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Otten M.H.,Erasmus MC Sophia Childrens Hospital | Anink J.,Erasmus MC Sophia Childrens Hospital | Prince F.H.M.,Erasmus MC Sophia Childrens Hospital | Twilt M.,Erasmus MC Sophia Childrens Hospital | And 14 more authors.
Annals of the Rheumatic Diseases | Year: 2015

Background: Treatment of juvenile idiopathic arthritis (JIA) has changed dramatically since the introduction of biological agents in 1999. Objective: To evaluate trends in prescription patterns of biological agents and the subsequent outcome of JIA. Methods: The Arthritis and Biologics in Children register (multicentre prospective observational study) aimed to include all consecutive patients with JIA in the Netherlands who had started biological agents since 1999. Patients were divided according to year of introduction of first biological agent. Patient characteristics at introduction of the first biological agent and its effectiveness were analysed over 12 years. Results: 335 patients with non-systemic JIA and 86 patients with systemic JIA started a biological agent between 1999 and 2010. Etanercept remained the most often prescribed biological agent for non-systemic JIA; anakinra became first choice for systemic JIA. The use of systemic glucocorticoids and synthetic disease-modifying antirheumatic drugs before biological agents decreased. During these 12 years of observation, biological agents were prescribed earlier in the disease course and to patients with lower baseline JADAS ( Juvenile Arthritis Disease Activity Score) disease activity. All baseline disease activity parameters were lowered in patients with non-systemic JIA. In systemic JIA, prescription patterns changed towards very early introduction of biological agents (median 0.4 years of disease duration) in patients with a low number of joints with active arthritis and high erythrocyte sedimentation rates. These changes for both systemic and non-systemic JIA resulted in more patients with inactive disease after 3 and 15 months of treatment. Conclusions: Biological agents are increasingly prescribed, earlier in the disease and in patients with JIA with lower disease activity. These changes are accompanied by better short-term disease outcomes. © 2015, BMJ Publishing Group. All rights reserved.


Otten M.H.,Erasmus MC Sophia Childrens Hospital | Prince F.H.M.,Erasmus MC Sophia Childrens Hospital | Anink J.,Erasmus MC Sophia Childrens Hospital | Ten Cate R.,Leiden University | And 12 more authors.
Annals of the Rheumatic Diseases | Year: 2013

Objective: To evaluate the effectiveness and safety of switching to a second or third biological agent in juvenile idiopathic arthritis ( JIA) after etanercept failure. Methods: The Arthritis and Biologicals in Children Register aims to include all Dutch JIA patients who have used biological agents. Data on the disease course were used to estimate drug survival with Kaplan-Meier and calculate adverse event (AE) rates. Results: Of 307 biologically naive JIA patients who started etanercept, 80 (26%) switched to a second and 22 (7%) to a third biological agent. During 1030 patientyears of follow-up after the introduction of etanercept, 49 switches to adalimumab, 28 infliximab, 17 anakinra, four abatacept and four trial drugs were evaluated. 84% (95% CI 80% to 88%) of patients who started etanercept as a first biological agent were, after 12 months, still on the drug, compared with 47% (95% CI 35% to 60%) who started a second and 51% (95% CI 26% to 76%) who started a third biological agent. Patients who switched because of primary ineffectiveness continued the second agent less often (32%, 95% CI 12% to 53%). After etanercept failure, drug continuation of adalimumab was similar to infliximab for patients with non-systemic JIA; anakinra was superior to a second TNF-blocker for systemic JIA. AE rates within first 12 months after initiation were comparable for each course and each biological agent. Conclusions: Switching to another biological agent is common, especially for systemic JIA patients. A second (and third) agent was less effective than the first. The choice of second biological agent by the physician mainly depends on availability and JIA category.


