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BACKGROUND: Tofacitinib is an oral Janus kinase inhibitor. This trial assessed the efficacy and safety of tofacitinib versus placebo in patients with polyarticular course juvenile idiopathic arthritis (JIA). METHODS: This double-blind, withdrawal phase 3 trial enrolled patients with polyarticular course JIA (extended oligoarthritis, rheumatoid factor-positive or rheumatoid factor-negative polyarthritis, or systemic JIA without active systemic features) aged 2 years to younger than 18 years, and was done at 64 centres of the Paediatric Rheumatology International Trials Organisation and Pediatric Rheumatology Collaborative Study Group networks in 14 countries. Patients with psoriatic arthritis or enthesitis-related arthritis were enrolled for exploratory endpoints. During part 1 of the study, patients received oral open-label tofacitinib (weight-based doses; 5 mg twice daily or lower) for 18 weeks. Patients achieving at least JIA/American College of Rheumatology 30 response were randomly assigned (1:1) using an Interactive Response Technology system to continue tofacitinib or switch to placebo in part 2 of the study for 26 weeks. The primary endpoint was JIA flare rate by week 44 in part 2 in patients with polyarticular course JIA; the intention-to-treat principle was applied. Safety was evaluated throughout part 1 and part 2 of the study in all patients who received one dose or more of study medication. This trial is registered with ClinicalTrials.gov, NCT02592434. FINDINGS: Between June 10, 2016, and May 16, 2019, of 225 patients enrolled, 184 (82%) patients had polyarticular course JIA, 20 (9%) had psoriatic arthritis, and 21 (9%) had enthesitis-related arthritis. 147 (65%) of 225 patients received concomitant methotrexate. In part 2, 142 patients with polyarticular course JIA were assigned to tofacitinib (n=72) or placebo (n=70). Flare rate by week 44 was significantly lower with tofacitinib (21 [29%] of 72 patients) than with placebo (37 [53%] of 70 patients; hazard ratio 0·46, 95% CI 0·27-0·79; p=0·0031). In part 2 of the study, adverse events occurred in 68 (77%) of 88 patients receiving tofacitinib and 63 (74%) of 85 in the placebo group. Serious adverse events occurred in one (1%) and two (2%), respectively. In the entire tofacitinib exposure period, 107 (48%) of 225 patients had infections or infestations. There were no deaths during this study. INTERPRETATION: The results of this pivotal trial show that tofacitinib is an effective treatment in patients with polyarticular course JIA. New oral therapies are particularly relevant for children and adolescents, who might prefer to avoid injections. FUNDING: Pfizer.
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Artritis Juvenil/tratamiento farmacológico , Inhibidores de las Cinasas Janus/uso terapéutico , Piperidinas/uso terapéutico , Pirimidinas/uso terapéutico , Administración Oral , Adolescente , Niño , Preescolar , Humanos , Resultado del TratamientoRESUMEN
ABSTRACT: Ocular point-of-care ultrasound has been used to assess for intraocular pathology, including retinal and vitreous detachment. We describe a pediatric patient whose initial point-of-care ultrasound examination appeared to be consistent with bilateral posterior vitreous detachment but who was ultimately diagnosed with intermediate uveitis.
