Cost-Effectiveness Analysis of First-Line Treatment With Biologic Agents in Polyarticular Juvenile Idiopathic Arthritis.

OBJECTIVE: The optimal timing of biologic agent treatment in polyarticular juvenile idiopathic arthritis (JIA) is unknown. This study evaluated the costs and outcomes of first-line treatment with etanercept (ETN), an anti-tumor necrosis factor (anti-TNF) agent, compared with step-wise therapy in JIA. METHODS: We compared 2 strategies: methotrexate (MTX) plus ETN as first-line therapy (ETN-first) and MTX monotherapy followed by ETN (ETN-second), using a cohort state-transition model of newly diagnosed JIA patients. The model's time horizon was 5 years, and the perspective was that of the Canadian health care system. The base case patient was 11 years old, weighed 40 kg, and had 5 or more active joints. Direct costs were calculated and discounted at a rate of 3% per year. Outcomes were expressed as quality-adjusted life years (QALYs). Scenario analyses varied multiple parameters simultaneously to model more severely and more mildly affected patients. RESULTS: ETN-first, compared to ETN-second, yielded a discounted incremental cost of $16,893 (95% confidence interval [95% CI] 9,348-25,310), incremental QALY of 0.19 (95% CI 0.08-0.32), and an incremental cost-effectiveness ratio of $88,815 per QALY gained. The results were sensitive to the cost of ETN, the time horizon of the model, and estimates of the efficacy of the first-line therapies. The cost per QALY for treating patients with severe JIA was $33,960. CONCLUSION: First-line therapy of ETN and MTX is relatively expensive compared to MTX alone, but may be economically attractive for more severely affected patients. More research is needed regarding the efficacy of first-line anti-TNF agents.

Cost-effectiveness analysis of clinic-based chloral hydrate sedation versus general anaesthesia for paediatric ophthalmological procedures.

BACKGROUND/AIMS: The inability of some children to tolerate detailed eye examinations often necessitates general anaesthesia (GA). The objective was to assess the incremental cost effectiveness of paediatric eye examinations carried out in an outpatient sedation unit compared with GA. METHODS: An episode of care cost-effectiveness analysis was conducted from a societal perspective. Model inputs were based on a retrospective cross-over cohort of Canadian children aged <7 years who had both an examination under sedation (EUS) and examination under anaesthesia (EUA) within an 8-month period. Costs ($CAN), adverse events and number of successful procedures were modelled in a decision analysis with one-way and probabilistic sensitivity analysis. RESULTS: The mean cost per patient was $406 (95% CI $401 to $411) for EUS and $1135 (95% CI $1125 to $1145) for EUA. The mean number of successful procedures per patient was 1.39 (95% CI 1.34 to 1.42) for EUS and 2.06 (95% CI 2.02 to 2.11) for EUA. EUA was $729 more costly on average than EUS (95% CI $719 to $738) but resulted in an additional 0.68 successful procedures per child. The result was robust to varying the cost assumptions. CONCLUSIONS: Cross-over designs offer a powerful way to assess costs and effectiveness of two interventions because patients serve as their own control. This study demonstrated significant savings when ophthalmological exams were carried out in a hospital outpatient clinic, although with slightly fewer procedures completed.

Parents' willingness to pay for biologic treatments in juvenile idiopathic arthritis.

BACKGROUND: Biologic therapies are considered the standard of care for children with the most severe forms of juvenile idiopathic arthritis (JIA). Inconsistent and inadequate drug coverage, however, prevents many children from receiving timely and equitable access to the best treatment. OBJECTIVE: The objective of this study was to evaluate parents' willingness to pay (WTP) for biologic and nonbiologic disease-modifying antirheumatic drugs (DMARDs) used to treat JIA. METHODS: Utility weights from a discrete choice experiment were used to estimate the WTP for treatment characteristics including child-reported pain, participation in daily activities, side effects, days missed from school, drug treatment, and cost. Conditional logit regression was used to estimate utilities for each attribute level, and expected compensating variation was used to estimate the WTP. Bootstrapping was used to generate 95% confidence intervals for all WTP estimates. RESULTS: Parents had the highest marginal WTP for improved participation in daily activities and pain relief followed by the elimination of side effects of treatment. Parents were willing to pay $2080 (95% confidence interval $698-$4065) more for biologic DMARDs than for nonbiologic DMARDs if the biologic DMARD was more effective. CONCLUSIONS: Parents' WTP indicates their preference for treatments that reduce pain and improve daily functioning without side effects by estimating the monetary equivalent of utility for drug treatments in JIA. In addition to evidence of safety and efficacy, assessments of parents' preferences provide a broader perspective to decision makers by helping them understand the aspects of drug treatments in JIA that are most valued by families.

The use of biologic response modifiers in polyarticular-course juvenile idiopathic arthritis: a systematic review.