Otten M.H.,Erasmus MC Sophia Childrens Hospital | Prince F.H.M.,Erasmus MC Sophia Childrens Hospital | Twilt M.,Leiden University | Van Rossum M.A.J.,Emma Childrens Hospital | And 8 more authors.
Journal of Rheumatology | Year: 2010

Objective. To evaluate response in patients with juvenile idiopathic arthritis (JIA) who failed to meet response criteria after 3 months of etanercept treatment. Methods. This was a prospective ongoing multicenter observational study of all Dutch patients with JIA using etanercept. Response according to American College of Rheumatology Pediatric 30 criteria was assessed at study start and at 3 and 15 months. Results. In total we studied 179 patients of median age 5.8 years at disease onset; 70% were female. Thirty-four patients did not respond after 3 months, of which 20 continued etanercept and 11 achieved response thereafter. Conclusion. The delayed clinically relevant response in a substantial proportion of patients who initially did not respond justifies the consideration of continuing therapy to at least 6 months. The Journal of Rheumatology Copyright © 2010. All rights reserved.


Anink J.,Erasmus MC Sophia Childrens Hospital | Otten M.H.,Erasmus MC Sophia Childrens Hospital | Prince F.H.M.,Erasmus MC Sophia Childrens Hospital | Hoppenreijs E.P.A.H.,Radboud University Nijmegen | And 12 more authors.
Rheumatology (United Kingdom) | Year: 2013

Objective. Because TNF inhibitors are not approved for persistent oligoarticular JIA (oJIA), although they are used off-label, we evaluated their effectiveness in patients in this category. Methods. Persistent oJIA patients were selected from the Dutch Arthritis and Biologicals in Children (ABC) register, an ongoing multicentre prospective study that aims to include all Dutch children with JIA using biologic agents. Response was assessed by the JIA core-set disease activity variables and modified Wallace criteria for inactive disease. Results. Until February 2011, 16 persistent oJIA patients (68.8% females) had been included in the register. Median age of onset was 8.4 years [interquartile range (IQR) 2.1-13.5 years]; history of uveitis in 18.8%; ANA-positive 56.3%. All had previously used MTX, and 81.3% had used IA CSs. Median follow-up after the introduction of biologic treatment was 13.7 months (IQR 8.3-16.7 months). Fourteen patients started etanercept and two patients who had active arthritis as well as uveitis started adalimumab. Although patients with persistent oJIA had few affected joints [median of two active joints at the start of biologic (IQR 1-3)], the patient/parent assessments of pain [median visual analogue score (VAS) 51 (IQR 1-64)] and well-being [median VAS 44 (IQR 6-66)] were high. Additionally, their physician evaluated the disease activity as moderately high [median VAS 36 (IQR 4-65)]. After 3 months this decreased to 0 (IQR 0-30) and 63% achieved inactive disease. After 15 months the disease was inactive in 9/10 observed patients. TNF inhibitors were tolerated well. Conclusion. TNF blocking agents seem an effective and justifiable option in persistent oJIA when treatment with IA CS injections and MTX has failed.


Otten M.H.,Erasmus MC Sophia Childrens Hospital | Anink J.,Erasmus MC Sophia Childrens Hospital | Prince F.H.M.,Erasmus MC Sophia Childrens Hospital | Twilt M.,Erasmus MC Sophia Childrens Hospital | And 14 more authors.
Annals of the Rheumatic Diseases | Year: 2014

Background: Treatment of juvenile idiopathic arthritis (JIA) has changed dramatically since the introduction of biological agents in 1999. Objective: To evaluate trends in prescription patterns of biological agents and the subsequent outcome of JIA. Methods: The Arthritis and Biologics in Children register (multicentre prospective observational study) aimed to include all consecutive patients with JIA in the Netherlands who had started biological agents since 1999. Patients were divided according to year of introduction of first biological agent. Patient characteristics at introduction of the first biological agent and its effectiveness were analysed over 12 years. Results: 335 patients with non-systemic JIA and 86 patients with systemic JIA started a biological agent between 1999 and 2010. Etanercept remained the most often prescribed biological agent for non-systemic JIA; anakinra became first choice for systemic JIA. The use of systemic glucocorticoids and synthetic disease-modifying antirheumatic drugs before biological agents decreased. During these 12 years of observation, biological agents were prescribed earlier in the disease course and to patients with lower baseline JADAS (Juvenile Arthritis Disease Activity Score) disease activity. All baseline disease activity parameters were lowered in patients with non-systemic JIA. In systemic JIA, prescription patterns changed towards very early introduction of biological agents (median 0.4 years of disease duration) in patients with a low number of joints with active arthritis and high erythrocyte sedimentation rates. These changes for both systemic and non-systemic JIA resulted in more patients with inactive disease after 3 and 15 months of treatment. Conclusions: Biological agents are increasingly prescribed, earlier in the disease and in patients with JIA with lower disease activity. These changes are accompanied by better short-term disease outcomes. © 2014 BMJ Publishing Group Ltd & European League Against Rheumatism.


