RESUMO
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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Artrite Juvenil/tratamento farmacológico , Inibidores de Janus Quinases/uso terapêutico , Piperidinas/uso terapêutico , Pirimidinas/uso terapêutico , Administração Oral , Adolescente , Criança , Pré-Escolar , Humanos , Resultado do TratamentoRESUMO
OBJECTIVES: To assess efficacy, pharmacokinetics (PK) and safety of intravenous (i.v.) golimumab in patients with polyarticular-course JIA (pc-JIA). METHODS: Children aged 2 to <18 years with active pc-JIA despite MTX therapy for ≥2 months received 80 mg/m2 golimumab at weeks 0, 4, then every 8 weeks through week 52 plus MTX weekly through week 28. The primary and major secondary endpoints were PK exposure and model-predicted steady-state area under the curve (AUCss) over an 8-week dosing interval at weeks 28 and 52, respectively. JIA ACR response and safety were also assessed. RESULTS: In total, 127 children were treated with i.v. golimumab. JIA ACR 30, 50, 70, and 90 response rates were 84%, 80%, 70% and 47%, respectively, at week 28 and were maintained through week 52. Golimumab serum concentrations and AUCss were 0.40 µg/ml and 399 µg â day/ml at week 28. PK exposure was maintained at week 52. Steady-state trough golimumab concentrations and AUCss were consistent across age categories and comparable to i.v. golimumab dosed 2 mg/kg in adults with rheumatoid arthritis. Golimumab antibodies and neutralizing antibodies were detected via a highly sensitive drug-tolerant assay in 31% (39/125) and 19% (24/125) of patients, respectively. Median trough golimumab concentration was lower in antibody-positive vs antibody-negative patients. Serious infections were reported in 6% of patients, including one death due to septic shock. CONCLUSION: Body surface area-based dosing of i.v. golimumab was well tolerated and provided adequate PK exposure for clinical efficacy in paediatric patients with active pc-JIA.ClinicalTrials.gov number NCT02277444.
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Anticorpos Monoclonais/administração & dosagem , Antirreumáticos/administração & dosagem , Artrite Juvenil/tratamento farmacológico , Artrite/tratamento farmacológico , Administração Intravenosa , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Resultado do TratamentoRESUMO
OBJECTIVE: To investigate the characteristics and risk factors of a novel parenchymal lung disease (LD), increasingly detected in systemic juvenile idiopathic arthritis (sJIA). METHODS: In a multicentre retrospective study, 61 cases were investigated using physician-reported clinical information and centralised analyses of radiological, pathological and genetic data. RESULTS: LD was associated with distinctive features, including acute erythematous clubbing and a high frequency of anaphylactic reactions to the interleukin (IL)-6 inhibitor, tocilizumab. Serum ferritin elevation and/or significant lymphopaenia preceded LD detection. The most prevalent chest CT pattern was septal thickening, involving the periphery of multiple lobes ± ground-glass opacities. The predominant pathology (23 of 36) was pulmonary alveolar proteinosis and/or endogenous lipoid pneumonia (PAP/ELP), with atypical features including regional involvement and concomitant vascular changes. Apparent severe delayed drug hypersensitivity occurred in some cases. The 5-year survival was 42%. Whole exome sequencing (20 of 61) did not identify a novel monogenic defect or likely causal PAP-related or macrophage activation syndrome (MAS)-related mutations. Trisomy 21 and young sJIA onset increased LD risk. Exposure to IL-1 and IL-6 inhibitors (46 of 61) was associated with multiple LD features. By several indicators, severity of sJIA was comparable in drug-exposed subjects and published sJIA cohorts. MAS at sJIA onset was increased in the drug-exposed, but was not associated with LD features. CONCLUSIONS: A rare, life-threatening lung disease in sJIA is defined by a constellation of unusual clinical characteristics. The pathology, a PAP/ELP variant, suggests macrophage dysfunction. Inhibitor exposure may promote LD, independent of sJIA severity, in a small subset of treated patients. Treatment/prevention strategies are needed.
