Peter A Nigrovic1,2, Timothy Beukelman3, George Tomlinson4, Brian M Feldman5, Laura E Schanberg6, Yukiko Kimura7. 1. 1 Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Boston, MA, USA. 2. 2 Division of Allergy and Immunology, Boston Children's Hospital, Boston, MA, USA. 3. 3 Division of Pediatric Rheumatology, The University of Alabama at Birmingham, Birmingham, AL, USA. 4. 4 Department of Medicine, University Health Network and Mt. Sinai Hospital, Institute of Health Policy Management & Evaluation, Dalla Lana School of Public Health, The University of Toronto, Toronto, ON, Canada. 5. 5 Division of Rheumatology, The Hospital for Sick Children, Department of Pediatrics, and Medicine, Faculty of Medicine, Institute of Health Policy Management & Evaluation, Dalla Lana School of Public Health, The University of Toronto, Toronto, ON, Canada. 6. 6 Division of Pediatric Rheumatology and Duke Clinical Research Institute, Duke University Medical Center, Durham, NC, USA. 7. 7 Division of Pediatric Rheumatology, Joseph M. Sanzari Children's Hospital, Hackensack University Medical Center, Hackensack, NJ, USA.
Abstract
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.
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 arthritispatients 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.
Authors: Alexei A Grom; Norman T Ilowite; Virginia Pascual; Hermine I Brunner; Alberto Martini; Daniel Lovell; Nicolino Ruperto; Karolynn Leon; Karine Lheritier; Ken Abrams Journal: Arthritis Rheumatol Date: 2016-01 Impact factor: 10.995
Authors: Ginger Janow; Laura E Schanberg; Soko Setoguchi; Victor Hasselblad; Elizabeth D Mellins; Rayfel Schneider; Yukiko Kimura Journal: J Rheumatol Date: 2016-06-15 Impact factor: 4.666
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Authors: Yukiko Kimura; Jennifer E Weiss; Kathryn L Haroldson; Tzielan Lee; Marilynn Punaro; Sheila Oliveira; Egla Rabinovich; Meredith Riebschleger; Jordi Antón; Peter R Blier; Valeria Gerloni; Melissa M Hazen; Elizabeth Kessler; Karen Onel; Murray H Passo; Robert M Rennebohm; Carol A Wallace; Patricia Woo; Nico Wulffraat Journal: Arthritis Care Res (Hoboken) Date: 2013-05 Impact factor: 4.794
Authors: Claudia Kedor; Joachim Listing; Jan Zernicke; Anja Weiß; Frank Behrens; Norbert Blank; Joerg Christoph Henes; Joern Kekow; Andrea Rubbert-Roth; Hendrik Schulze-Koops; Eva Seipelt; Christof Specker; Eugen Feist Journal: Ann Rheum Dis Date: 2020-05-13 Impact factor: 27.973