Polyarticular-course Juvenile Idiopathic Arthritis Research Articles

Cost‐effectiveness of biologics in polyarticular‐course juvenile idiopathic arthritis patients unresponsive to disease‐modifying antirheumatic drugs

Juvenile idiopathic arthritis (JIA) is the most common chronic pediatric rheumatic disease and can have long-term effects leading to disability in adulthood. Biologics are a new class of drugs increasingly used to treat JIA. The primary study objective was to determine the incremental costs of biologics per additional responder compared to conventional treatment (methotrexate). A separate decision model was created for etanercept, infliximab, adalimumab, and abatacept. The study population consisted of polyarticular-course JIA patients with a prior inadequate response or intolerance to disease-modifying antirheumatic drugs (DMARDs). The effectiveness measure was the proportion of patients who had a treatment response at 1 year according to the American College of Rheumatology (ACR) Pediatric 30 (Pedi 30) improvement criteria. Direct and indirect costs were calculated in 2008 Canadian dollars. Incremental cost-effectiveness ratios and 95% confidence intervals (95% CIs) were calculated for each biologic agent using probabilistic sensitivity analyses. The additional costs per additional ACR Pedi 30 responder at 1 year were $26,061 (95% CI $17,070, $41,834), $46,711 (95% CI $30,042, $75,787), $16,204 (95% CI $11,393, $22,608), and $31,209 (95% CI $16,659, $66,220) for etanercept, adalimumab, abatacept, and infliximab, respectively. Biologics are more effective than methotrexate in achieving a short-term response in JIA patients with prior inadequate responses to DMARDs; however, this comes at a high annual cost. Adequate long-term data with respect to both safety and effectiveness are not currently available, nor are utility estimates. Such data will be important to estimate value for money for treating JIA with biologic drugs over the long term.

Tumor Necrosis Factor Inhibitors in the Management of Juvenile Idiopathic Arthritis

Juvenile idiopathic arthritis (JIA) is a chronic inflammatory disorder of unknown origin that is often treated with a variety of disease-modifying agents. Tumor necrosis factor (TNF) inhibitors are a group of genetically engineered biologic agents that target the proinflammatory cytokine TNF. This review focuses on the use of TNF inhibitors in JIA. Etanercept was the first TNF inhibitor approved for use in children with moderate to severe polyarticular-course JIA following encouraging results from a randomized, double-blind, placebo-controlled, multicenter trial in children. Open-label extension studies of the original trial involving 8 years of follow-up demonstrated the long-term safety and efficacy of etanercept in children. Other studies from established registries also corroborate the safety of etanercept in JIA. The second TNF inhibitor to be approved for use in JIA is adalimumab following recent favorable results from another randomized, placebo-controlled, multicenter study in polyarticular-course JIA. While infliximab is not approved by the US FDA for use in JIA, it is frequently used in clinical practice for this indication. However, because the chimeric structure of infliximab incorporates murine components, it has the potential for allergic and infusion reactions. Patient responses to individual TNF inhibitors may vary depending on concomitant medications such as methotrexate, and also on the category of JIA.

Performance of rheumatoid arthritis disease activity measures and juvenile arthritis disease activity scores in polyarticular‐course juvenile idiopathic arthritis: Analysis of their ability to classify the American College of Rheumatology pediatric measures of response and the preliminary criteria for flare and inactive disease

AbstractObjectiveTo measure the abilities of the continuous measures of disease activity used in rheumatoid arthritis (RA) and the 3 versions of the Juvenile Arthritis Disease Activity Score (JADAS; based upon 10‐, 27‐, and 71‐joint counts) to accurately classify the American College of Rheumatology (ACR) pediatric measures of response, flare, and inactive disease in polyarticular‐course juvenile idiopathic arthritis (JIA).MethodsWe conducted a secondary analysis of a randomized trial of infliximab in polyarticular‐course JIA. Disease activity was calculated at baseline and weeks 14, 28, and 52 using the Disease Activity Score (DAS), DAS in 28 joints, Simplified Disease Activity Index, Clinical Disease Activity Index, and JADAS. The ability of the RA measures and JADAS to classify each ACR pediatric measure, flare, and inactive disease was measured by areas under the receiver operating characteristic curve (AUCs). Positive predictive values (PPVs) for inactive disease were calculated.ResultsData from 97 participants were available. The AUCs for the RA scores for each ACR pediatric measure were 0.73–0.89. The AUCs of the JADAS for the ACR pediatric measures were 0.75–0.92. The PPVs of the RA scores for inactive disease were 0.33–0.67. The PPVs of the JADAS for inactive disease were each 0.93. Based on the RA and JADAS scores, the percentage of visits misclassified as inactive disease ranged from 7–67%.ConclusionThe RA measures and JADAS versions showed acceptable to excellent ability to classify participants for each pediatric outcome measure, but the clinical significance of differences between AUCs for these scores could not be assessed. Misclassification of active disease versus inactive disease by the RA and JADAS scores was not uncommon in this cohort.