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Artrite Juvenil/complicações , Pneumopatias/epidemiologia , Pulmão/diagnóstico por imagem , Biópsia , Criança , Pré-Escolar , Feminino , Seguimentos , Humanos , Incidência , Lactente , Pneumopatias/diagnóstico , Pneumopatias/etiologia , Masculino , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida/tendências , Tomografia Computadorizada por Raios X , Estados Unidos/epidemiologiaRESUMO
OBJECTIVE: To determine the efficacy in improving pain and health-related quality of life (HRQOL) of an online self-management program for adolescents with juvenile idiopathic arthritis (JIA). METHODS: Youth ages 12-18 years with JIA were recruited from 10 rheumatology clinics across the United States and randomized to complete an online self-management program (n = 144) or an online disease education program (n = 145). Participants in the self-management group worked through multimedia-based modules comprising psychoeducation, training in cognitive-behavioral coping skills and stress management, and other self-management topics over a 12-week period. Participants in the control group viewed a series of preselected quality educational websites about JIA over the same interval. Online content for both groups was made available in English and Spanish to facilitate inclusion of Hispanic participants. Blinded assessment of main outcomes (pain intensity, pain interference, and HRQOL) and process outcomes (disease knowledge, self-efficacy, pain coping, and emotional adjustment) occurred at baseline, posttreatment, and at 6- and 12-month postrandomization follow-up visits. RESULTS: Participants on average demonstrated significant improvements over the study period in the main outcomes, with no significant group differences in the degree of improvement. Effect sizes for these improvements were small. The amount of improvement in self-efficacy, emotional avoidance coping, disease knowledge, and emotional functioning in part predicted improvement in pain and HRQOL outcomes. CONCLUSIONS: Primarily self-directed online self-management training and online disease education comparably and modestly improve pain and HRQOL in youth with JIA.
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Artralgia/terapia , Artrite Juvenil/terapia , Educação de Pacientes como Assunto/normas , Avaliação de Programas e Projetos de Saúde , Qualidade de Vida , Autogestão , Telemedicina/normas , Adolescente , Criança , Feminino , Humanos , Masculino , Educação de Pacientes como Assunto/métodos , Autogestão/métodos , Telemedicina/métodosRESUMO
OBJECTIVE: This report aims to determine the safety, pharmacokinetics (PK) and efficacy of subcutaneous golimumab in active polyarticular-course juvenile idiopathic arthritis (polyJIA). METHODS: In this three-part randomised double-blinded placebo-controlled withdrawal trial, all patients received open-label golimumab (30 mg/m2 of body surface area; maximum: 50 mg/dose) every 4 weeks together with weekly methotrexate during Part 1 (weeks 0-16). Patients with at least 30% improvement per American College of Rheumatology Criteria for JIA (JIA ACR30) in Part 1 entered the double-blinded Part 2 (weeks 16-48) after 1:1 randomisation to continue golimumab or start placebo. In Part 3, golimumab was continued or could be restarted as in Part 1. The primary outcome was JIA flares in Part 2; secondary outcomes included JIA ACR50/70/90 responses, clinical remission, PK and safety. RESULTS: Among 173 patients with polyJIA enrolled, 89.0% (154/173) had a JIA ACR30 response and 79.2%/65.9%/36.4% demonstrated JIA ACR50/70/90 responses in Part 1. At week 48, the primary endpoint was not met as treatment groups had comparable JIA flare rates (golimumab vs placebo: 32/78=41% vs 36/76=47%; p=0.41), and rates of clinical remission were comparable (golimumab vs placebo: 10/78=12.8% vs 9/76=11.8%). Adverse event and serious adverse event rates were similar in the treatment groups during Part 2. Injection site reactions occurred with <1% of all injections. PK analysis confirmed adequate golimumab dosing for polyJIA. CONCLUSION: Although the primary endpoint was not met, golimumab resulted in rapid, clinically meaningful, improvement in children with active polyJIA. Golimumab was well tolerated, and no unexpected safety events occurred. CLINICAL TRIAL REGISTRATION: NCT01230827; Results.
