Search

Background: Children with juvenile idiopathic arthritis (JIA) are at risk of uveitis. The role of adalimumab (Humira ® ; AbbVie Inc., Ludwigshafen, Germany) in the management of uveitis in children needs to be determined., Objective: To compare the efficacy, safety and cost-effectiveness of adalimumab in combination with methotrexate (MTX) versus placebo with MTX alone, with regard to controlling disease activity in refractory uveitis associated with JIA., Design: This was a randomised (applying a ratio of 2 : 1 in favour of adalimumab), double-blind, placebo-controlled, multicentre parallel-group trial with an integrated economic evaluation. A central web-based system used computer-generated tables to allocate treatments. A cost-utility analysis based on visual acuity was conducted and a 10-year extrapolation by Markov modelling was also carried out., Setting: The setting was tertiary care centres throughout the UK., Participants: Patients aged 2-18 years inclusive, with persistently active JIA-associated uveitis (despite optimised MTX treatment for at least 12 weeks)., Interventions: All participants received a stable dose of MTX and either adalimumab (20 mg/0.8 ml for patients weighing < 30 kg or 40 mg/0.8 ml for patients weighing ≥ 30 kg by subcutaneous injection every 2 weeks based on body weight) or a placebo (0.8 ml as appropriate according to body weight by subcutaneous injection every 2 weeks) for up to 18 months. A follow-up appointment was arranged at 6 months., Main Outcome Measures: Primary outcome - time to treatment failure [multicomponent score as defined by set criteria based on the Standardisation of Uveitis Nomenclature (SUN) criteria]. Economic outcome - incremental cost per quality-adjusted life-year (QALY) gained from the perspective of the NHS in England and Personal Social Services providers. Full details of secondary outcomes are provided in the study protocol., Results: A total of 90 participants were randomised (adalimumab, n  = 60; placebo, n  = 30). There were 14 (23%) treatment failures in the adalimumab group and 17 (57%) in the placebo group. The analysis of the data from the double-blind phase of the trial showed that the hazard risk (HR) of treatment failure was significantly reduced, by 75%, for participants in the adalimumab group (HR 0.25, 95% confidence interval 0.12 to 0.51; p  < 0.0001 from log-rank test). The cost-effectiveness of adalimumab plus MTX was £129,025 per QALY gained. Adalimumab-treated participants had a much higher incidence of adverse and serious adverse events., Conclusions: Adalimumab in combination with MTX is safe and effective in the management of JIA-associated uveitis. However, the likelihood of cost-effectiveness is < 1% at the £30,000-per-QALY threshold., Future Work: A clinical trial is required to define the most effective time to stop therapy. Prognostic biomarkers of early and complete response should also be identified., Trial Registration: Current Controlled Trials ISRCTN10065623 and European Clinical Trials Database number 2010-021141-41., Funding: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment ; Vol. 23, No. 15. See the NIHR Journals Library website for further project information. This trial was also funded by Arthritis Research UK (grant reference number 19612). Two strengths of adalimumab (20 mg/0.8 ml and 40 mg/0.8 ml) and a matching placebo were manufactured by AbbVie Inc. (the Marketing Authorisation holder) and supplied in bulk to the contracted distributor (Sharp Clinical Services, Crickhowell, UK) for distribution to trial centres., Competing Interests: Athimalaipet V Ramanan reports grants from the National Institute for Health Research (NIHR) Health Technology Assessment (HTA) programme and Arthritis Research UK during the conduct of the study and others from AbbVie Inc. (Ludwigshafen, Germany) and the University Hospitals Bristol NHS Foundation Trust, outside the submitted work. He has received speaker fees from AbbVie Inc. and lectured in symposia, sponsored by AbbVie Inc.. He has also been on an Advisory Board organised by AbbVie Inc. and has been supported by AbbVie Inc. to attend European and American Rheumatology Society meetings. Andrew D Dick reports