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Desprendimiento de Retina , Uveítis Intermedia , Desprendimiento del Vítreo , Adolescente , Niño , Femenino , Humanos , Sistemas de Atención de Punto , UltrasonografíaAsunto(s)
Dermatomiositis , Hemoperfusión , Enfermedades Pulmonares Intersticiales , Autoanticuerpos/inmunología , Niño , Dermatomiositis/diagnóstico , Dermatomiositis/tratamiento farmacológico , Progresión de la Enfermedad , Humanos , Helicasa Inducida por Interferón IFIH1/inmunología , Enfermedades Pulmonares Intersticiales/diagnóstico , Enfermedades Pulmonares Intersticiales/tratamiento farmacológico , Polimixina BRESUMEN
OBJECTIVE: Examine levels of candidate blood-based biomarkers (CBB) in juvenile idiopathic arthritis (JIA) treated with tofacitinib. METHODS: JIA patients who participated in clinical trial NCT02592434 received tofacitinib from baseline to week 18. Serial serum samples were assayed for CBB (S100A8/9, S100A12, IL-18, SAA, resistin, VEGF, Angiopoietin-1, Angiopoietin-2, MMP8, MMP2, TIMP1, Leptin, CXCL9, sIL2R, ICAM-1, sTNFr, IL-6, IL-23, MCP1, CCL18, and CCL20). Association of CBB with JIA response to treatment from baseline to week 18 were assessed. RESULTS: This study included 166 patients with polyarticular-course JIA. Paired serum samples from 143 patients were available at both baseline and week 18. There were 35% (50/143) of patients with a JIA-American College of Rheumatology 90 (JIA-ACR90) level improvement while 90/121/137 (63%/85%/96%) achieved JIA-ACR70/50/30 improvement at wk18. Despite small numerical differences by JIA category, there were no baseline CBB values that independently predicted a decrease in JADAS-27 or JIA-ACR90 response by week 18. Decrease in resistin level (baseline to week 18) was significantly associated with wk18 improvement in JADAS-27 and JIA-ACR90 response, after adjusting for age, sex, JIA disease duration and baseline resistin [(r2 0.79, SE, 0.070, p<0.01 and OR(95%CI) = 1.134(1.018, 1.264)]. HLA-B27 positivity was significantly associated with not achieving a JIA-ACR90 response at week 18 (p=0.0097). CONCLUSION: Among the CBB included, only resistin was significantly associated with treatment response, and no CBB was identified that forecasts JIA improvement after initiation of tofacitinib. The association of HLA-B27 positivity with lower response to tofacitinib in JIA is intriguing and merits further study.
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OBJECTIVE: The objective was to develop consensus treatment plans (CTPs) for patients with refractory moderately severe juvenile dermatomyositis (JDM) treated with biologic disease-modifying antirheumatic drugs (bDMARDs). METHODS: The Biologics Workgroup of the Childhood Arthritis and Rheumatology Research Alliance JDM Research Committee used case-based surveys, consensus framework, and nominal group technique to produce bDMARD CTPs for patients with refractory moderately severe JDM. RESULTS: Four bDMARD CTPs were proposed: tumor necrosis factor α (TNFα) inhibitor (adalimumab or infliximab), abatacept, rituximab, and tocilizumab. Each CTP has different options for dosing and/or route. Among 76 respondents, consensus was achieved for the proposed CTPs (93% [67 of 72]) as well as for patient characteristics, assessments, outcome measures, and follow-up. By weighted average, respondents indicated that they would most likely administer rituximab, followed by abatacept, TNFα inhibitor, and tocilizumab. CONCLUSION: CTPs for the administration of bDMARDs in refractory moderately severe JDM were developed using consensus methodology. The implementation of the bDMARD CTPs will lay the groundwork for registry-based prospective comparative effectiveness studies.
