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Consensus treatment plans for new-onset systemic juvenile idiopathic arthritis.

ABSTRACT: There is wide variation in therapeutic approaches to systemic juvenile idiopathic arthritis (JIA) among North American rheumatologists. Understanding the comparative effectiveness of the diverse therapeutic options available for treatment of systemic JIA can result in better health outcomes. The Childhood Arthritis and Rheumatology Research Alliance (CARRA) developed consensus treatment plans and standardized assessment schedules for use in clinical practice to facilitate such studies.Case-based surveys were administered to CARRA members to identify prevailing treatments for new-onset systemic JIA. A 2-day consensus conference in April 2010 employed modified nominal group technique to formulate preliminary treatment plans and determine important data elements for collection. Followup surveys were employed to refine the plans and assess clinical acceptability.The initial case-based survey identified significant variability among current treatment approaches for new-onset systemic JIA, underscoring the utility of standardized plans to evaluate comparative effectiveness. We developed 4 consensus treatment plans for the first 9 months of therapy, as well as case definitions and clinical and laboratory monitoring schedules. The 4 treatment regimens included glucocorticoids only, or therapy with methotrexate, anakinra, or tocilizumab, with or without glucocorticoids. This approach was approved by >78% of the CARRA membership.Four standardized treatment plans were developed for new-onset systemic JIA. Coupled with data collection at defined intervals, use of these treatment plans will create the opportunity to evaluate comparative effectiveness in an observational setting to optimize initial management of systemic JIA.

SUBMITTER: DeWitt EM

PROVIDER: S-EPMC3368104 | biostudies-literature | 2012 Jul

REPOSITORIES: biostudies-literature

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Consensus treatment plans for new-onset systemic juvenile idiopathic arthritis.

DeWitt Esi Morgan EM Kimura Yukiko Y Beukelman Timothy T Nigrovic Peter A PA Onel Karen K Prahalad Sampath S Schneider Rayfel R Stoll Matthew L ML Angeles-Han Sheila S Milojevic Diana D Schikler Kenneth N KN Vehe Richard K RK Weiss Jennifer E JE Weiss Pamela P Ilowite Norman T NT Wallace Carol A CA

Arthritis care & research 20120701 7

<h4>Objective</h4>There is wide variation in therapeutic approaches to systemic juvenile idiopathic arthritis (JIA) among North American rheumatologists. Understanding the comparative effectiveness of the diverse therapeutic options available for treatment of systemic JIA can result in better health outcomes. The Childhood Arthritis and Rheumatology Research Alliance (CARRA) developed consensus treatment plans and standardized assessment schedules for use in clinical practice to facilitate such ...[more]

PMID: 22290637

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Project description:BACKGROUND:Systemic juvenile idiopathic arthritis is a rare febrile arthritis of childhood characterized by a potentially severe course, including prolonged glucocorticoid exposure, growth failure, destructive arthritis, and life-threatening macrophage activation syndrome. Early cytokine-blocking biologic therapy may improve long-term outcomes, although some systemic juvenile idiopathic arthritis patients respond well to non-biologic treatment, leaving optimal management undefined. Consequently, treatment of new-onset systemic juvenile idiopathic arthritis by expert clinicians varies widely. PURPOSE:To describe a pragmatic, observational comparative effectiveness study that takes advantage of diversity in the management of a rare disease: FiRst-Line Options for Systemic juvenile idiopathic arthritis Treatment (FROST), comparing non-biologic and biologic consensus treatment plans for new-onset systemic juvenile idiopathic arthritis within the 60-center Childhood Arthritis and Rheumatology Research Alliance Registry (CARRA). METHODS:FiRst-Line Options for Systemic juvenile idiopathic arthritis Treatment (FROST) is a multicenter, prospective, non-randomized study that compares four Childhood Arthritis and Rheumatology Research Alliance (CARRA) consensus treatment plans for new-onset systemic juvenile idiopathic arthritis: (1) glucocorticoids alone, (2) methotrexate, (3) interleukin-1 blockade, and (4) interleukin-6 blockade. Patients consenting to participation in the Childhood Arthritis and Rheumatology Research Alliance (CARRA) Registry are started on one of four Consensus Treatment Plans at the discretion of the treating physician. The outcome of primary interest is clinically inactive disease off glucocorticoids at 9 months, comparing non-biologic (Consensus Treatment Plans 1 + 2) versus biologic (Consensus Treatment Plans 3 + 4) strategies. Bayesian analytic methods will be employed to evaluate response rates, using propensity scoring to balance treatment groups for potential confounding. With 200 patients in a 2:1 ratio of biologic to non-biologic, there is a >90% probability of finding biologic consensus treatment plans more effective if the rate of clinically inactive disease is 30% higher than for non-biologic therapy. Additional outcomes include Patient-Reported Outcomes Measurement Information System measures and other parent-/patient-reported outcomes reported in real time using smartphone technology. Routine operation of the Childhood Arthritis and Rheumatology Research Alliance (CARRA) Registry will allow assessment of outcomes over at least 10 years. RESULTS:FiRst-Line Options for Systemic juvenile idiopathic arthritis Treatment (FROST) began enrollment in November 2016. LIMITATIONS:The observational design may not provide balance in measured and unmeasured confounders. Use of consensus treatment plan (CTP) strategies at frequencies more unbalanced than predicted could reduce the chance of finding differences in efficacy. CONCLUSION:FiRst-Line Options for Systemic juvenile idiopathic arthritis Treatment (FROST) will provide the first prospective comparison of Childhood Arthritis and Rheumatology Research Alliance's (CARRA's) consensus-derived non-biologic versus biologic management strategies in systemic juvenile idiopathic arthritis, performed in a real-world setting wherein each patient receives standard-of-care treatment selected by the treating physician. Outcomes include clinician- and patient-/family-reported outcomes, empowering both physician and patient decision making in new-onset systemic juvenile idiopathic arthritis.

