Differential access to biologics likely results in substan-tial differences in disease duration and severity at thetime of starting treatment. Given the differences inpatient enrolment and data collection techniques, as wellas geographical differences in treatment approaches,genetic background of the patients, and varying inci-dences of comorbid conditions and endemic pathogens(such as tuberculosis), simple pooling of data may not bethe most appropriate approach to evaluate drug safety oreffectiveness. In addition, there may be restrictions onthe sharing of data, depending on the ethical approvaland patient consent obtained in each study. Overcomingthese hurdles to facilitate collaborative research in JIAwill be challenging and will require an internationaleffort involving multiple stakeholders. Within the JIAresearch community, initial steps have been taken tobegin to address these obstacles [33].Sophisticated methods for combining data should beexplored, such as nested case-control studies or meta-analyses of individual register data analysis. Theseapproaches were adopted by the EULAR Registers andObservational Drug Studies (RODS) Working Group toexplore the risk of malignant melanoma associated withTNFi therapies in patients with RA across Europe [34].Methodological approaches that consider the individualBeukelman et al. Pediatric Rheumatology  (2017) 15:31 Page 7 of 9data source will likely provide more accurate results andnew insights about confounders and effect modifiers ofoutcome. Despite the significant resources required, theseanalyses would be a unique opportunity to answer criticalquestions about JIA and should be undertaken.ConclusionsThis study identified a wide range of ongoing JIA cohortstudies and registries around the world. Many of thechallenges in the long-term study of childhood-onsetdiseases were highlighted. Nevertheless, the results indi-cate significant potential for future collaborative workusing both combined and comparative analyses of datafrom different studies. New approaches to maximise datacapture beyond childhood will be crucial to answerimportant questions about long-term outcomes.AbbreviationsABC: Arthritis and biologicals in children; ACR: American college ofrheumatology; AJC: Active joint count; BCRD: Biologics for children withrheumatic diseases; BiKeR: Biologics in pediatric rheumatology; BSPAR-ETN: British society for pediatric and adolescent rheumatolgy-etanercept;BSRBRc: British society for rheumatology biologics register; CAPS: Childhoodarthritis prospective study; CARRA: Childhood arthritis and rheumatologyresearch alliance; CHAQ: Childhood health assessment questionnaire; CRP:C-reactive protein; ESR: Erythrocyte sedimentation rate; HAQ: Healthassessment questionnaire; ICON: Inception cohort of newly diagnosedchildren with jia; ILAR: International league of associations for rheumatology;JACS: Juvenile arthritis cohort study; JADAS: Juvenile arthritis diseaseactivity score; JAMAR: Juvenile arthritis multidimensional assessmentreport; JIA: Juvenile idiopathic arthritis; JuMBO: Juvenile arthritismethotrexate biologics long-term observation; LJC: Limited joint count;MD: Physician; N: No; NPRD: National pediatric rheumatology database;Pharmachild: Pharmacovigilance in juvenile idiopathic arthritis patients;PRINTO: Pediatric rheumatology international trials organization;RA: Rheumatoid arthritis; ReACCh Out: Research in arthritis in canadianchildren emphasizing outcomes; RODS: Registers and observational drugstudies; UK: United Kingdom; USA: United States of America; Y: YesAcknowledgementsThe authors thank all children with JIA and their families who havecontributed to these studies.ICON: coordinator Angela Zink; consortium partners Dirk Foell and ArndHeiligenhaus; funded by a research grant of the Federal Ministry ofEducation and Research (FKZ 01ER0812); made possible by the support andparticipation of more than 300 German paediatric and adult rheumatologistswhom we thank.NPRD: funded by the German child arthritis foundation; made possible bythe support and participation of more than 300 German paediatric and adultrheumatologists whom we thank.JuMBO: Co-PI Angela Zink; funded by an unconditional grant from Pfizerand Abbvie; made possible by the support and participation of more than300 German paediatric and adult rheumatologists whom we thank.CAPS: funded by Arthritis Research UK (Grant # 20542)BCRD: funded by Arthritis Research UK (Grant # 20747)BSRBR: funded by British Society for