Belderok S.-M.,Public Health Service GGD | Sonder G.J.B.,Public Health Service GGD | Sonder G.J.B.,National Coordination Center for Travellers Health Advice | van Rossum M.,Emma Childrens Hospital | And 6 more authors.
Vaccine | Year: 2013

Objective: A phase IV interventional study with a combined hepatitis A and B vaccine was conducted in HIV-infected children and children receiving immunosuppressive medication for treatment of rheumatic diseases to evaluate immune responses. Methods: Both groups (1-16 years of age) received combined (inactivated) HAV and (rDNA) HBV vaccine Ambirix® at months 0 and 6. Serum samples were taken at four time points and tested for anti-HAV and anti-HBs antibodies. Anti-HAV concentrations ≥20mIU/mL or anti-HBs concentrations ≥10mIU/mL were considered protective. Seropositivity percentages were calculated and geometric mean concentrations (GMCs) were compared by nonparametric Mann-Whitney U-test or Kruskal-Wallis one-way-analysis-of-variance. Results: Of 80 HIV-infected children who completed the study, 67 were HAV-susceptible and 68 HBV-susceptible at enrolment. Of 80 children with rheumatic diseases who completed the study, 65 were HAV-susceptible and 74 HBV-susceptible at enrolment. Immune responses to HAV after first dose of vaccine in both study groups were low: 71% and 55% respectively, whereas immune responses after the second dose were 99% and 100% respectively. Immune response to HBV after first dose of vaccine in both groups was also low: 27% and 17% respectively. Immune responses after the second dose were 97% and 93%, respectively. A larger proportion of children on combination antiretroviral therapy (cART) and of children with viral load <50. copies/mL responded to HBV, and also showed a significantly higher GMC. Conclusions: Although immune response after full series of combined HAV and HBV vaccine in both groups was excellent and comparable to healthy children, a substantial proportion of both groups was not protected for HAV after first dose of vaccine. This protection gap is especially important for HAV in travel health and postexposure prophylactic treatment: both groups of children should be serologically tested for anti-HAV prior to travel to ensure protection if there is no time to await second dose of vaccine. © 2013 Elsevier Ltd.


Otten M.H.,Erasmus MC Sophia Childrens Hospital | Prince F.H.M.,Erasmus MC Sophia Childrens Hospital | Twilt M.,Erasmus MC Sophia Childrens Hospital | Twilt M.,Leiden University | And 15 more authors.
Journal of Rheumatology | Year: 2011

Objective. To evaluate the effectiveness and safety of biological agents in children with enthe - sitis-related arthritis (ERA). Methods. All patients with ERA in whom a biological agent was initiated between 1999 and 2010 were selected from the Dutch Arthritis and Biologicals in Children (ABC) register. In this ongoing multicenter observational register, data on the course of the disease and medication use are retrieved prospectively at the start of the biological agent, after 3 months, and yearly thereafter. Inactive disease was assessed in accordance with the Wallace criteria. Results. Twenty-two patients with ERA started taking 1 or more biological agents: 20 took etanercept, 2 took adalimumab (1 switched from etanercept to adalimumab), and 2 took infliximab (1 switched from etanercept to infliximab). Characteristics: 77% were male, 77% had enthesitis, 68% were HLA-B27-positive. The median age of onset was 10.4 (IQR 9.4-12.0) years; median follow-up from the start of the biological agent was 1.2 (IQR 0.5-2.4) years. Intention-to-treat analysis shows that inactive disease was achieved in 7 of 22 patients (32%) after 3 months, 5 of 13 patients (38%) after 15 months, and 5 of 8 patients (63%) after 27 months of treatment. Two patients discontinued etanercept because of ineffectiveness, and switched to adalimumab (inactive disease achieved) or infliximab (decline in joints with arthritis after 3 months of treatment). One patient discontinued etanercept because of remission, but had flare and restarted treatment, with good clinical response. No serious adverse events occurred. Conclusion. Tumor necrosis factor (TNF)-blocking agents seem effective and safe for patients with ERA that was previously unresponsive to 1 or more DMARD. However, a sustained disease-free state could not be achieved, and none discontinued TNF-blocking agents successfully. The Journal of Rheumatology Copyright © 2011. All rights reserved.


