Rheumatol Int (2011) 31:1259–1262

DOI 10.1007/s00296-011-2062-0

EDITORIAL

Progress in pediatric rheumatology: apprehend the opportunities of the future without forgetting the lessons from the past

Hans-Iko Huppertz · Dirk Föll · Hermann Girschick · Kirsten Minden · Gerd HorneV

Received: 12 July 2011 / Accepted: 20 July 2011 / Published online: 8 September 2011© Springer-Verlag 2011

What you have inherited from your fathers, acquire itin order to possess it

[Was du ererbt von deinen Vätern hast, erwirb es, umes zu besitzen]

GoetheFaust

Juvenile idiopathic arthritis (JIA), the most frequentchronic inXammatory disease in cildren and adolescents, isdeWned by the most accurate description of seven exclusivesubtypes [1]. In contrast, the latest classiWcation criteria forrheumatoid arthritis (RA), a joint project by the EuropeanLeague against Rheumatism (EULAR) and the American

College of Rheumatology (ACR), describe the disorder bycriteria that compel the attending rheumatologist to pre-scribe a disease-modifying antirheumatic drug, mostlymethotrexate [2]. Investigators mainly from North Americaand endorsed by the ACR have chosen a similar path bydeWning treatment groups for JIA and giving recommenda-tions for the treatment of JIA [3]. Beukelman and coinvesti-gators Wrst assembled the relevant literature excludingreview articles between 1966 and 2009 and found 221 arti-cles that were reviewed and abstracted by a group ofexperts. Since diVerential treatment between the diVerentcategories of JIA is not established, the authors developedtreatment groups that are in part similar to older categoriesof pediatric rheumatic disorders including oligoarthritis,polyarthritis, sacroiliac arthritis, systemic arthritis with sys-temic features and systemic arthritis with arthritis. For eachcategory, they deWned features of poor prognosis and threelevels of disease activity. Finally, the authors created 1,539clinical scenarios with a given treatment group and historyof treatment and description of disease activity and progno-sis. All these scenarios were evaluated individually by eachmember of a task force of experts, practitioners and a par-ent and assessed for the appropriateness of initiating a cer-tain treatment option. The expert group then translated theresults into text and Wnally determined the level of evidenceof each recommendation. The authors added algorithms forfour of the Wve treatment groups. Beukelman et al. haveundertaken a gigantic project and achieved an unparalleledstep ahead in the development of pediatric rheumatology.

Already in the introduction, the authors admit that theydid not consider indications for systemic glucocorticoidsfor the treatment of synovitis since they could not Wnd anypublished evidence [3]. This is a remarkable statementsince generations of pediatric rheumatologists have reliedon the administration of systemic glucocorticoids and were

H.-I. Huppertz (&)Klinikum Bremen-Mitte, Bremen and Children’s Hospital, University of Göttingen, Göttingen, Germanye-mail: huppertz.bremen@t-online.de

D. FöllDepartment of Translational Inflammation Research, Institute of Immunology, University of Muenster, Münster, Germanye-mail: dfoell@uni-muenster.de

H. GirschickKlinik für Kinder- und Jugendmedizin, Klinikum am Friedrichshain, Berlin, Germanye-mail: Hermann.Girschick@vivantes.de

K. MindenDepartment of Pediatric Rheumatology, Charité University Medicine Berlin, Berlin, Germanye-mail: kirsten.minden@charite.de

G. HorneVAsklepios Children’s Hospital, Sankt Augustin, Germanye-mail: g.horneff@asklepios.com

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and are experts in using the beneWcial antirheumatic prop-erties while avoiding the adverse eVects.

In fact, there are several reasons to question the appro-priateness of excluding systemic glucocorticoids from thetreatment of arthritis in children with JIA.

• It is textbook knowledge that synovitis is amenable totreatment with systemic glucocorticoids including a longrecord of eYcacy and adverse eVects. The vast knowl-edge of adverse eVects of glucocorticoids and the ”intel-ligent” use of glucocorticoids for the beneWt of thepatient while avoiding the unwanted eVects are proof ofthe extensive knowledge of eYcacy. Intelligent use ofglucocorticoids includes topical administration such asintra-articular glucocorticoids (which are being acceptedby Beukelman et al.), low-dose glucocorticoids, whichimplies the avoidance of cushingoid side eVects, and glu-cocorticoid pulse therapy which may be repeated after afew weeks without the occurrence of long-term adverseeVects [4]. So, there is ample knowledge on the treatmentof arthritis with systemic steroids, but this predates theintroduction of controlled trials.