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Anticorpos Monoclonais/administração & dosagem , Antirreumáticos/administração & dosagem , Artrite Juvenil/tratamento farmacológico , Artrite/tratamento farmacológico , Metotrexato/administração & dosagem , Adolescente , Artrite/patologia , Artrite Juvenil/patologia , Criança , Pré-Escolar , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Humanos , Injeções Subcutâneas , Masculino , Indução de Remissão , Exacerbação dos Sintomas , Resultado do TratamentoRESUMO
BACKGROUND: Juvenile idiopathic arthritis (JIA) comprises a heterogeneous group of conditions that can cause marked disability and diminished quality of life. Data on predictors of clinical response are insufficient to guide selection of the appropriate biologic agent for individual patients. This study aimed to investigate the propensity of S100A8/9 and S100A12 as predictive biomarkers of abatacept response in polyarticular-course juvenile idiopathic arthritis (pJIA). METHODS: Data from a phase 3 trial (NCT01844518) of subcutaneous abatacept in patients with active pJIA (n = 219) were used in this exploratory analysis. Association between biomarker levels at baseline and improvements in JIA-American College of Rheumatology (ACR) criteria responses or baseline disease activity (measured by Juvenile Arthritis Disease Activity Score in 27 joints using C-reactive protein [JADAS27-CRP]) were assessed. Biomarker level changes from baseline to month 4 were assessed for disease outcome prediction up to 21 months. RESULTS: At baseline, 158 patients had available biomarker samples. Lower baseline S100A8/9 levels (≤ 3295 ng/mL) were associated with greater odds of achieving JIA-ACR90 (odds ratio [OR]: 2.54 [95% confidence interval (CI): 1.25-5.18]), JIA-ACR100 (OR: 3.72 [95% CI: 1.48-9.37]), JIA-ACR inactive disease (ID; OR: 4.25 [95% CI: 2.03-8.92]), JADAS27-CRP ID (OR: 2.34 [95% CI: 1.02-5.39]) at month 4, and JIA-ACR ID (OR: 3.01 [95% CI: 1.57-5.78]) at month 16. Lower baseline S100A12 levels (≤ 176 ng/mL) were associated with greater odds of achieving JIA-ACR90 (OR: 2.52 [95% CI: 1.23-5.13]), JIA-ACR100 (OR: 3.68 [95% CI: 1.46-9.28]), JIA-ACR ID (OR: 3.66 [95% CI: 1.76-7.61]), JIA-ACR90 (OR: 2.03 [95% CI: 1.07-3.87]), JIA-ACR100 (OR: 2.14 [95% CI: 1.10-4.17]), and JIA-ACR ID (OR: 4.22 [95% CI: 2.15-8.29]) at month 16. From baseline to month 4, decreases in S100A8/9 and S100A12 generally exceeded 50% among JIA-ACR90/100/ID responders. CONCLUSION: Lower baseline levels of S100A8/9 and S100A12 proteins predicted better response to abatacept treatment than higher levels and may serve as early predictive biomarkers in pJIA. Decreases in these biomarker levels may also predict longer-term response to abatacept in pJIA.
