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)-naïve 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 (€) 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 € or 678 € 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 €, and for IFX + MTX vs MTX 31,435 € 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. TRIAL REGISTRATION: This trial was primarily registered with the Ethical Board of Helsinki District University Hospital ( https://www.hus.fi ), clinical trial number 211864, and later with ClinicalTrials.gov, number NCT01015547.

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. TRIAL REGISTRATION: This study was registered within the Hospital District of Helsinki and Uusimaa (http://www.hus.fi) clinical trials, number 211864 in October 2002, and later on with ClinicalTrials.gov, number NCT01015547.

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.

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

OBJECTIVES: To 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. METHODS: Data 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. RESULTS: We 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. CONCLUSION: New clinically derived criteria for HDA in JIA and both JADAS and cJADAS cut-off values for HDA were proposed.

Finding specific 10-joint Juvenile Arthritis Disease Activity Score (JADAS10) and clinical JADAS10 cut-off values for disease activity levels in non-systemic juvenile idiopathic arthritis: a Finnish multicentre study.

OBJECTIVES: To establish the cut-off values for inactive disease, as well as low disease activity (LDA), moderate disease activity (MDA) and high disease activity (HDA) in non-systemic JIA based on the Juvenile Arthritis Disease Activity Score (JADAS) and assessed with the 10-joint JADAS (JADAS10) and clinical JADAS10 (cJADAS10). METHODS: In a multicentre cross-sectional study consisting of ∼20% of all patients with JIA in Finland (n = 509), we obtained data on their most recent registered visits between January 2013 and January 2014. We calculated the JADAS10 and cJADAS10 and established the cut-off values of both of these scores using two different receiver operating characteristics-based statistical methods. RESULTS: Of the 509 patients studied, 65.8% were females and 53.8% had polyarticular disease. The most suitable method for determining cut-off values was the Youden index. In oligoarticular patients, a JADAS10 score of 0-0.5 represented inactive disease, 0.6-2.7 LDA and ≥2.8 MDA. In polyarticular disease, a JADAS10 score of 0-0.7 represented inactive disease, 0.8-3.9 LDA and ≥4.0 MDA. The cut-off values for HDA were not possible to establish because only two visits fulfilled HDA criteria. CONCLUSION: We established cut-off values for LDA and MDA. A reliable definition for HDA will require more patients. In the clinical setting, both the cJADAS10 and JADAS10 serve equally well both for research and quality control purposes. In the future, uniform clinical disease activity levels should be established. We also suggest revising and validating the criteria for HDA. Valid and robust cut-off values for disease activity levels can guide both clinicians and researchers and equip them for quality control.

Occurrence of adverse events in patients with JIA receiving biologic agents: long-term follow-up in a real-life setting.

OBJECTIVE: The aim of this study was to carry out a safety evaluation of biologic agents in patients with JIA and associated uveitis. METHODS: In three tertiary centres in Finland, all adverse events (AEs) in 348 consecutive patients were collected. AEs were classified according to the Common Terminology Criteria for AEs. RESULTS: A total of 1516 patient-years (py) were included: 710 on etanercept, 591 on infliximab, 188 on adalimumab, 8 on rituximab, 5 on anakinra, 6 on tocilizumab, 6 on abatacept and 1 on golimumab. The median follow-up of an individual patient was 51 months (range 1-155). The most common of the 2902 AEs (191/100 py) observed were mild infections, infusion or injection site reactions and alanine aminotransferase elevations. At least one AE occurred in 319 (92%) patients and 121 (35%) had at least one serious AE (SAE). The rate of SAEs was 11.4/100 py on etanercept, 11.8 on infliximab, 10.1 on adalimumab, 15.7 on abatacept, 31.2 on tocilizumab and 87.5 on rituximab, higher than with most anti-TNF agents (P = 0.005). No cases of malignant neoplasms or tuberculosis were detected. New-onset uveitis occurred in 9 patients, psoriasis or psoriasiform lesions in 13 and IBD in 6. CONCLUSION: Mild and moderate AEs in patients with JIA treated with biologics were more frequent than previously reported. SAEs were observed in one-third of the patients, but SAEs seldom led to drug discontinuation.