other from data and revenue sharing outside the submitted work for consultancy work, paid to University of Bristol by AbbVie Inc., Ashley P Jones, Andrew McKay, Anna Rosala-Hallas, Ben Hardwick, Helen Hickey, Naomi Rainford, Graeme Hickey, Ruwanthi Kolamunnage-Dona and Paula R Williamson report grants from the NIHR HTA programme and Arthritis Research UK during the conduct of the study, other from AbbVie Inc. and University Hospitals Bristol NHS Foundation Trust and personal fees from University of Liverpool, outside the submitted work. In addition, Paula R Williamson is the Director of the Clinical Trials Research Centre, which is the Clinical Trials Unit that managed the day-to-day running of this trial. Dyfrig Hughes and Patricia Woo report grants from the NIHR HTA programme and Arthritis Research UK during the conduct of the study and other from AbbVie Inc., outside the submitted work. Giovanna Culeddu and Eifiona Wood report grants from Arthritis Research UK during the conduct of the study. Sandrine Compeyrot-Lacassagne reports grants from the NIHR HTA programme and Arthritis Research UK during the conduct of the study, and grants and others from AbbVie Inc., outside the submitted work. Clive Edelsten reports grants from the NIHR HTA programme and Arthritis Research UK during the conduct of the study, and others and personal fees from AbbVie Inc., outside the submitted work. Michael W Beresford reports grants from the NIHR HTA programme and Arthritis Research UK during the conduct of the study and others from AbbVie Inc. and the University Hospitals Bristol NHS Foundation Trust, outside the submitted work.

Purpose: To investigate the cost effectiveness of adalimumab in combination with methotrexate, compared with methotrexate alone, for the management of uveitis associated with juvenile idiopathic arthritis (JIA)., Design: A cost-utility analysis based on a clinical trial and decision analytic model., Participants: Children and adolescents 2 to 18 years of age with persistently active uveitis associated with JIA, despite optimized methotrexate treatment for at least 12 weeks., Methods: The SYCAMORE (Randomised controlled trial of the clinical effectiveness, SafetY and Cost effectiveness of Adalimumab in combination with MethOtRExate for the treatment of juvenile idiopathic arthritis associated uveitis) trial (identifier, ISRCTN10065623) of methotrexate (up to 25 mg weekly) with or without fortnightly administered adalimumab (20 or 40 mg, according to body weight) provided data on resource use (based on patient self-report and electronic records) and health utilities (from the Health Utilities Index questionnaire). Surgical event rates and long-term outcomes were based on data from a 10-year longitudinal cohort. A Markov model was used to extrapolate the effects of treatment based on visual impairment., Main Outcome Measures: Medical costs to the National Health Service in the United Kingdom, utility of defined health states, quality-adjusted life-years (QALYs), and incremental cost per QALY., Results: Adalimumab in combination with methotrexate resulted in additional costs of £39 316, with a 0.30 QALY gain compared with methotrexate alone, resulting in an incremental cost-effectiveness ratio of £129 025 per QALY gained. The probability of cost effectiveness at a threshold of £30 000 per QALY was less than 1%. Based on a threshold analysis, a price reduction of 84% would be necessary for adalimumab to be cost effective., Conclusions: Adalimumab is clinically effective in uveitis associated with JIA; however, its cost effectiveness is not demonstrated compared with methotrexate alone in the United Kingdom setting., (Copyright © 2018 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Background: Adalimumab, a fully human anti-tumor necrosis factor α monoclonal antibody, is effective in the treatment of juvenile idiopathic arthritis (JIA). We tested the efficacy of adalimumab in the treatment of JIA-associated uveitis., Methods: In this multicenter, double-blind, randomized, placebo-controlled trial, we assessed the efficacy and safety of adalimumab in children and adolescents 2 years of age or older who had active JIA-associated uveitis. Patients who were