Project description:Background: Systemic-Onset Juvenile Idiopathic Arthritis (SJIA) is a rare disease associated with dysregulated interleukin (IL)-1 activity. Objectives: To assess the efficacy and safety of Anakinra, an IL-1 receptor antagonist in SJIA and its effects on gene expression profiling. Methods: We conducted a multicenter, randomized, double-blind placebo-controlled trial. The primary objective was to compare the efficacy of a one-month treatment with anakinra (2 mg/kg subcutaneoulsy daily, maximum 100 mg) to a placebo between 2 groups of 12 SJIA patients each. Response was defined by a 30% improvement of the pediatric American College of Rheumatology criteria for JIA, resolution of systemic symptoms and a decrease of at least 50% of both C-reactive protein and erythrocyte sedimentation rate compared to baseline. An intention-to-treat analyze was performed. After Month 1 (M1), patients taking placebo were switched to Anakinra. Secondary objectives included tolerance and efficacy assessment for 12 months. Results: At M1, concluding the randomized trial, there was a significant difference in the response rate between patients treated with Anakinra (8/12 responders) and placebo (1/12) (p=0.003). The number of adverse events, mainly pain to injections, was similar between both groups. Ten patients from the placebo group switched to Anakinra at M1; nine were responders at M2. Between M1 and M12, six patients stopped treatment for an adverse event (Crohn’s disease, hepatitis), a lack of efficacy or a disease flare (2 cases each). Blood gene expression profiling at enrollment and upon follow-up allowed us to identify one set of dysregulated genes that reverted to normal values in the clinical responders and a second set, including interferon-inducible genes, that was induced by Anakinra. Conclusion: Anakinra is an effective treatment of SJIA. Its effect is associated with normalization of blood gene expression profiles in clinical responders and de novo induction of an interferon signature. (Clinical trials registration number: NCT00339157)

Project description:BackgroundTo explore the effects of extracellular histones released by activated neutrophils on systemic-onset juvenile idiopathic arthritis (SoJIA), and to study the change of serum histone level between the active and remissive stage of SoJIA, then to clarify the role of serum histone in the pathogenesis of SoJIA.MethodsTwenty-six patients with SoJIA were recruited, and clinical informations were collected, and the serum histone was detected by ELISA. While neutrophils from normal children were incubated with the serum from the patients with SoJIA, also including incubated with FeCL3 and histone, the extracellular histone was detected, respectively; heparin was added to the above-mentioned groups to observe the changes of extracellular histone levels. The proportions of neutrophils, which released NETs, were calculated by confocal microscope.ResultsThe levels of serum histones in active SoJIA group (0.90 ± 0.90) were significantly higher than in remissive SoJIA group (0.17 ± 0.10) (P = 0.0009), and also higher than in control group (0.14 ± 0.09) (P = 0.246). Histone affects on clinical manifestations (including fever, rash, joint pain, liver and spleen enlargement, and serositis), except for joint pain. The proportions of neutrophils releasing NETs, that neutrophils were incubated with the serum from active SoJIA group, were 31.93% significantly higher than 12.32% from remissive SoJIA group (P < 0.0001). The proportions of neutrophils releasing NETs, that neutrophils were incubated with different concentration FeCl3 or with different concentration histones respectively, were positively correlated with the concentration of incubation; while heparins were added, NETs from neutrophils could be reduced effectively.ConclusionsThe level of serum histone is positively correlated with the activity of SoJIA. Serum histone may be from NETs, which were released by activated neutrophils. Free iron can activate neutrophils to produce NETs, which may release histones, and histones can further promote NETs to be released, that results in a positive feedback loop of histones, and that may be one of the pathogenesis of acute SoJIA or MAS secondary to SoJIA. Histones maybe play one of important roles in the pathogenesis of SoJIA. Heparin can act on histones to prevent histone-induced inflammation.Trial registrationChiCTR-OOC-15006228. Registered 9 April 2015, http://www.chictr.org.cn/showproj.aspx?proj=10752.

Dataset Information

Consensus treatment plans for new-onset systemic juvenile idiopathic arthritis.

Publications

Consensus treatment plans for new-onset systemic juvenile idiopathic arthritis.

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