Paediatric and AdolescentRheumatology and the British Society for RheumatologyBSPAR-ETN: funded by British Society for Paediatric and AdolescentRheumatology and the British Society for RheumatologyCARRA Legacy Registry: funded by United States National Institutes ofHealth/National Institute of Arthritis and Musculoskeletal and Skin Diseases(1RC2AR058934), Friends of CARRA, Arthritis FoundationCARRA Registry: funded by Arthritis Foundation, Novartis, Roche; ExecutiveCommittee members Laura Schanberg, Yukiko Kimura, Timothy Beukelman,Jason Jones, and Helen BristowJACS: Justine Ellis was supported by an Australian Research Council FutureFellowship, FT120100253Pharmachild: funded by European Union Framework Programme 7 grant(260353); Chiara Pallotti (PRINTO coordination center)BiKeR: made possible by the collaboration of numerous German andAustrian pediatric rheumatologists, patients and their parents and bynon-restricted grants from Abbvie, Chugai, Novartis, Pfizer, and Roche.Swedish JIA Register: Board of the RegistryReuma.pt: made possible by the collaboration of pediatric and adultrheumatologists, rheumatology nurses, patients, and by unrestricted grantsfrom AbbVie, Celegene, Hospira, MSD, Pfizer, Roche, and UCB.Nordic JIA Study: conducted by the Nordic Study Group of PediatricRheumatology (NoSPeR)FundingThis work was supported in part by the Arthritis Research UK Centre forEpidemiology (Grant #20380). The funding body had no role in the designof the study or the collection, analysis, or interpretation of the data, or thewriting of the manuscript.Availability of data and materialsData sharing is not applicable to this article as no datasets were generatedor analysed during the current study.Authors’ contributionsThe study was conceived by TB, LES, and KH. All authors contributed to theacquisition and interpretation of data. The manuscript was drafted by TB,LKF, and KH. All authors revised the manuscript critically and gave approvalof the final version.Competing interestsThe authors declare that they have no competing interests.Consent for publicationNot applicableEthics approval and consent to participateNot applicablePublisher’s NoteSpringer Nature remains neutral with regard to jurisdictional claims inpublished maps and institutional affiliations.Author details1University of Alabama at Birmingham, Birmingham, USA. 2Erasmus MedicalCenter, Rotterdam, The Netherlands. 3Uppsala University Hospital, Uppsala,Sweden. 4Children’s Hospital of Eastern Ontario, Ottawa, Canada. 5MurdochChildren’s Research Institute, Genes, Environment & Complex Disease,Parkville, Australia. 6Aarhus University Hospital, Aarhus, Denmark. 7Universityof British Columbia, Vancouver, Canada. 8Asklepios Klinik Sankt Augsutin,Sankt Augustin, Germany. 9University of Manchester, Manchester, UK.10German Rheumatism Research Center, Berlin, Germany. 11KarolinskaUniversity Hospital, Stockholm, Sweden. 12Royal Children’s Hospital,Melbourne, Australia. 13University Hospital of North Norway, Tromso, Norway.14Istituto Giannina Gaslini, Genoa, Italy. 15Hospital Garcia de Orta, Almada,Portugal. 16Duke University, Durham, USA. 17University Medical CenterUtrecht, Utrecht, The Netherlands. 18University of Manchester and CentralManchester Foundation Trust, Manchester, UK. 19Division of PediatricRheumatology, The University of Alabama at Birmingham, 1600 7thAvenue South, CPP 210, Birmingham, AL 35233-1711, USA.Received: 25 January 2017 Accepted: 7 April 2017References1. Petty RE, Southwood TR, Manners P, Baum J, Glass DN, Goldenberg J, et al.International league of associations for rheumatology classification ofjuvenile idiopathic arthritis: second revision, Edmonton, 2001. J Rheumatol.2004;31:390–2.2. Thierry S, Fautrel B, Lemelle I, Guillemin F. Prevalence and incidence of juvenileidiopathic arthritis: a systematic review. Joint Bone Spine. 2014;81:112–7.Beukelman et al. Pediatric Rheumatology  (2017) 15:31 Page 8 of 93. Guzman J, Gomez-Ramirez O, Jurencak R, Shiff NJ, Berard RA, Duffy CM,et al. What matters most for patients, parents, and clinicians in the courseof juvenile idiopathic arthritis? a qualitative study. J Rheumatol. 2014;41:2260–9.4. van Pelt P, Wulffraat NM. Transition of care in rheumatology: managing therheumatic patient from childhood to adulthood. In: Harrison A, editor.Insights and perspectives in rheumatology: InTech. 