Anti-TNF treatment in juvenile idiopathic arthritis and associated uveitis : Clinical perspectives on growth, uveitis, and drug survival

Juvenile idiopathic arthritis (JIA) is a heterogeneous group of childhood chronic arthritides, associated with chronic uveitis in 20% of cases. For JIA patients responding inadequately to conventional disease-modifying anti-rheumatic drugs (DMARDs), biologic therapies, anti-tumor necrosis factor (anti-TNF) agents are available. In this retrospective multicenter study, 258 JIA-patients refractory to DMARDs and receiving biologic agents during 1999-2007 were included. Prior to initiation of anti-TNFs, growth velocity of 71 patients was delayed in 75% and normal in 25%. Those with delayed growth demonstrated a significant increase in growth velocity after initiation of anti-TNFs. Increase in growth rate was unrelated to pubertal growth spurt. No change was observed in skeletal maturation before and after anti-TNFs. The strongest predictor of change in growth velocity was growth rate prior to anti-TNFs. Change in inflammatory activity remained a significant predictor even after decrease in glucocorticoids was taken into account. In JIA-associated uveitis, impact of two first-line biologic agents, etanercept and infliximab, and second-line or third-line anti-TNF agent, adalimumab, was evaluated. In 108 refractory JIA patients receiving etanercept or infliximab, uveitis occurred in 45 (42%). Uveitis improved in 14 (31%), no change was observed in 14 (31%), and in 17 (38%) uveitis worsened. Uveitis improved more frequently (p=0.047) and frequency of annual uveitis flares was lower (p=0.015) in those on infliximab than in those on etanercept. In 20 patients taking adalimumab, 19 (95%) had previously failed etanercept and/or infliximab. In 7 patients (35%) uveitis improved, in one (5%) worsened, and in 12 (60%) no change occurred. Those with improved uveitis were younger and had shorter disease duration. Serious adverse events (AEs) or side-effects were not observed. Adalimumab was effective also in arthritis. Long-term drug survival (i.e. continuation rate on drug) with etanercept (n=105) vs. infliximab (n=104) was at 24 months 68% vs. 68%, and at 48 months 61% vs. 48% (p=0.194 in log-rank analysis). First-line anti-TNF agent was discontinued either due to inefficacy (etanercept 28% vs. infliximab 20%, p=0.445), AEs (7% vs. 22%, p=0.002), or inactive disease (10% vs. 16%, p=0.068). Females, patients with systemic JIA (sJIA), and those taking infliximab as the first therapy were at higher risk for treatment discontinuation. One-third switched to the second anti-TNF agent, which was discontinued less often than the first. In conclusion, in refractory JIA anti-TNFs induced enhanced growth velocity. Four-year treatment survival was comparable between etanercept and infliximab, and switching from first-line to second-line agent a reasonable therapeutic option. During anti-TNF treatment, one-third with JIA-associated anterior uveitis improved.Lastenreuma on invalidisoiva heterogeeninen tautiryhmä, jonka esiintyvyys lapsiväestössä on 0.1%, ja johon liittyy 20%:lla yleensä silmän etuosan reumaattinen krooninen tulehdus, anteriorinen uveiitti. Tavanomaisen antireumaattisen hoidon teho on riittämätön 20-30%:lla. Uudet biologiset lääkkeet, lähinnä tuumorinekroosifaktori (TNF) salpaajat, ovat parantaneet hoitotuloksia. Väitöskirjatyö sisälsi neljä osatyötä. Näissä seurattiin TNF-salpaajien vaikutusta lasten kasvunopeuteen ja krooniseen uveiittiin sekä lääkehoidon jatkuvuutta ja hoidon keskeyttämiseen johtavia syitä, mistä tutkimuksen alkaessa oli vähän tai ei lainkaan julkaistuja havaintoja. Tutkimusaineisto TNF-salpaajahoitoa vuosina 1999-2007 saaneista 258 lapsireumaatikosta kerättiin Helsingin ja Oulun yliopistollisista keskussairaaloista sekä Reumasäätiön sairaalasta. Ennen TNF-salpaajahoidon aloitusta 71 lapsen kasvunopeus oli hidastunut 75%:lla ja normaali 25%:lla. Merkittävällä osalla, erityisesti aiemmin hitaasti kasvaneilla, kasvunopeus kiihtyi TNF-salpaajahoidon aloitusta seuraavan kahden vuoden aikana vaikuttamatta luuston kypsymisaikatauluun. Positiivinen vaikutus kasvuun oli TNF-salpaajahoidon aikana vähentyneellä glukokortikoidien käytöllä, vaikkakaan tämä ei yksin selittänyt kasvun paranemista. Molemmat TNF-salpaajat, etanersepti ja infliksimabi vaikuttivat tulehdusaktiviteettia hillitsevästi ja todennäköisesti tämän takia kasvua edistäen. Uveiitti lievittyi 43%:lla infliksimabia ja 21%:lla etanerseptia käyttäneistä 45 lapsireumaatikosta. Vaikeahoitoisen, TNF-salpaajahoitoa pääosin niveloireiden takia saavan 108 potilaan kohortissa uveiitin esiintyvyys seuranta-aikana oli poikkeuksellisen korkea, 42%. Adalimumabi vaikutti lievittävän uveiittia 35%:lla 20:sta lapsipotilaasta, joista 95% oli joutunut keskeyttämään etanerseptin ja/tai infliksimabin tehottomuuden tai sivuvaikutusten takia. Adalimumabin teho lastenreuman niveloireisiin oli hyvä eikä vakavia haittatapahtumia todettu. Etanersepti- ja infliksimabihoito jatkui noin puolella potilasta vielä neljän vuoden jälkeen hoidon aloituksesta. Näiden lääkeaineiden välillä ei keskeyttäneiden kokonaisosuuksissa ollut eroa, vaikkakin sivuvaikutusten takia infliksimabihoito keskeytyi useammin. Lääkkeen keskeytyksen vaarasuhde oli myös suurempi tytöillä sekä systeemistä lastenreumaa sairastavilla. Kolmasosa lapsista vaihtoi TNF-salpaajan joko tehottomuuden tai sivuvaikutusten takia toiseen biologiseen valmisteeseen, ja joutuivat jälkimmäisen valmisteen keskeyttämään harvemmin. Tulokset viittaavat TNF-salpaajahoidon laaja-alaiseen hyödyllisyyteen lapsireumaatikoilla myös pitkäaikaiskäytössä. Reumataudin rauhoittumisen myötä lasten kasvunopeuden normaalistuminen mahdollistuu, ja arviolta kolmasosalla krooninen uveiitti lievittyy