• There is good evidence for the appropriateness of usingseveral biological DMARDs because these new sub-stances were required to demonstrate eVectiveness incontrolled trials prior to obtaining an FDA/EMA licensefor children. Such randomized placebo-controlled trialsare costly, and there is no Wnancial incentive to test howthe oldest antirheumatic drug on the market, glucocorti-coids, could be most reasonably used. Consequently, theauthors’ path favors new costly therapies and neglectsold inexpensive treatments such as glucocorticoids thathave been available for decades.

• Glucocorticoids can be administered in various ways,i.e., oral, i.v., local, the dosage per kg body weight andthe distribution of the doses over the day, the duration oftreatment (days, weeks or months) and the repetition oftreatment as in pulse therapies vary widely and manyregimens have been described as being eVective. Theseextreme variations render handling of this drug in theauthors’ project very diYcult if not impossible. How-ever, if a probably very valuable drug cannot be assessedby an analytical method, the consequence should be toadmit this methodological problem rather than the exclu-sion of the drug.

• The authors do not discuss the concept of glucocorticoidsas a bridging agent. Systemic glucocorticoids renderrapid relief to patients with polyarthritis during theperiod from initiation of slowly acting drugs includingmethotrexate till the onset of their eYcacy.

• The actual algorithms for the treatment of polyarticularJIA include the administration of systemic glucocorti-coids. In fact, all recent controlled studies allowed for the

administration of low-dose glucocorticoids [5]. If theauthors believe glucocorticoids are not necessary, theyshould have recommended testing their new approachagainst standard treatment, i.e.,methotrexate + glucocorticoids versus methotrexatealone or versus methotrexate + early introduction ofTNF-�-blocker rather than excluding glucocorticoids.

• The concept proposed by the authors argues for the earlyintroduction of biological DMARDs including TNF-�-blocker [3]. The therapeutic eYcacy and the safetyrecord of these drugs are impressive. However, the unre-solved debate on the rare, but possible induction ofmalignant lymphoma due to administration of TNF-�-blockers should remind us of the necessity of continuingvigilance. The wide variation between studies excludingor showing an association of the treatment with TNF-�-blockers and the detection of malignant lymphoma mightbe due to the administration of systemic glucocorticoidsin several treatment protocols. Glucocorticoids have along record of antilymphoproliferative activity and mighthave curbed development of lymphomas at a very earlystage. We should remember that the Wrst trials in whichchildren obtained TNF-�-blockers are just a decade agoand there are no patients with JIA in their forties whoreceived biological DMARDs in their childhood [6]. So,in the absence of long-term safety data, biologicalDMARDs should be started when conventional treat-ment with methotrexate and glucocorticoids has failed.

• The strongest argument for the early introduction ofTNF-�-blockers rests on the assumption that early andaggressive treatment of RA may prevent deWnitive dam-age due to suppression of inXammation and pannus for-mation and even might hinder the establishment of thefalse immune reaction leading to chronic inXammatoryjoint disease. However, in contrast to RA, the pathogene-sis of JIA does not progress rapidly to joint destructionwith the exception of a few cases of rheumatoid factorpositive polyarticular JIA that resembles RA startingalready in adolescence. There is no lasting damage inJIA and no loss of a window of opportunity during theperiod of the slowly starting eYcacy of methotrexateespecially in the presence of concomitant treatment withsystemic glucocorticoids.

We believe it is wrong to withhold systemic glucocorticoidsfrom children with polyarticular JIA. It is correct that theeYcacy of the drug should be tested in controlled trials. Thelack of the appropriate evidence is the pediatric rheumatol-ogy community’s fault and this negligence should not lead toour patients’ disadvantage. We have to acquire the drug inour modern way by controlled trials. Till these results will beavailable, we should keep the drug and continue using itbased on the therapeutic experience of the last decades.

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The authors suggest updating their recommendationswhich is laudable [3]. However, they should not only focuson areas of newly published evidence, but include availableolder knowledge on eVective treatment of JIA and trans-form it into new evidence by controlled studies. Moreover,the authors might consider broadening the basis of theirrecommendations by including the Pediatric RheumatologyEuropean Society. Recent recommendations concerningRA were jointly published by ACR and EULAR.

Further criticisms include:

• Tocilizumab is not mentioned since the authors claim thedrug is not widely commercially available. It is licensedfor JIA in Japan, for systemic JIA in the US and for RAin Europe and has just been licensed for systemic JIA inEurope.

• Hydroxychloroquine is labeled inappropriate for activesynovitis [3]. However, the results of trials are inconclu-sive and the largest study included patients with severearthritis and an unexplained improvement in the placebogroup [7]. The drug is known to act very slowly and ifthere are other means including intra-articular steroids tocontrol acute arthritis, it may well prevent Xare with avery good safety record.