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Abatacepte , Antirreumáticos , Artrite Juvenil , Biomarcadores , Humanos , Abatacepte/uso terapêutico , Artrite Juvenil/tratamento farmacológico , Artrite Juvenil/sangue , Masculino , Feminino , Criança , Biomarcadores/sangue , Antirreumáticos/uso terapêutico , Calgranulina B/sangue , Adolescente , Resultado do Tratamento , Pré-Escolar , Calgranulina A/sangue , Proteína S100A12/sangue , Proteínas S100/sangueRESUMO
OBJECTIVE: To investigate the frequency and trajectories of individual patients with polyarticular-course juvenile idiopathic arthritis (JIA) achieving novel composite end points on abatacept. METHODS: Data from a clinical trial of subcutaneous abatacept (NCT01844518) and a post hoc analysis of intravenous abatacept (NCT00095173) in patients with polyarticular-course JIA were included. Three end points were defined and evaluated: combined occurrence of low disease activity (LDA) measured by the Juvenile Arthritis Disease Activity Score; 50% improvement in American College of Rheumatology criteria for JIA (ACR50); and patient-reported outcomes. Patient-reported outcomes included visual analog scale score of minimal pain (pain-min) and Childhood Health Assessment Questionnaire disability index score of 0 (C-HAQ DI0). In this post hoc analysis, maintenance of month 13 and 21 end points (LDA+pain-min, LDA+C-HAQ DI0, and ACR50+pain-min) in those who achieved them at month 4 was determined. RESULTS: Composite end points (LDA+pain-min, LDA+C-HAQ DI0, and ACR50+pain-min) were achieved at month 4 (44.7%, 19.6%, and 58.9% of the 219 patients treated with subcutaneous abatacept, respectively). Of those who achieved LDA+pain-min at month 4, 84.7% (83 of 98) and 65.3% (64 of 98) maintained LDA+pain-min at months 13 and 21, respectively. The proportions of patients meeting LDA+pain-min outcomes increased from 44.7% (98 of 219) at month 4 to 54.8% (120 of 219) at month 21. The frequency of patients who met an LDA+C-HAQ DI score of 0 increased from 19.6% (43 of 219) at month 4 to 28.8% (63 of 219) at month 21. CONCLUSION: Among individual patients with polyarticular-course JIA treated with abatacept who achieved 1 of the combined clinical and patient-reported outcomes composite end points, many maintained them over 21 months of abatacept treatment.
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Antirreumáticos , Artrite Juvenil , Humanos , Criança , Abatacepte/efeitos adversos , Artrite Juvenil/diagnóstico , Artrite Juvenil/tratamento farmacológico , Antirreumáticos/efeitos adversos , Resultado do Tratamento , DorRESUMO
OBJECTIVE: To evaluate safety and effectiveness of adalimumab (ADA) in polyarticular-course juvenile idiopathic arthritis (JIA) in the STRIVE registry. METHODS: STRIVE enrolled patients with polyarticular-course JIA into 2 arms based on treatment with methotrexate (MTX) alone or ADA with/without MTX (ADA ± MTX). Adverse events (AEs) per 100 patient-years of observation time were analyzed by registry arm. Patients who entered the registry within 4 weeks of starting MTX or ADA ± MTX, defined as new users, were evaluated for change in disease activity assessed by the 27-joint Juvenile Arthritis Disease Activity Score with the C-reactive protein level (JADAS-27CRP ). RESULTS: At the 7-year cutoff date (June 1, 2016), data from 838 patients were available (MTX arm n = 301, ADA ± MTX arm n = 537). The most common AEs were nausea (10.3%), sinusitis (4.7%), and vomiting (4.3%) in the MTX arm and arthritis (3.9%), upper respiratory tract infection (3.5%), sinusitis, tonsillitis, and injection site pain (3.0% each) in the ADA ± MTX arm. Rates of serious infection were 1.5 events/100 patient-years in the MTX arm and 2.0 events/100 patient-years in the ADA ± MTX arm. AE and serious AE rates were similar in patients receiving ADA with versus without MTX. No deaths or malignancies were reported. New users in the ADA ± MTX arm showed a trend toward lower mean JADAS-27CRP compared with new users in the MTX arm in the first year of STRIVE. CONCLUSION: The STRIVE registry 7-year interim results support the idea that ADA ± MTX is well tolerated by most children. Registry median ADA exposure was 2.47 (interquartile range 1.0-3.6) years, with 42% of patients continuing ADA at the 7-year cutoff date.