Health-related quality of life during early aggressive treatment in patients with polyarticular juvenile idiopathic arthritis : results from randomized controlled trial

Background Juvenile Idiopathic Arthritis (JIA) may cause significant impairment in health-related quality of life (HrQoL), despite effective therapies. The aim of this study was to assess HrQoL during first-year treatment in patients with new-onset polyarticular JIA, and to compare treatment strategies. Methods In ACUTE-JIA Study, 60 patients with new-onset JIA were randomized to receive either infliximab with methotrexate (IFX+MTX); a triple therapy of methotrexate, hydroxychloroquine, and sulfasalazine (Triple); or methotrexate monotherapy (MTX). Efficacy was measured with American College of Rheumatology pediatric (ACRp) score, and juvenile arthritis disease activity score (JADAS). HrQoL was evaluated with Child Health Questionnaire (CHQ), which includes physical and psychosocial summary scores (PhS and PsS). Linear mixed models were utilized to compare groups over time. Results In the whole group of 60 patients, mean physical summary score (PhS) improved from 26.2 (SD 8.7) at week 0 to 49.7 (SD 13.2) at week 54 (p=0.046). Mean improvement of PhS was 20.3 (95% CI -15.5 to 56.2); 22.6 (-19.5 to 64.7); and 26.6 (-12.1 to 65.3) in IFX+MTX, Triple, and MTX, respectively. Changes in psychosocial summary score (PsS) were smaller: from 51.0 (SD 8.5) to 54.7 (6.3) (p=0.019) in all patients. No differences between the three treatment groups were detected in either of the measures. In multivariate analyses, Child Health Assessment Questionnaire (CHAQ), pain VAS, and time spent in inactive disease contributed to improvement in PhS; gender and CHAQ to PsS. Conclusions HrQol improved during the first year on therapy for JIA irrespective of the treatment strategy. The timing of change in the different dimensions of HrQoL varied; improvement occurred earlier in physical than psychosocial domains of HrQol.Peer reviewe