taking a stable dose of methotrexate were randomly assigned in a 2:1 ratio to receive either adalimumab (at a dose of 20 mg or 40 mg, according to body weight) or placebo, administered subcutaneously every 2 weeks. Patients continued the trial regimen until treatment failure or until 18 months had elapsed. They were followed for up to 2 years after randomization. The primary end point was the time to treatment failure, defined according to a multicomponent intraocular inflammation score that was based on the Standardization of Uveitis Nomenclature criteria., Results: The prespecified stopping criteria were met after the enrollment of 90 of 114 patients. We observed 16 treatment failures in 60 patients (27%) in the adalimumab group versus 18 treatment failures in 30 patients (60%) in the placebo group (hazard ratio, 0.25; 95% confidence interval [CI], 0.12 to 0.49; P<0.0001 [the prespecified stopping boundary]). Adverse events were reported more frequently in patients receiving adalimumab than in those receiving placebo (10.07 events per patient-year [95% CI, 9.26 to 10.89] vs. 6.51 events per patient-year [95% CI, 5.26 to 7.77]), as were serious adverse events (0.29 events per patient-year [95% CI, 0.15 to 0.43] vs. 0.19 events per patient-year [95% CI, 0.00 to 0.40])., Conclusions: Adalimumab therapy controlled inflammation and was associated with a lower rate of treatment failure than placebo among children and adolescents with active JIA-associated uveitis who were taking a stable dose of methotrexate. Patients who received adalimumab had a much higher incidence of adverse events and serious adverse events than those who received placebo. (Funded by the NIHR Health Technology Assessment Programme and Arthritis Research UK; SYCAMORE EudraCT number, 2010-021141-41 .).

Background: Juvenile idiopathic arthritis (JIA) is the most common rheumatic disease in children. Children with JIA are at risk of inflammation of the uvea in the eye (uveitis). Overall, 20% to 25% of paediatric uveitis is associated with JIA. Major risk factors for development of uveitis in JIA are oligoarticular pattern of arthritis, an age at onset of arthritis of less than seven years of age, and antinuclear antibody positivity. In the initial stages of mild to moderate inflammation the uveitis is asymptomatic. This has led to current practice of screening all children with JIA for uveitis. Approximately 12% to 38% of patients with JIA develop uveitis in seven years following onset of arthritis. In 30% to 50% of children with JIA-associated uveitis structural complications are present at diagnosis. Furthermore about 50% to 75% of those with severe uveitis will eventually develop visual impairment secondary to ocular complications such as cataract and glaucoma. Defining the severity of inflammation and structural complications in uveitis patients is now possible following Standardised Uveitis Nomenclature (SUN) guidelines, and modified to incorporate the consensus of end point and outcome criteria into the design of randomised trials. Despite current screening and therapeutic options (pre-biologics) 10% to 15% of children with JIA-associated uveitis may develop bilateral visual impairment and certified legally blind. To date, there remains no controlled trial evidence of benefits of biologic therapy., Methods/design: This study will randomise 154 patients aged 2 to 18 years with active JIA-associated uveitis (despite methotrexate (MTX) treatment for at least 12 weeks). All participants will be treated for 18 months, with follow up of 3 years from randomisation (continuing on MTX throughout). All participants will receive a stable dose of MTX and in addition either adalimumab (20 mg/0.8 ml for patients<30 kg or 40 mg/0.8 ml for patients weighing 30 kg or more, subcutaneous (s/c) injection every 2 weeks based on body weight), or placebo (0.8 ml as appropriate according to body weight) s/c injection every 2 weeks., Discussion: This is the first randomised controlled trial that will assess the clinical effectiveness, safety and cost effectiveness of adalimumab in combination with methotrexate for the treatment of juvenile idiopathic arthritis associated uveitis., Trial Registration: ISRCTN10065623.