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Adalimumab/uso terapêutico , Antirreumáticos/uso terapêutico , Artrite Juvenil/tratamento farmacológico , Sistema de Registros , Adolescente , Artrite Juvenil/complicações , Criança , Pré-Escolar , Quimioterapia Combinada , Feminino , Humanos , Masculino , Metotrexato/uso terapêutico , Uveíte/tratamento farmacológico , Uveíte/etiologiaRESUMO
OBJECTIVE: To document the need for additional Food and Drug Administration (FDA)-approved medications for the treatment of juvenile idiopathic arthritis (JIA). METHODS: The electronic medical records of JIA patients treated at Cincinnati Children's Hospital Medical Center (CCHMC) and data from JIA patients enrolled in the Childhood Arthritis and Rheumatology Research Alliance (CARRA) Registry were included in this study. Unmet medication need was defined in 2 ways: (a) the presence of chronically uncontrolled JIA, defined as a physician global assessment of JIA activity ≥3 (on a 0-10 scale, where 0 = inactive) OR ≥3 joints with active arthritis OR a patient global assessment of well-being ≥3 (on a 0-10 scale, where 0 = very well), despite sequential use of ≥2 biologic disease-modifying antirheumatic drugs (bDMARDs); and (b) the use of ≥1 bDMARD not approved for any JIA category. RESULTS: At CCHMC, 829 of 1,599 JIA patients (52%) were treated with ≥1 bDMARD, and 304 (19%) had been exposed to ≥1 unapproved bDMARD. In the CARRA Registry, 4,766 of 7,379 children (65%) had received ≥1 bDMARD, and 1,122 (15%) had been prescribed ≥1 unapproved bDMARD. Of those children treated with ≥2 bDMARDs for whom complete data were available, 52% (255 of 487) at CCHMC and 45% (527 of 1,159) in the CARRA Registry had chronically uncontrolled JIA despite the use of ≥2 bDMARDs. CONCLUSION: Despite the availability of bDMARDs currently approved for JIA, there is persistent need for additional therapies to control JIA signs and symptoms. Since FDA approval is critical to ensure access to bDMARDs, the study and licensing of new medications is critical to address the unmet medication need and to further improve JIA outcomes.
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Antirreumáticos/uso terapêutico , Artrite Juvenil/tratamento farmacológico , Necessidades e Demandas de Serviços de Saúde , Criança , Humanos , Sistema de RegistrosRESUMO
BACKGROUNDUndifferentiated systemic autoinflammatory diseases (USAIDs) present diagnostic and therapeutic challenges. Chronic interferon (IFN) signaling and cytokine dysregulation may identify diseases with available targeted treatments.METHODSSixty-six consecutively referred USAID patients underwent underwent screening for the presence of an interferon signature using a standardized type-I IFN-response-gene score (IRG-S), cytokine profiling, and genetic evaluation by next-generation sequencing.RESULTSThirty-six USAID patients (55%) had elevated IRG-S. Neutrophilic panniculitis (40% vs. 0%), basal ganglia calcifications (46% vs. 0%), interstitial lung disease (47% vs. 5%), and myositis (60% vs. 10%) were more prevalent in patients with elevated IRG-S. Moderate IRG-S elevation and highly elevated serum IL-18 distinguished 8 patients with pulmonary alveolar proteinosis (PAP) and recurrent macrophage activation syndrome (MAS). Among patients with panniculitis and progressive cytopenias, 2 patients were compound heterozygous for potentially novel LRBA mutations, 4 patients harbored potentially novel splice variants in IKBKG (which encodes NF-κB essential modulator [NEMO]), and 6 patients had de novo frameshift mutations in SAMD9L. Of additional 12 patients with elevated IRG-S and CANDLE-, SAVI- or Aicardi-Goutières syndrome-like (AGS-like) phenotypes, 5 patients carried mutations in either SAMHD1, TREX1, PSMB8, or PSMG2. Two patients had anti-MDA5 autoantibody-positive juvenile dermatomyositis, and 7 could not be classified. Patients with LRBA, IKBKG, and SAMD9L mutations showed a pattern of IRG elevation that suggests prominent NF-κB activation different from the canonical interferonopathies CANDLE, SAVI, and AGS.CONCLUSIONSIn patients with elevated IRG-S, we identified characteristic clinical features and 3 additional autoinflammatory diseases: IL-18-mediated PAP and recurrent MAS (IL-18PAP-MAS), NEMO deleted exon 5-autoinflammatory syndrome (NEMO-NDAS), and SAMD9L-associated autoinflammatory disease (SAMD9L-SAAD). The IRG-S expands the diagnostic armamentarium in evaluating USAIDs and points to different pathways regulating IRG expression.TRIAL REGISTRATIONClinicalTrials.gov NCT02974595.FUNDINGThe Intramural Research Program of the NIH, NIAID, NIAMS, and the Clinical Center.