Economic evaluation of infliximab, synthetic triple therapy and methotrexate in the treatment of newly diagnosed juvenile idiopathic arthritis

Background: Evaluation of costs and short-term cost-effectiveness of infliximab plus methotrexate (IFX + MTX); triple therapy of hydroxychloquine, sulphasalazine, and methotrexate (TRIPLE); or methotrexate monotherapy (MTX) in patients with new-onset polyarticular juvenile idiopathic arthritis (JIA).Methods: In a prospective multicenter study (ACUTE-JIA), costs and health outcomes of 60 randomized patients with new-onset disease-modifying anti-rheumatic drug (DMARD)-naive polyarticular JIA were analyzed during the first year. A mapping algorithm was used to obtain utility values from Child Health Assessment Questionnaire (CHAQ). Wallace criteriae were used to assess clinically inactive disease (CID). Linear regression with non-parametric bootstrapping was used to adjust imbalances at baseline.Results: Using prices for IFX biosimilar, adjusted annual mean (SD) costs of treatment (euro) were 21,164 (4158), 12,136 (5286), and 18,300 (8635) on IFX + MTX, TRIPLE, and MTX, respectively. Incremental cost-effectiveness ratio (ICER) for IFX + MTX as compared with TRIPLE or MTX were 3442 euro or 678 euro per additional month spent in CID. Mean (SD) quality-adjusted life years (QALYs) for IFX + MTX, TRIPLE and MTX were 0.755 (0.065), 0.725 (0.062), and 0.686 (0.124). ICER for IFX + MTX vs TRIPLE was 294,433 euro, and for IFX + MTX vs MTX 31,435 euro per QALY gained.Conclusions: In short-term, biosimilar IFX + MTX can be considered cost-effective when compared with MTX alone. TRIPLE was cost-effective when compared with MTX and showed cost advantage when compared with IFX + MTX. Cost per time spent in CID showed similar results than ICER evaluations.Peer reviewe

Medical treatment of juvenile idiopathic arthritis

Peer reviewe

Validating 10-joint juvenile arthritis disease activity score cut-offs for disease activity levels in non-systemic juvenile idiopathic arthritis

Objectives To validate cut-offs of the Juvenile Arthritis Disease Activity Score 10 (JADAS10) and clinical JADAS10 (cJADAS10) and to compare them with other patient cohorts. Methods In a national multicentre study, cross-sectional data on recent visits of 337 non-systemic patients with juvenile idiopathic arthritis (JIA) were collected from nine paediatric outpatient units. The cut-offs were tested with receiver operating characteristic curve-based methods, and too high, too low and correct classification rates (CCRs) were calculated. Results Our earlier presented JADAS10 cut-offs seemed feasible based on the CCRs, but the cut-off values between low disease activity (LDA) and moderate disease activity (MDA) were adjusted. When JADAS10 cut-offs for clinically inactive disease (CID) were increased to 1.5 for patients with oligoarticular disease and 2.7 for patients with polyarticular disease, as recently suggested in a large multinational register study, altogether 11 patients classified as CID by the cut-off had one active joint. We suggest JADAS10 cut-off values for oligoarticular/polyarticular disease to be in CID: 0.0-0.5/0.0-0.7, LDA: 0.6-3.8/0.8-5.1 and MDA: >3.8/5.1. Suitable cJADAS10 cut-offs are the same as JADAS10 cut-offs in oligoarticular disease. In polyarticular disease, cJADAS10 cut-offs are 0-0.7 for CID, 0.8-5.0 for LDA and > 5.0 for MDA. Conclusion I nternational consensus on JADAS cutoff values is needed, and such a cut-off for CID should preferably exclude patients with active joints in the CID group.Peer reviewe

Validating 10-joint juvenile arthritis disease activity score cut-offs for disease activity levels in non-systemic juvenile idiopathic arthritis