Objective: Growth retardation is a frequent complication of severe juvenile idiopathic arthritis (JIA). Biologic treatments may improve growth velocity by controlling systemic inflammation and reducing corticosteroids. Our goals were to compare growth velocity before and after the onset of biologic therapy and to determine whether the JIA subtype, the use of steroids, the requirement of one or several biologic agents, or the disease activity influenced growth velocity., Methods: We retrospectively analyzed the growth of children with JIA who never received growth hormone treatment, who started biologic treatment before puberty, and who were followed for at least 6 months afterward., Results: We included 100 children (33 boys). Median patient age was 7.1 years (range: 1.6-15.7) at the onset of biologic treatment and 11.0 years (range: 2.3-19.5) at the latest followup. Forty-six patients had received corticosteroid and 34 had received more than 1 biologic agent. Patient median height expressed as SD score (SDS) was 0.31 (range: -2.47 to 5.46) at disease onset, -0.24 (-3.63 to 2.90) at biologic therapy onset (p < 0.0001), and -0.15 (-4.95 to 3.52) at the latest followup (p = 0.171 compared to biologic treatment onset). Patients who required several biologics and systemic patients had a significantly lower growth velocity after the onset of biologic treatment. At the latest followup, 18% of our study group had low growth velocities and 19% were below -2SD or shorter than genetically programmed., Conclusion: In a subset of patients, particularly systemic JIA patients and patients who required more than 1 biologic, biologic therapy may be insufficient to restore normal growth velocity.

Background: Anakinra pharmacokinetics and pharmacodynamics were investigated in children and adolescents treated for systemic-onset juvenile idiopathic arthritis (SJIA) and autoinflammatory syndromes., Methods: Anakinra was given subcutaneously at doses between 2 and 10 mg/kg (maximum 100 mg) per day. Anakinra concentrations were recorded in patients, as well as C-reactive protein (CRP) levels, on different occasions. The data were fitted to a pharmacokinetic-pharmacodynamic model via a population approach using Monolix., Results: A total of 87 children and adolescents, 8 months to 21 years old, were available for pharmacokinetic evaluation. A one compartment model with linear absorption and elimination described the pharmacokinetics. Taking into account bodyweight to explain variations in apparent clearance (CL/F) and distribution volume (V/F) significantly reduced the associated between-subject and between-occasion variabilities. The final estimates were 6.24 L/h/70 kg and 65.2 L/70 kg for CL/F and V/F respectively. A mixture pharmacodynamic model described the CRP level change during anakinra treatment for the SJIA patients with 2 subpopulations, patients with high baseline and large CRP decrease and patients with low baseline and small CRP decrease followed by a re-increase in CRP levels. There was no significant effect of the combined anti-inflammatory treatment. The proportion of patients for which the development of a resistance to treatment was significant was 62% and the corresponding time was approximately 60 days., Conclusions: Based on effects in SJIA, a prospective dosage adjustment was proposed based on a 0.4 mg/L Css target in order to obtain a CRP decrease to 10 mg/L or below.

Objectives: To investigate the functional status of difficult-to-treat JIA patients, including patients receiving biotherapies, and to correlate functional status to disease activity., Methods: All JIA patients consecutively evaluated in a paediatric rheumatology referral centre (November 2008 to March 2009) were enrolled in an observational cross-sectional study. The Childhood HAQ (CHAQ), physician's assessment of overall disease activity, parent's assessment of well-being and pain, and active and limited joint numbers were measured., Results: We enrolled 95 patients [27% systemic, 29% polyarticular, 22% enthesitis-related arthritis (ERA) and 23% oligoarticular JIA]. Median disease duration was 3.5 years. Treatment included NSAIDs (56%), MTX (23%), CSs (21%) and biologics (45%). Of all patients, 31 and 56%, respectively, had inactive and minimally active disease. The median CHAQ score was 0.375 (range 0-3). Most patients had no or mild functional disability (61%), impaired well-being (63%) or pain (55%); 10% reported severely impaired function and well-being, 19% severe pain. ERA patients reported worse well-being and pain. CHAQ scores correlated with disease activity. Long-lasting disease and biologic treatment were associated with better well-being and pain scores., Conclusion: Despite the high proportion of severe JIA patients in this cohort, CHAQ values are within the lower range of recent reports, probably related to new therapeutic approaches. Impaired function and well-being remain a challenge for at least 10% of the patients. Impaired well-being and pain in ERA patients require further study. The strong correlation between functional status and well-being underlines the importance of improving function to optimize quality of life.