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OBJECTIVE: Rheumatoid arthritis is associated with an excess of agalactosylated (G0) IgG that is considered relatively proinflammatory. Assessment of this association in juvenile idiopathic arthritis (JIA) is complicated by age-dependent IgG glycan variation. The aim of this study was to conduct the first large-scale survey of IgG glycans in healthy children and patients with JIA, with a focus on early childhood, the time of peak JIA incidence. METHODS: IgG glycans from healthy children and disease-modifying antirheumatic drug-naive patients with JIA were characterized using high-performance liquid chromatography. Agalactosylated glycans were quantitated with reference to monogalactosylated (G1) species. Associations were sought between the G0:G1 ratio and disease characteristics. RESULTS: Among healthy children ages 9 months to 16 years (n = 165), the G0:G1 ratio was highly age dependent, with the ratio peaking to 1.19 in children younger than age 3 years and declining to a nadir of 0.83 after age 10 years (Spearman's ρ = 0.60, P < 0.0001). In patients with JIA (n = 141), the G0:G1 ratio was elevated compared with that in control subjects (1.32 versus 1.02; P < 0.0001). The G0:G1 ratio corrected for age was abnormally high in all JIA subtypes (enthesitis-related arthritis was not assessed), most strikingly in systemic JIA. Glycosylation aberrancy was comparable in patients with and those without antinuclear antibodies and in both early- and late-onset disease and exhibited at most a weak correlation with markers of inflammation. CONCLUSION: IgG glycosylation is skewed toward proinflammatory G0 variants in healthy children, in particular during the first few years of life. This deviation is exaggerated in patients with JIA. The role for IgG glycan variation in immune function in children, including the predilection of JIA for early childhood, remains to be defined.
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Artritis Juvenil/inmunología , Inmunoglobulina G/metabolismo , Adolescente , Artritis Juvenil/metabolismo , Niño , Preescolar , Femenino , Glicosilación , Humanos , Lactante , Inflamación/inmunología , Inflamación/metabolismo , MasculinoRESUMEN
BACKGROUND: Despite new and better treatments for juvenile dermatomyositis (JDM), not all patients with moderate severity disease respond adequately to first-line therapy. Those with refractory disease remain at higher risk for disease and glucocorticoid-related complications. Biologic disease-modifying antirheumatic drugs (DMARDs) have become part of the arsenal of treatments for JDM. However, prospective comparative studies of commonly used biologics are lacking. METHODS: The Childhood Arthritis and Rheumatology Research Alliance (CARRA) JDM biologics workgroup met in 2019 and produced a survey assessing current treatment escalation practices for JDM, including preferences regarding use of biologic treatments. The cases and questions were developed using a consensus framework, requiring 80% agreement for consensus. The survey was completed online in 2020 by CARRA members interested in JDM. Survey results were analyzed among all respondents and according to years of experience. Chi-square or Fisher's exact test was used to compare the distribution of responses to each survey question. RESULTS: One hundred twenty-one CARRA members responded to the survey (denominators vary for each question). Of the respondents, 88% were pediatric rheumatologists, 85% practiced in the United States, and 43% had over 10 years of experience. For a patient with moderately severe JDM refractory to methotrexate, glucocorticoids, and IVIG, approximately 80% of respondents indicated that they would initiate a biologic after failing 1-2 non-biologic DMARDs. Trials of methotrexate and mycophenolate were considered necessary by 96% and 60% of respondents, respectively, before initiating a biologic. By weighed average, rituximab was the preferred biologic over abatacept, tocilizumab, and infliximab. Over 50% of respondents would start a biologic by 4 months from diagnosis for patients with refractory moderately severe JDM. There were no notable differences in treatment practices between respondents by years of experience. CONCLUSION: Most respondents favored starting a biologic earlier in disease course after trialing up to two conventional DMARDs, specifically including methotrexate. There was a clear preference for rituximab. However, there remains a dearth of prospective data comparing biologics in refractory JDM. These findings underscore the need for biologic consensus treatment plans (CTPs) for refractory JDM, which will ultimately facilitate comparative effectiveness studies and inform treatment practices.