OBJECTIVE: To systematically review the clinical efficacy and safety evidence of biologic drugs used to treat the polyarticular category of juvenile idiopathic arthritis (JIA). METHODS: The literature was searched between 2000 and September 2012 for randomized controlled trials (RCTs), non-randomized comparative studies, and non-comparative observational cohort studies. The drugs evaluated included etanercept, infliximab, adalimumab, abatacept, anakinra, and ritixumab. Eligible studies included 20 or more patients with JIA, the majority of whom had polyarticular course disease. Outcomes of interest were disease improvement defined by the American College of Rheumatology criteria for Pediatrics, disease flares, rates of inactive disease, remissions, discontinuations, and adverse events (severe and non-severe). RESULTS: Thirty-seven studies were included, the majority focused on etanercept. Seven RCTs were identified, including one each for etanercept, infliximab, adalimumab, abatacept, and anakinra, and one each looking at etanercept or infliximab as first-line therapies. There was strong evidence to support the efficacy and safety of biologics over the short-term, but a lack of long-term data for treatments other than etanercept. Several high-quality patient registries confirmed the efficacy and safety of etanercept over the long-term. CONCLUSIONS: Current evidence shows that a short-term improvement in treatment response is achieved when patients with polyarticular JIA with an inadequate response to conventional treatment are treated with biologics. Long-term effectiveness data, however, are sparse leaving many questions regarding switches between biologics, handling patients that achieve disease remission, and long-term safety. Study designs other than RCTs may be important in understanding the role of biologics in JIA over the long-term.

Parents' preferences for drug treatments in juvenile idiopathic arthritis: a discrete choice experiment.

OBJECTIVE: To examine parents' preferences for drug treatments and health outcomes in juvenile idiopathic arthritis (JIA) and identify demographic and health-related factors that significantly impact choice. METHODS: A discrete choice experiment was conducted with 105 parents of children with JIA who were cared for by a rheumatologist at The Hospital for Sick Children in Canada. Attributes evaluated included "drug treatment," "child reported pain from arthritis," "participation in daily activities," "side effects," "days missed from school," and "cost to you." Multinomial logit regression was used to estimate the relative importance of each attribute level and interaction term. RESULTS: Parents made tradeoffs between characteristics of the drug treatments and health outcomes. "Participation in daily activities" was the most important attribute, followed by "child reported pain from arthritis" and "cost to you." Parents of children with longer disease durations had stronger preferences for improved participation in daily activities, whereas parents of older JIA patients had stronger preferences for improved control of pain. CONCLUSION: Parents of children with JIA demonstrated strong preferences for treatments that reduce pain and improve daily functioning regardless of the associated side effects, level of responsibility required for drug administration, and days missed from school. Parents of children with longer disease durations and those who had been prescribed aggressive therapies had a greater preference for treatment effectiveness. These findings support the need for considering parental preferences in decisions regarding the choice of treatment for JIA.

Herpes simplex virus-1 disarms the unfolded protein response in the early stages of infection.

Accumulation of mis- and unfolded proteins during viral replication can cause stress in the endoplasmic reticulum (ER) and trigger the unfolded protein response (UPR). If unchecked, this process may induce cellular changes detrimental to viral replication. In the report, we investigated the impact of HSV-1 on the UPR during lytic replication. We found that HSV-1 effectively disarms the UPR in early stages of viral infection. Only ATF6 activation was detected during early infection, but with no upregulation of target chaperone proteins. Activity of the eIF2α/ATF4 signaling arm increased at the final stage of HSV-1 replication, which may indicate completion of virion assembly and egress, thus releasing suppression of the UPR. We also found that the promoter of viral ICP0 was responsive to ER stress, an apparent mimicry of cellular UPR genes. These results suggest that HSV-1 may use ICP0 as a sensor to modulate the cellular stress response.

Identification and characterization of the DNA-binding properties of a Zhangfei homologue in Japanese pufferfish, Takifugu rubripes.

Zhangfei is a basic region-leucine zipper (bZIP) transcription factor identified through its interaction with a herpesvirus-related host cell factor HCF1 (C1). Unlike most bZIP proteins, the mammalian Zhangfei protein does not bind DNA as homodimers. It is believed due to the absence of an asparagine residue in the basic region, which forms the DNA-recognition motif, NxxAAxxCR, in all bZIP proteins. Here, we report the identification and characterization of a novel Zhangfei homologue in Takifugu rubripes, which has an intact DNA-recognition motif by sequence analysis. We found that the pufferfish Zhangfei (pZF) appeared to have all the functional domains known in human Zhangfei, including the conserved HCF1-binding motif; however, pZF did not appear to bind DNA either. These findings suggest that the distinct property of the Zhangfei basic region is conserved during the evolution of vertebrates and that Zhangfei requires interaction with other proteins to regulate transcription from target promoters.