[Medical treatment of juvenile idiopathic arthritis]. / Lastenreuman hoito kehittyy.

Although etiology of juvenile idiopathic arthritis (JIA) is currently not known, better understanding of immunologic pathways of inflammation and the development of new therapies with biologic agents have remarkably improved the treatment of JIA. However, approximately 30% of the patients with JIA do not seem to response adequately to conventional anti-rheumatic drugs but the arthritis runs a continuously active course and may lead to the evolution of erosions. Such patients benefit from biologic agents, of which the longest clinical experience comes from anti-TNF therapies. Molecules targeting IL-1, IL-6 and B- and T-lymphocytes are also used in the treatment of severe JIA.

Aggressive combination drug therapy in very early polyarticular juvenile idiopathic arthritis (ACUTE-JIA): a multicentre randomised open-label clinical trial.

OBJECTIVES: In juvenile idiopathic arthritis (JIA), the efficacy of very early disease-modifying drug therapy, synthetic or biological, is not well known. Three alternative strategies were compared for treating recent-onset polyarticular JIA. METHODS: In a 54-week multicentre open-label clinical trial, 60 disease-modifying antirheumatic drug (DMARD)-naive patients aged 4-15 years were randomly assigned into three treatment arms. The efficacy of infliximab plus methotrexate (TNF) was compared to that of two synthetic therapies: methotrexate alone (MTX) and DMARD methotrexate, sulphasalazine and hydroxychloroquine in combination (COMBO). Primary endpoint was American College of Rheumatology paediatric 75% improvement (ACR Pedi 75). Secondary endpoints were inactive disease and safety. RESULTS: In 59 patients, mean (±SE) age at baseline was 9.6±0.4 years, duration of JIA 1.9±0.2 months and number of active joints 18±1. ACR Pedi 75 was achieved in 100% (19/19) of patients receiving TNF, 65% (13/20) on COMBO (95% CI 44% to 86%) and 50% (10/20) on methotrexate (95% CI 28% to 72%) p<0.0001. Thirteen patients receiving TNF (68%; 95% CI 47% to 89%) achieved inactive disease, whereas eight (40%; 95% CI 22% to 63%) on COMBO and five (25%; 95% CI 6% to 44%) on methotrexate did (p=0.002). Patients on TNF spent a mean 26 weeks (95% CI 18 to 34) with inactive disease, longer than did those receiving COMBO (13 weeks; 95% CI 6 to 20), or methotrexate (6 weeks; 95% CI 2 to 10). Serious adverse events were rare. CONCLUSION: In early polyarticular JIA, targeting to achieve minimally active or inactive disease, infliximab plus methotrexate was superior to synthetic DMARD in combination and strikingly superior to methotrexate alone.

Infliximab and etanercept in the treatment of chronic uveitis associated with refractory juvenile idiopathic arthritis.

OBJECTIVE: To evaluate the efficacy of anti-tumour necrosis factor (anti-TNF) treatment in juvenile idiopathic arthritis (JIA)-associated uveitis. METHODS: 24 patients with uveitis taking etanercept and 21 taking infliximab were studied. The endpoint ophthalmological evaluation was at 24 months or at the termination of the first biological agent. The ocular inflammatory activity was graded on the basis of the number of anterior chamber cells. RESULTS: Of the 45 patients, uveitis improved in 14 (31%), no change was observed in 14 (31%) and the activity of uveitis increased in 17 (38%). Inflammatory activity improved more frequently (p=0.047) in the patients taking infliximab than in those taking etanercept. The number of uveitis flares/year was higher (p=0.015) in the patients taking etanercept (mean 1.4, range 0-3.2) than in those taking infliximab (mean 0.7, range 0-2). Uveitis developed for the first time while taking anti-TNF treatment in five patients-4 taking etanercept (2.2/100 patient-years) and 1 taking infliximab (1.1/100 patient-years). CONCLUSIONS: During anti-TNF treatment, the ophthalmological condition improved in one-third of the patients with uveitis. In chronic anterior uveitis, associated with refractory JIA, infliximab may be more effective than etanercept.