Etanercept improves linear growth and bone mass acquisition in MTX-resistant polyarticular-course juvenile idiopathic arthritis

Chronic inflammation in juvenile idiopathic arthritis interferes with linear growth and bone mass acquisition. We prospectively evaluated and compared linear growth and evolution of bone mass acquisition and body composition in MTX-resistant polyarticular-course JIA (polyJIA) patients started on etanercept and in recently diagnosed polyJIA patients started on MTX monotherapy. Sixteen MTX-resistant polyJIA patients were given add-on etanercept, eight recently diagnosed polyJIA patients were started on MTX. Patients were evaluated at baseline and at 1, 6, 12 and 18 months with respect to disease activity, linear growth, BMD and body composition. Baseline patient and disease characteristics were similar in both groups. Clinical disease activity (Pediatric ACR30) was equally well controlled in both groups. Growth velocity increased significantly allowing catch-up growth in the etanercept + MTX group only. BMD (lumbar spine Z-score) improved significantly in both groups. A significant increase of bone mineral content and lean:fat mass ratio was seen in the etanercept + MTX group, but not in the MTX group. Clinical control of disease activity by etanercept in MTX-refractory polyJIA is associated with rapidly instituted catch-up growth and improvement of bone mineralization and body composition. In recently diagnosed polyJIA patients treated with MTX the relation between clinical response and these parameters was less evident. Preliminary data on serum IL-6 and osteoprotegerin levels indicate that the beneficial effects seen with etanercept therapy may be related to its control of systemic IL-6 production and enhancement of osteoblast activity.

Associations between the American College of Rheumatology pediatric response measures and the continuous measures of disease activity used in adult rheumatoid arthritis: A secondary analysis of clinical trial data from children with Polyarticular‐Course Juvenile Idiopathic Arthritis

To measure associations between the American College of Rheumatology (ACR) pediatric criteria for improvement and the continuous measures of disease activity used for rheumatoid arthritis in adult patients with polyarticular-course juvenile idiopathic arthritis (JIA). In this retrospective analysis of 2 etanercept trials, disease activity was calculated at baseline, 3 months, and 6 months using the Disease Activity Score (DAS), the DAS based on 28 joints (DAS28), the Simplified Disease Activity Index (SDAI), and the Clinical Disease Activity Index (CDAI). The ACR pediatric response and the European League Against Rheumatism (EULAR) response were also determined for the 3-month and 6-month evaluations. Data were analyzed in 94 patients with JIA independent of the treatment arm. Correlation coefficients between measures were calculated for each visit. The areas under the receiver operating characteristic curve (AUC of ROC) were calculated to assess the discriminative properties of the scores for the ACR pediatric response measures. The mean DAS, DAS28, CDAI score, and SDAI score were 3.7, 4.7, 30.8, and 36.4, respectively, at baseline, corresponding to high levels of disease activity (CDAI/SDAI) or moderate levels of disease activity (DAS/DAS28). At 3 months, the mean scores corresponded to low (DAS/DAS28) or moderate (CDAI/SDAI) disease activity. At 6 months, the mean scores corresponded to low disease activity (DAS/DAS28/CDAI) or moderate disease activity (SDAI). Most children met the criteria for a good or moderate EULAR response at 3 months and 6 months. The correlation between continuous outcome measures and each pediatric core set component was moderate to very good. The AUC of ROC values for each measure were high (range 0.76-0.98). Good correlation and discriminative abilities were seen between the DAS, DAS28, CDAI, and SDAI for the ACR pediatric criteria for improvement. These disease activity measures may be useful for research and clinical care in polyarticular-course JIA.