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Antirreumáticos , Artritis Juvenil , Dermatomiositis , Reumatología , Humanos , Niño , Metotrexato/uso terapéutico , Artritis Juvenil/tratamiento farmacológico , Dermatomiositis/diagnóstico , Rituximab/uso terapéutico , Estudios Prospectivos , Antirreumáticos/uso terapéutico , Glucocorticoides/uso terapéuticoRESUMEN
BACKGROUND: Global disease activity scores (gVAS) capture patient or family (PF) and physician (MD) assessments of disease. This study sought to measure discordance between PF and MD global activity scores in juvenile dermatomyositis (JDM), and determine factors associated with discordance. METHODS: Patients with JDM were included from the Childhood Arthritis and Rheumatology Research Alliance (CARRA) Legacy Registry (N = 563). PF and MD gVAS were assessed for discordance, defined as a ≥ 2-point difference. Factors associated with discordant gVAS were compared in univariate analysis. Multivariable regression analysis was used to identify predictors of discordance. RESULTS: Almost 40% (N = 219) of PF and MD gVAS were discordant. Among discordant scores, 68% of PF rated gVAS ≥2-points above MD, which was associated with calcinosis and lower quality of life and functional scores (p < 0.01). MD gVAS rated ≥2-points above PF in 32%, which was associated with abnormal laboratory results, weakness, arthritis, rash and other skin changes, and current intravenous steroid treatment (p < 0.01). In multivariate analysis, predictors for higher PF rating included calcinosis, lower quality of life and functional scores, while predictors for higher MD rating included rash, calcinosis, nailfold capillaroscopy changes, and current intravenous steroid treatment. CONCLUSIONS: Discordance between PF and MD gVAS was common in this JDM cohort. Overall, higher PF rating was associated with poorer patient reported outcome (PRO) scores, while higher MD rating was associated with poorer objective measures. This suggests PF and MD assessments of gVAS may be measuring different aspects of disease, highlighting the importance of integrating PROs into clinical practice and research.
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Dermatomiositis/diagnóstico , Disentimientos y Disputas , Adolescente , Niño , Dermatomiositis/patología , Familia/psicología , Femenino , Humanos , Modelos Logísticos , Masculino , Pacientes/psicología , Médicos/psicología , Índice de Severidad de la EnfermedadRESUMEN
BACKGROUND: A standardized set of quality measures for juvenile idiopathic inflammatory myopathies (JIIM) is not in use. Discordance has been shown between the importance ascribed to quality measures between patients and families and physicians. The objective of this study was to assess and compare the importance of various aspects of high quality care to patients with JIIM and their families with healthcare providers, to aid in future development of comprehensive quality measures. METHODS: Surveys were developed by members of the Childhood Arthritis and Rheumatology Research Alliance (CARRA) Juvenile Dermatomyositis Workgroup through a consensus process and administered to patients and families through the CureJM Foundation and to healthcare professionals through CARRA. The survey asked respondents to rate the importance of 19 items related to aspects of high quality care, using a Likert scale. RESULTS: Patients and families gave generally higher scores for importance to most of the quality measurement themes compared with healthcare professionals, with ratings of 13 of the 19 measures reaching statistical significance (p < 0.05). Of particular importance, however, was consensus between the groups on the top five most important items: quality of life, timely diagnosis, access to rheumatology, normalization of functioning/strength, and ability for self care. CONCLUSIONS: Despite overall differences in the rating of importance of quality indicators between patients and families and healthcare professionals, the groups agreed on the most important aspects of care. Recognizing areas of particular importance to patients and families, and overlapping in importance with providers, will promote the development of standardized quality measures with the greatest potential for improving care and outcomes for children with JIIM.