Objectives To validate cut-offs of the Juvenile Arthritis Disease Activity Score 10 (JADAS10) and clinical JADAS10 (cJADAS10) and to compare them with other patient cohorts.Methods In a national multicentre study, cross-sectional data on recent visits of 337 non-systemic patients with juvenile idiopathic arthritis (JIA) were collected from nine paediatric outpatient units. The cut-offs were tested with receiver operating characteristic curve-based methods, and too high, too low and correct classification rates (CCRs) were calculated.Results Our earlier presented JADAS10 cut-offs seemed feasible based on the CCRs, but the cut-off values between low disease activity (LDA) and moderate disease activity (MDA) were adjusted. When JADAS10 cut-offs for clinically inactive disease (CID) were increased to 1.5 for patients with oligoarticular disease and 2.7 for patients with polyarticular disease, as recently suggested in a large multinational register study, altogether 11 patients classified as CID by the cut-off had one active joint. We suggest JADAS10 cut-off values for oligoarticular/polyarticular disease to be in CID: 0.0–0.5/0.0–0.7, LDA: 0.6–3.8/0.8–5.1 and MDA: >3.8/5.1. Suitable cJADAS10 cut-offs are the same as JADAS10 cut-offs in oligoarticular disease. In polyarticular disease, cJADAS10 cut-offs are 0–0.7 for CID, 0.8–5.0 for LDA and >5.0 for MDA.Conclusion International consensus on JADAS cut-off values is needed, and such a cut-off for CID should preferably exclude patients with active joints in the CID group.</div

Defining new clinically derived criteria for high disease activity in non-systemic juvenile idiopathic arthritis: a Finnish multicentre study

ObjectivesTo redefine criteria for high disease activity (HDA) in JIA, to establish HDA cut-off values for the 10-joint Juvenile Arthritis Disease Activity Score (JADAS10) and clinical JADAS10 (cJADAS10) and to describe the distribution of patients’ disease activity levels based on the JADAS cut-off values in the literature.MethodsData on 305 treatment-naïve JIA patients were collected from nine paediatric units treating JIA. The median parameters of the JADAS were proposed to be the clinical criteria for HDA. The cut-off values were assessed by using two receiver operating characteristics curve–based methods. The patients were divided into disease activity levels based on currently used JADAS cut-off values.ResultsWe proposed new criteria for HDA. At least three of the following criteria must be satisfied in both disease courses: in oligoarthritis, two or more active joints, ESR above normal, physician global assessment (PGA) of disease activity ≥2 and parent/patient global assessment (PtGA) of well-being ≥2; in polyarthritis, six or more active joints, ESR above normal, PGA of overall disease activity ≥4 and PtGA of well-being ≥2. The HDA cut-off values for JADAS10 (cJADAS) were ≥6.7 (6.7) for oligoarticular and ≥15.3 (14.1) for polyarticular disease. The distribution of the disease activity levels based on the JADAS cut-off values in the literature varied markedly based on which cut-offs were used.ConclusionNew clinically derived criteria for HDA in JIA and both JADAS and cJADAS cut-off values for HDA were proposed.</div

Systems thinking and adult cognitive development

This chapter explores the links between scientific systems approaches and adult cognitive development. First, it describes the premises and basic concepts of systems thinking. It then continues to give an overview of the history of systems approach and the development of the main models and theories from its roots, which lie in the natural sciences. This is followed by an examination of the three systems paradigms, namely, Closed Systems, Open Systems, and Dynamic Systems and their implications to research and operational interests, in addition to their explanatory power in today’s world. Second part of the chapter focuses on describing the intersections between the Dynamic Systems paradigm theories and Jan Sinnott’s theory of postformal thought. This is carried out by describing the key theories behind the paradigm, that is, self-organizing and self-referential systems and their applications to social systems. Furthermore, it examines Sinnott’s theory’s overlap with the third paradigm approach. The chapter concludes that there are some linkages between the fields. It suggests that both research fields could benefit from each other by gaining new understanding and insight, and a genuine merger could lead to new discoveries. The chapter is providing inspiration for future research by raising new questions, settings, and methodologies.nonPeerReviewe