Otten M.H.,Erasmus MC Sophia Childrens Hospital | Prince F.H.M.,Erasmus MC Sophia Childrens Hospital | Armbrust W.,University of Groningen | Ten Cate R.,Leiden University | And 11 more authors.
JAMA - Journal of the American Medical Association | Year: 2011

Context: Since the introduction of biologic therapies, the pharmacological treatment approach for juvenile idiopathic arthritis ( JIA) has changed substantially, with achievement of inactive disease as a realistic goal. Objective: To determine the response to therapy after initiation of etanercept therapy among patients with JIA and to examine the association between baseline factors and response to etanercept treatment. Design, Setting, and Patients: The Arthritis and Biologicals in Children Register, an ongoing prospective observational study since 1999, includes all Dutch JIA patients who used biologic agents. All biologically naive patients who started etanercept before October 2009 were included, with follow-up data to January 2011. Among the 262 patients, 185 (71%) were female, 46 (18%) had systemic-onset, and the median age at initiation of etanercept treatment was 12.4 years. Main Outcome Measures: Excellent response (inactive disease or discontinuation earlier due to disease remission), intermediate response (more than 50% improvement from baseline, but no inactive disease), and poor response (less than 50% improvement from baseline or discontinuation earlier due to ineffectiveness or intolerance) evaluated 15 months after initiation of etanercept. Results: At 15 months after treatment initiation, 85 patients (32%) were considered excellent responders; 92 (36%), intermediate responders; and 85 (32%), poor responders. Compared with an intermediate or poor response, an excellent response was associated with lower baseline disability score (range, 0-3 points, with 0 being the best score; adjusted odds ratio [OR] per point increase, 0.49; 95% CI, 0.33-0.74); fewer diseasemodifying antirheumatic drugs (DMARD) (including methotrexate) used before initiating etanercept (adjusted OR per DMARD used, 0.64; 95% CI, 0.43-0.95), and younger age at onset (adjusted OR per year increase, 0.92; 95% CI, 0.84-0.99). Compared with an intermediate or excellent response, a poor response was associated with systemic JIA (adjusted OR systemic vs nonsystemic categories, 2.92; 95% CI, 1.26-6.80), and female sex (adjusted OR female vs male, 2.16; 95% CI, 1.12-4.18). Within the first 15 months of etanercept treatment, 119 patients experienced 1 or more infectious, noninfectious, or serious adverse events, including 37 among those with an excellent response, 36 with an intermediate response, and 46 with a poor response. Within the first 15 months of treatment, 61 patients discontinued etanercept treatment, including 4 with an excellent response, 0 with an intermediate response, and 57 with a poor response. In a secondary analysis of 262 patients with a median follow-up of 35.6 months after initiation of etanercept, a range of 37% to 49% of patients reached inactive disease. The mean adherence to etanercept was 49.2 months (95% CI, 46.4-52.0) for patients with an excellent response after 15 months, 47.5 months (95% CI, 44.9-50.1) for patients with an intermediate response, and 17.4 months (95% CI, 13.6-21.2) for patients with a poor response. Conclusions: Among patients with JIA who initiated treatment with etanercept, onethird achieved an excellent response, one-third an intermediate response, and onethird a poor response to therapy. Achievement of an excellent response was associated with low baseline disability scores, DMARDs used before initiating etanercept, and younger age at onset of JIA. Achievement of a poor treatment response was associated with systemic JIA and female sex. ©2011 American Medical Association. All rights reserved.

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