2012. p. 255–74.5. Ellis JA, Ponsonby AL, Pezic A, Chavez RA, Allen RC, Akikusa JD, et al.CLARITY - ChiLdhood arthritis risk factor identification sTudY. PediatrRheumatol Online J. 2012;10:37.6. Consolaro A, Ruperto N, Filocamo G, Lanni S, Bracciolini G, Garrone M, et al.Seeking insights into the EPidemiology, treatment and outcome ofchildhood arthritis through a multinational collaborative effort: introductionof the EPOCA study. Pediatr Rheumatol Online J. 2012;10:39.7. McErlane F, Foster HE, Davies R, Lunt M, Watson KD, Symmons DP, et al.Biologic treatment response among adults with juvenile idiopathic arthritis:results from the British society for rheumatology biologics register.Rheumatology (Oxford). 2013;52:1905–13.8. Minden K, Niewerth M, Zink A, Seipelt E, Foeldvari I, Girschick H, et al.Long-term outcome of patients with JIA treated with etanercept, resultsof the biologic register JuMBO. Rheumatology (Oxford). 2012;51:1407–15.9. Canhao H, Faustino A, Martins F, Fonseca JE. Rheumatic diseasesPortuguese register board coordination PSoR. Reuma.pt - the rheumaticdiseases Portuguese register. Acta Reumatol Port. 2011;36:45–56.10. Horneff G, De Bock F, Foeldvari I, Girschick HJ, Michels H, Moebius D, et al.Safety and efficacy of combination of etanercept and methotrexatecompared to treatment with etanercept only in patients with juvenileidiopathic arthritis (JIA): preliminary data from the German JIA registry.Ann Rheum Dis. 2009;68:519–25.11. Schmeling H, Minden K, Foeldvari I, Ganser G, Hospach T, Horneff G. Efficacyand safety of adalimumab as the first and second biologic agent in juvenileidiopathic arthritis: the German biologics JIA registry. Arthritis Rheumatol.2014;66:2580–9.12. Davies R, Southwood TR, Kearsley-Fleet L, Lunt M, Hyrich KL, British Societyfor P, et al. Medically significant infections Are increased in patients withjuvenile idiopathic arthritis treated with etanercept: results from the Britishsociety for paediatric and adolescent rheumatology etanercept cohortstudy. Arthritis Rheumatol. 2015;67:2487–94.13. Kearsley-Fleet L, Davies R, Baildam E, Beresford MW, Foster HE, SouthwoodTR, et al. Factors associated with choice of biologic among children withjuvenile idiopathic arthritis: results from two UK paediatric biologic registers.Rheumatology (Oxford). 2016;55:1556–65.14. Beukelman T, Kimura Y, Ilowite NI, Mieszkalski K, Natter MD, Burrell G, et al.The new Childhood Arthritis and Rheumatology Research Alliance (CARRA)Registry: design, rationale, and characteristics of patients enrolled in the first12 months. (in press).15. Filocamo G, Consolaro A, Schiappapietra B, Dalpra S, Lattanzi B, Magni-Manzoni S, et al. A new approach to clinical care of juvenile idiopathicarthritis: the juvenile arthritis multidimensional assessment report. JRheumatol. 2011;38:938–53.16. Giannini EH, Ruperto N, Ravelli A, Lovell DJ, Felson DT, Martini A. Preliminarydefinition of improvement in juvenile arthritis. Arthritis Rheum. 1997;40:1202–9.17. Consolaro A, Ruperto N, Bazso A, Pistorio A, Magni-Manzoni S, Filocamo G,et al. Development and validation of a composite disease activity score forjuvenile idiopathic arthritis. Arthritis Rheum. 2009;61:658–66.18. McErlane F, Beresford MW, Baildam EM, Chieng SE, Davidson JE, Foster HE, et al.Validity of a three-variable juvenile arthritis disease activity score in children withnew-onset juvenile idiopathic arthritis. Ann Rheum Dis. 2013;72:1983–8.19. Adib N, Hyrich K, Thornton J, Lunt M, Davidson J, Gardner-Medwin J, et al.Association between duration of symptoms and severity of disease at firstpresentation to paediatric rheumatology: results from the childhood arthritisprospective study. Rheumatology (Oxford). 2008;47:991–5.20. Packham JC, Hall MA. Long-term follow-up of 246 adults with juvenile idiopathicarthritis: functional outcome. Rheumatology (Oxford). 2002;41:1428–35.21. Bruinooge LN, El Moussaoui R, Taal E, Dijkmans BA, Van Soesbergen RM.Outcome in adults with juvenile idiopathic arthritis. Comparison of theDUTCH-AIMS2 between JIA and RA. Scand J Rheumatol. 2003;32:89–94.22. Foster HE, Marshall N, Myers A, Dunkley P, Griffiths ID. Outcome in adultswith juvenile idiopathic arthritis: a quality of life study. Arthritis Rheum.2003;48:767–75.23. Peterson LS, Mason T, Nelson AM, O’Fallon WM, Gabriel SE. Psychosocialoutcomes and health status of adults who have had juvenile rheumatoidarthritis: a controlled, population-based study. Arthritis Rheum. 1997;40:2235–40.24. Nordal E, Zak M, Aalto K, Berntson L, Fasth A, Herlin T, et al. Ongoingdisease activity and changing categories in a long-term nordic cohort studyof juvenile idiopathic arthritis. Arthritis Rheum. 