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Miositis/terapia , Garantía de la Calidad de Atención de Salud/métodos , Indicadores de Calidad de la Atención de Salud/estadística & datos numéricos , Calidad de la Atención de Salud/normas , Actitud Frente a la Salud , Niño , Consenso , Atención a la Salud/normas , Familia , Femenino , Humanos , Masculino , Satisfacción del Paciente/estadística & datos numéricos , Pacientes , Médicos , Encuestas y CuestionariosRESUMEN
OBJECTIVE: To highlight the opportunities and challenges of developing and implementing performance outcome measures in rheumatology for accountability purposes. METHODS: We constructed a hypothetical performance outcome measure to demonstrate the benefits and challenges of designing quality measures that assess patient outcomes. We defined the data source, measure cohort, reporting period, period at risk, measure outcome, outcome attribution, risk adjustment, reliability and validity, and reporting approach. We discussed outcome measure challenges specific to rheumatology and to fields where patients have predominantly chronic, complex, ambulatory care-sensitive conditions. RESULTS: Our hypothetical outcome measure was a measure of rheumatoid arthritis disease activity intended for evaluating Accountable Care Organization performance. We summarized the components, benefits, challenges, and tradeoffs between feasibility and usability. We highlighted how different measure applications, such as for rapid cycle quality improvement efforts versus pay for performance programs, require different approaches to measure development and testing. We provided a summary table of key take-home points for clinicians and policymakers. CONCLUSION: Performance outcome measures are coming to rheumatology, and the most effective and meaningful measures can only be created through the close collaboration of patients, providers, measure developers, and policymakers. This study provides an overview of key issues and is intended to stimulate a productive dialogue between patients, practitioners, insurers, and government agencies regarding optimal performance outcome measure development.
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Evaluación de Resultado en la Atención de Salud/normas , Calidad de la Atención de Salud/normas , Enfermedades Reumáticas/terapia , Reumatología/normas , Sociedades Médicas/normas , Humanos , Estados UnidosRESUMEN
OBJECTIVE: To report and analyze quality improvement (QI) efforts that are aimed at increasing adherence to preventive guidelines for glucocorticoid-induced osteoporosis (GIOP). METHODS: We performed a PubMed literature search for full-length articles in English between 1966 and 2013, describing approaches for improving the quality of GIOP care. We reviewed articles using a structured approach and abstracted information on the patient population, study design, QI intervention, and primary outcome measures. A descriptive analysis was then performed. RESULTS: Literature search identified 661 articles; 38 were screened by abstract, 10 were identified for full review, and 7 were included. Two non-randomized, uncontrolled studies of system changes showed significant improvements in GIOP prevention: one increased concomitant prescriptions of glucocorticoids and calcium (37-49%, p < 0.0001) and vitamin D (38-53%, p < 0.0001) using a computerized order entry system; another used a dedicated clinical team to increase vitamin D levels from 19.5 to 29.4 (p = 0.001) and improve GIOP-related habits. Five articles described education-based interventions, including 3 randomized controlled trials (RCTs). Two non-significant RCTs focused on physicians, but one directed towards pharmacists and patients did increase calcium supplementation in the intervention vs. control arm (55.7% vs. 31.6%, p < 0.05). Two other non-randomized educational interventions did not show benefits. Comparison of articles was limited by the heterogeneity of the intervention methods and outcome measures used. CONCLUSION: None of the interventions produced robust changes, with overall adherence to GIOP guidelines remaining low. System-based interventions appeared more effective than education-based interventions, but a diverse array of factors likely needs to be addressed, requiring more randomized controlled trials and greater standardization of outcome measures.
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Glucocorticoides/efectos adversos , Osteoporosis/prevención & control , Mejoramiento de la Calidad , Calidad de la Atención de Salud , Humanos , Osteoporosis/inducido químicamenteRESUMEN
OBJECTIVE: Documentation of quality measures (QMs) in rheumatoid arthritis (RA) is used as a surrogate for measure of quality of care, but the association of this documentation with radiographic outcomes is uncertain. We examined documentation of RA QMs, for disease activity and functional status and the association with radiographic outcomes. METHODS: Data were analyzed for 438 RA patients in a longitudinal cohort with complete data on van der Heijde-modified Total Sharp Score (TSS). All rheumatologist (N = 18) notes in the electronic medical record during a 24-month period were reviewed for RA QMs. Any mention of disease activity categorized as low, moderate, or high was considered documentation of the QM for disease activity. Functional status QM documentation included any mention of the impact of RA on function. Change in TSS was quantified with progression defined as ≥1 unit per year. We compared percent of visits with an RA QM documented and mean change in TSS. RESULTS: The mean age in the cohort was 56.9 years, disease duration was 10.8 years, baseline DAS28 score was 3.8 (±1.6), 67.7% were seropositive, and 33.9% used a biologic DMARD. Radiographic progression was observed in 28.5%. Disease activity was documented for 29.0% of patient visits and functional status in 74.7%; neither had any significant relationship to mean TSS change (both P > 0.10). CONCLUSION: The documentation of RA QMs was infrequent and not associated with radiographic outcomes over 24 months.