• Rituximab is recommended as a possible alternativewhen TNF-�-blocker and abatacept have failed. This isbased solely on references concerning RA. There is nopediatric evidence beyond case reports. The drug isknown to aVect permanently the growing B-cell-com-partment in children and there are no data on long-termsafety. Rituximab should be reserved for very rare casesor given in controlled trials in JIA only.

• Methotrexate is recommended at 15 mg/m2 administeredby parenteral route. The drug usually is given at 10–12 mg/m2, and there is no convincing evidence in chil-dren that the parenteral route is superior to the oral routewhich might be more appropriate for children. Most ofthe recent controlled trials for the assessment of new bio-logical DMARDs included as an inclusion criterion fail-ure or toxicity of oral methotrexate at the lower dosage.A PRINTO study demonstrated the eYcacy of 15 mg/m2

via the parenteral route after 8–12.5 mg/m2 orally hadfailed [8]. However, the study had no control group andcontinuation of the oral treatment might have beenequally eVective. Thus, when oral methotrexate fails tocontrol arthritis, a TNF-�-blocker may be consideredwithout having administered parenteral methotrexate.

• Abatacept is a special, although instructive, case: there isa single-controlled trial in polyarticular JIA whichshowed eYcacy and which was followed by FDA andEMA approval [9]. The authors recommend the drug forpolyarticular JIA which did not improve on TNF-�-blockers. However, there are no other data conWrming

the initial publication, and there are no data on long-termsafety. It is not enough to show a drug’s eYcacy in onecontrolled trial. The drug has to show consistent eYcacyover years and a good safety record which can be deter-mined by registries as has been shown for etanercept[10–13]. Such registries are missing for abatacept, toc-ilizumab and adalimumab. Manufacturers should beforced to continue surveillance of drug safety andeYcacy after license under the threat of revoking licenseif there is lack of compliance.

• The authors use scenarios based on key clinical decisionparameters (disease phenotype, prognostic features, dis-ease activity and current therapy). They state that thedeWnitions and values of all these key parameters were“as evidence-based as possible” [3]. However, the pro-cess of achieving evidence obviously was based uponexpert opinion on “their personal clinical experience”gathered via electronic mail. This discrepancy betweenthe strict adherence to evidence from controlled trials ontherapeutic agents on the one hand and the method ofdeWning key parameters of patient stratiWcation on theother hand is remarkable.

• As the authors point out, their recommendations requireclear deWnitions of disease activity including biomarkersto make rational therapeutic choices. While certainlynormal levels of C-reactive protein and erythrocyte sedi-mentation rate are consistent with the deWnition of lowdisease activity, there is evidence that these measures arenot sensitive enough to exclude local inXammatory activ-ity related to joint destruction. The need for more sophis-ticated molecular markers indicating disease activity butalso prognosis is evident, and Wrst encouraging exampleshave recently been published in JIA [14].

Our remarks are meant to encourage discussion and not tobelittle the tremendous progress for the treatment of JIAwhich has been achieved by creating these recommenda-tions. The authors have altered the approach to the patientwith JIA by creating the JIA treatment groups, by establish-ing features of poor prognosis and by formulating diVerentlevels of disease activity. Use of these features all over theworld will show if these new tools will stand up against thenecessities of daily care and how they might be modiWed.However, treating children with JIA will not be the same asbefore the publication of these recommendations.

Summary

Investigators mainly from North America have establisheda new classiWcation of juvenile idiopathic arthritis (JIA) bycreating treatment groups, levels of disease activity andprognostic features [3]. After scanning the available litera-

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ture for controlled trials the authors recommend treatmentoptions. Due to the lack of published evidence theseauthors could not Wnd an indication for the use of systemicsteroids in chronic synovitis. Since this drug may be veryuseful for patients with JIA and its introduction predatesevidence-based medicine, it should not be removed fromtreatment algorithms, but should be tested in controlled tri-als. Further topics of discussion relate to treatment withtocilizumab, rituximab, methotrexate, hydroxychloro-quine, abatacept and to varying levels of evidence in treat-ment recommendations. Beukelman et al. will have alasting impact on the treatment of JIA. European Societiesfor Pediatric Rheumatology should participate in futuredevelopments.

Disclosure Huppertz: HIH served as board member for Abbott, PWz-er, Roche and Swedish Orphan and received speaking fees from Abbottand PWzer.Foell: DF served as board member for Roche.Girschick: no disclosures.Minden: KM served as board member for Abbott, BMS, PWzer andRoche and received an unconditional grant from PWzer.HorneV: GH served as board member for Abbott, Novartis, Nycomed,PWzer, Roche and Swedish Orphan, received unconditional grants fromAbbott and PWzer and speaking fees from Abbott, Chugai, Novartisand PWzer.

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