2011;63:2809–18.25. Zak M, Pedersen FK. Juvenile chronic arthritis into adulthood: a long-termfollow-up study. Rheumatology (Oxford). 2000;39:198–204.26. French AR, Mason T, Nelson AM, O’Fallon WM, Gabriel SE. Increasedmortality in adults with a history of juvenile rheumatoid arthritis: apopulation-based study. Arthritis Rheum. 2001;44:523–7.27. Arkela-Kautiainen M, Haapasaari J, Kautiainen H, Leppanen L, Vilkkumaa I,Malkia E, et al. Functioning and preferences for improvement of healthamong patients with juvenile idiopathic arthritis in early adulthood usingthe WHO ICF model. J Rheumatol. 2006;33:1369–76.28. Fantini F, Gerloni V, Gattinara M, Cimaz R, Arnoldi C, Lupi E. Remission injuvenile chronic arthritis: a cohort study of 683 consecutive cases with amean 10 year followup. J Rheumatol. 2003;30:579–84.29. Selvaag AM, Aulie HA, Lilleby V, Flato B. Disease progression into adulthoodand predictors of long-term active disease in juvenile idiopathic arthritis.Ann Rheum Dis. 2016;75:190–5.30. Beukelman T, Xie F, Chen L, Baddley JW, Delzell E, Grijalva CG, et al. Rates ofhospitalized bacterial infection associated with juvenile idiopathic arthritisand its treatment. Arthritis Rheum. 2012;64:2773–80.31. Beukelman T, Haynes K, Curtis JR, Xie F, Chen L, Bemrich-Stolz CJ, et al.Rates of malignancy associated with juvenile idiopathic arthritis and itstreatment. Arthritis Rheum. 2012;64:1263–71.32. Nordstrom BL, Mines D, Gu Y, Mercaldi C, Aquino P, Harrison MJ. Risk ofmalignancy in children with juvenile idiopathic arthritis not treated withbiologic agents. Arthritis Care Res (Hoboken). 2012;64:1357–64.33. Robinson E, Albani S, Beresford MW, de Jager W, de Roock S, Duong T, et al.Towards stratified medicine in juvenile idiopathic arthritis [abstract]. 2016Pediatric Rheumatology European Society (PReS) Congress.34. Mercer LK, Askling J, Raaschou P, Dixon WG, Dreyer L, Hetland ML, et al.Risk of invasive melanoma in patients with rheumatoid arthritis treatedwith biologics: results from a collaborative project of 11 European biologicregisters. Ann Rheum Dis. 2017;76(2):386–91.35. Sengler C, Klotsche J, Niewerth M, Liedmann I, Foll D, Heiligenhaus A, et al.The majority of newly diagnosed patients with juvenile idiopathic arthritisreach an inactive disease state within the first year of specialised care: datafrom a German inception cohort. RMD open. 2015;1:e000074.36. Oen K, Tucker L, Huber AM, Miettunen P, Scuccimarri R, Campillo S, et al.Predictors of early inactive disease in a juvenile idiopathic arthritis cohort:results of a Canadian multicenter, prospective inception cohort study.Arthritis Rheum. 2009;61:1077–86.37. Beukelman T, Ringold S, Davis TE, DeWitt EM, Pelajo CF, Weiss PF, et al.Disease-modifying antirheumatic drug use in the treatment of juvenileidiopathic arthritis: a cross-sectional analysis of the CARRA Registry. JRheumatol. 2012;39:1867–74.38. Minden K, Niewerth M, Listing J, Zink A. German study group of pediatric R.Health care provision in pediatric rheumatology in Germany–nationalrheumatologic database. J Rheumatol. 2002;29:622–8.39. Prince FH, Twilt M, ten Cate R, van Rossum MA, Armbrust W, HoppenreijsEP, et al. Long-term follow-up on effectiveness and safety of etanercept injuvenile idiopathic arthritis: the Dutch national register. Ann Rheum Dis.2009;68:635–41.Beukelman et al. Pediatric Rheumatology  (2017) 15:31 Page 9 of 9

Cite

Citation Scheme:

        

Citations by CSL (citeproc-js)

Usage Statistics

Share

Embed

Customize your widget with the following options, then copy and paste the code below into the HTML of your page to embed this item in your website.
                        
                            <div id="ubcOpenCollectionsWidgetDisplay">
                            <script id="ubcOpenCollectionsWidget"
                            src="{[{embed.src}]}"
                            data-item="{[{embed.item}]}"
                            data-collection="{[{embed.collection}]}"
                            data-metadata="{[{embed.showMetadata}]}"
                            data-width="{[{embed.width}]}"
                            async >
                            </script>
                            </div>
                        
                    
IIIF logo Our image viewer uses the IIIF 2.0 standard. To load this item in other compatible viewers, use this url:
https://iiif.library.ubc.ca/presentation/dsp.52383.1-0366874/manifest

Comment

Related Items