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Antirreumáticos/uso terapéutico , Artritis Reumatoide/diagnóstico por imagen , Adulto , Anciano , Artritis Reumatoide/tratamiento farmacológico , Progresión de la Enfermedad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Indicadores de Calidad de la Atención de Salud , Calidad de la Atención de Salud , Radiografía , Índice de Severidad de la EnfermedadRESUMEN
OBJECTIVE: Children often develop arthritis secondary to Lyme disease; however, optimal treatment of Lyme arthritis in pediatric patients remains ill-defined. We sought to characterize the outcomes of a large cohort of children with Lyme arthritis treated using the approach recommended by the American Academy of Pediatrics and the Infectious Diseases Society of America. METHODS: Medical records of patients with Lyme arthritis seen by rheumatologists at a tertiary care children's hospital from 1997 to 2007 were reviewed. Patients were classified with antibiotic responsive or refractory arthritis based on absence or presence of persisting joint involvement 3 months after antibiotic initiation. Treatment regimens and outcomes in patients with refractory arthritis were analyzed. RESULTS: Of 99 children with Lyme arthritis, 76 had arthritis that responded fully to antibiotics, while 23 developed refractory arthritis. Most patients with refractory arthritis were successfully treated with nonsteroidal antiinflammatory drugs (6 patients), intraarticular steroid injections (4), or disease-modifying antirheumatic drugs (DMARD) (2). Five were lost to followup. Six patients with refractory arthritis were initially treated elsewhere and received additional antibiotic therapy, with no apparent benefit. Three subsequently required DMARD, while 3 had gradual resolution of arthritis without further therapy. Antibiotic responsiveness could not be predicted from our clinical or laboratory data. CONCLUSION: Lyme arthritis in children has an excellent prognosis. More than 75% of referred cases resolved with antibiotic therapy. Of patients with antibiotic refractory arthritis, none in whom followup data were available developed chronic arthritis, joint deformities, or recurrence of infection, supporting current treatment guidelines.
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Antiinfecciosos/uso terapéutico , Antiinflamatorios no Esteroideos/uso terapéutico , Antirreumáticos/uso terapéutico , Enfermedad de Lyme/tratamiento farmacológico , Adolescente , Borrelia burgdorferi , Niño , Preescolar , Protocolos Clínicos , Estudios de Cohortes , Femenino , Humanos , Masculino , Pronóstico , Estudios Retrospectivos , Estadísticas no Paramétricas , Resultado del TratamientoRESUMEN
Protein microarrays offer a new means by which to conduct quantitative profiling of disease-associated proteins. The knowledge gained may provide novel strategies for early detection, diagnosis and therapeutic intervention. A variety of sophisticated approaches, including gene arrays, sequencing consortiums and large-scale two-dimensional gel electrophoresis, continue to generate lists of proteins potentially linked to disease aetiology and progression. The challenge is to evaluate quantitatively promising lead protein candidates using matched normal and diseased cell populations. In contrast to the antibody array, the reverse phase protein microarrays (RPPA) do not require labelling of cellular protein lysates, and constitute a sensitive high throughput platform for marker screening, pathophysiology investigation and therapeutic monitoring. In this paper, examples will be provided using RPPAs in the study of the apoptotic signalling cascade and in the evaluation of the expression of organ-specific protein makers using microdissected human organ cell lysates configured as 'human body arrays'.