Tocilizumab

Tocilizumab (RoActemra or Actemra) is a recombinant humanized monoclonal antibody that acts as an interleukin (IL)-6 receptor antagonist. Intravenous tocilizumab 8 mg/kg (and no less than 4.8 mg), in combination with methotrexate, is approved in the EU for the treatment of moderate to severe active rheumatoid arthritis in adult patients with inadequate response to, or who are intolerant of, prior disease-modifying anti-rheumatic drug (DMARD) or tumour necrosis factor (TNF) antagonist therapy. It may also be administered as monotherapy in patients intolerant of methotrexate or in whom methotrexate therapy is inappropriate. Tocilizumab is also approved in Japan for the treatment of polyarticular-course juvenile idiopathic arthritis, systemic-onset juvenile idiopathic arthritis and Castleman's disease. Intravenous tocilizumab was effective and generally well tolerated when administered either as monotherapy or in combination with conventional DMARDs in several well designed clinical studies in adult patients with moderate to severe rheumatoid arthritis. Tocilizumab-based therapy was consistently more effective than placebo, methotrexate or other DMARDs in reducing disease activity, and some trials also showed significant benefits with tocilizumab in terms of reducing structural joint damage and improving health-related quality of life (HR-QOL). Notably, tocilizumab-based therapy was effective in patients with long-standing disease in whom anti-TNF therapy had previously failed. More data are required to determine the comparative efficacy and safety of tocilizumab versus other biological agents and to establish their relative cost effectiveness. However, the present data suggest that tocilizumab is an important emerging treatment option in adult patients with moderate to severe rheumatoid arthritis.

Methotrexate improves the health-related quality of life of children with juvenile idiopathic arthritis

Objectives:To examine the change in health-related quality of life (HRQOL) and its determinants in children with juvenile idiopathic arthritis (JIA) treated with methotrexate (MTX).Methods:Patients were extracted from the PRINTO clinical...

Wnt‐1–inducible signaling pathway protein 3 and susceptibility to juvenile idiopathic arthritis

To determine whether Wnt-1-inducible signaling pathway protein 3 (WISP3) polymorphisms are associated with susceptibility to juvenile idiopathic arthritis (JIA). The exons and the intron/exon boundaries of the WISP3 gene were mutation-screened by denaturing high-performance liquid chromatography in 86 patients with polyarticular-course JIA (>/=5 joints affected) and 15 controls. Seven single-nucleotide polymorphisms (SNPs) were genotyped, using allelic discrimination, in a case-control study. Initially, 159 patients with polyarticular-course JIA and 263 controls were studied, followed by study of a replication cohort of 181 patients with polyarticular-course JIA and 355 controls. Available parents of patients with polyarticular-course JIA were also genotyped. Finally, other JIA subgroups were studied (initial cohort, n = 218; replication cohort, n = 213). Single-point and haplotype analysis was carried out. Positive association with SNP WISP3*G84A was observed and replicated in 2 cohorts of patients with polyarticular-course JIA. Specifically, homozygosity of the mutant allele (WISP3*84AA) conferred a 2-fold increased risk of disease susceptibility (for the initial cohort, odds ratio [OR] 2.1, 95% confidence interval [95% CI] 1.1-4.2, P = 0.03; for the replication cohort, OR 2.0, 95% CI 1.0-4.3, P = 0.05). Strong linkage disequilibrium was observed between SNPs; however, no haplotypic effect of an order of magnitude greater than the single-point WISP3*G84A association was observed. Using the transmission disequilibrium test, a trend toward overtransmission of the WISP3*84A allele was observed in patients with polyarticular-course JIA. No association of any WISP3 polymorphism was observed in the other JIA subgroups. Association and replication of a polymorphism within the first intron of the WISP3 gene have been shown in patients with polyarticular-course JIA. The functional significance of the WISP3*G84A SNP is being determined.

A randomized, double‐blind clinical trial of two doses of meloxicam compared with naproxen in children with juvenile idiopathic arthritis: Short‐ and long‐term efficacy and safety results

In an international, multicenter, double-blind, randomized clinical trial we evaluated the short-term (3 months) and long-term (12 months) efficacy and safety of 2 different doses of meloxicam oral suspension compared with the efficacy and safety of naproxen oral suspension in children with oligoarticular-course (oligo-course) or polyarticular-course (poly-course) juvenile idiopathic arthritis (JIA). Children ages 2-16 years who had active oligo-course or poly-course JIA and who required therapy with a nonsteroidal antiinflammatory drug were eligible for this trial. Patients were randomly allocated to receive therapy with meloxicam oral suspension, 0.125 mg/kg body weight in a single daily dose; meloxicam oral suspension, 0.25 mg/kg body weight in a single daily dose; or naproxen, 10 mg/kg body weight in 2 daily doses. The trial drugs were administered in a double-blind, double-dummy design for up to 12 months. Response rates were determined according to the American College of Rheumatology pediatric 30% improvement criteria (ACR pediatric 30). Safety parameters were assessed by evaluating the frequency of adverse events in the 3 groups. Of 232 patients enrolled, 225 received treatment, 6 were not eligible for randomization, and 1 randomized patient was not treated. One hundred eighty-two patients (81%) completed the 12-month treatment period. Response rates according to the ACR pediatric 30 criteria improved from month 3 to month 12, as follows: from 63% to 77% in the meloxicam 0.125 mg/kg group, from 58% to 76% in the meloxicam 0.25 mg/kg group, and from 64% to 74% in the naproxen group. No statistically significant differences in response rates were observed between the groups. There were no differences in the frequency of adverse events or abnormal laboratory values between the 3 groups. The short- and long-term safety and efficacy of meloxicam oral suspension appear to be comparable with the safety and efficacy of naproxen oral suspension in the treatment of oligo-course and poly-course JIA. The once-daily administration of meloxicam oral suspension might represent an improvement in the treatment of JIA.

Prognostic factors for radiographic progression, radiographic damage, and disability in juvenile idiopathic arthritis.

To investigate the rate of radiographic progression and identify prognostic factors of radiographic progression, radiographic damage, and physical disability in juvenile idiopathic arthritis (JIA). Ninety-four JIA patients with a median disease duration of 1.1 years were followed up prospectively for a median of 4.5 years. Bilateral wrist radiographs were obtained at baseline, at 1 year, and at the last followup visit. Radiographic damage was assessed by the carpal length (Poznanski score), and physical disability by the Childhood Health Assessment Questionnaire (C-HAQ). Yearly radiographic progression, the Poznanski score at the final visit, and the C-HAQ score at the final visit were used as outcome measures. Baseline parameters included demographic, clinical, laboratory, and radiographic data. The mean +/- SD Poznanski score was -1.2 +/- 1.3 at baseline, -1.7 +/- 1.8 at the 1-year visit, and -1.9 +/- 2.2 at the final visit (P < 0.0001). Radiographic progression was greater during the first year (mean +/- SD -0.5 +/- 1.1) than between the 1-year visit and the final visit (-0.2 +/- 1.3). The mean yearly radiographic progression during the entire study period was -0.1 +/- 0.4. Logistic regression analysis revealed that radiographic progression during the first year was the only baseline parameter that was predictive of all 3 study outcomes. The final Poznanski score was also predicted by the baseline Poznanski score, whereas female sex was protective against radiographic progression. We identified the prognostic factors for poorer outcome in polyarticular-course JIA. The changes in the early Poznanski score can be used to predict long-term joint damage and physical disability.

Amoebiasis in homosexual men.

The clinical, histopathological, and serological features of 35 homosexual men with infection with Entamoeba histolytica were studied and compared with a group of 35 non-infected homosexual men. Each isolate was of Zymodeme type I. Although there was no significant difference in the numbers of infected and non-infected men with gastrointestinal symptoms (48.6% and 28.6% respectively), the mean duration of symptoms was greater in with amoebiasis (p less than 0.05). The histology of the rectal mucosa was abnormal in 17 (63.0%) of the 27 men with amoebic infection only and in two (7.4%) of the 27 control subjects (p less than 0.001). Serum antibodies reactive with E. histolytica were not shown in any patient.