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Doenças Autoimunes , Interferon Tipo I , Interleucina-18 , Síndrome de Ativação Macrofágica , Mutação , Paniculite , Proteinose Alveolar Pulmonar , Doenças Autoimunes/genética , Doenças Autoimunes/imunologia , Feminino , Humanos , Interferon Tipo I/genética , Interferon Tipo I/imunologia , Interleucina-18/genética , Interleucina-18/imunologia , Síndrome de Ativação Macrofágica/genética , Síndrome de Ativação Macrofágica/imunologia , Masculino , Paniculite/genética , Paniculite/imunologia , Proteinose Alveolar Pulmonar/genética , Proteinose Alveolar Pulmonar/imunologiaRESUMO
Poststreptococcal reactive arthritis (PSRA) is associated with prior group A ß-hemolytic streptococcal infection and has a reported annual incidence of 1 to 2 cases per 100,000 persons, approximately twice that of acute rheumatic fever (ARF) in the US. Children who present with reactive arthritis are not uncommon in a busy general pediatric practice in the US, whereas children who present with ARF are very rare. Distinguishing PSRA from ARF can be challenging because the symptoms and signs are similar, but the diseases differ in long-term therapy, follow-up evaluation, and prognosis. We review the diagnostic criteria for PSRA, the pertinent features of the 2015 ARF diagnostic guideline from the American Heart Association, and the major characteristics that differentiate PSRA from ARF.
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Febre Reumática/diagnóstico , Febre Reumática/etiologia , Infecções Estreptocócicas/complicações , Doença Aguda , Anti-Inflamatórios não Esteroides/uso terapêutico , Ecocardiografia Doppler , Humanos , Miocardite/etiologia , Miocardite/fisiopatologia , Febre Reumática/diagnóstico por imagem , Febre Reumática/tratamento farmacológico , Fatores de Risco , Estados UnidosRESUMO
IMPORTANCE: Specialized research networks are essential to achieve drug approvals for rare pediatric diseases. Such networks help realize the potential of global legislation enacted upon the recognition that most children are treated with drugs whose most beneficial dose and regimen have not been established in pediatric patients. The Pediatric Rheumatology Collaborative Study Group (PRCSG) is a North American clinical trials network that is specialized in the performance of clinical trials of new therapies for pediatric populations with rheumatic diseases. This review provides an overview of the strategies employed by this research network to achieve drug and biologic approvals for children with pediatric rheumatic diseases, particularly juvenile idiopathic arthritis. OBSERVATIONS: Clinical trial conduct in rare pediatric diseases has required global recruitment. Supported or led by the PRCSG, highly responsive, validated, composite measures have been established to assess drug efficacy. For pediatric orphan diseases with high disease burdens, specialized investigative sites and study designs are needed to complete adequately powered trials at the high standard necessary to enable drug labeling by regulatory agencies. Novel trial designs have been utilized for more efficient testing of innovative drug candidates. All these have been developed or co-developed by the PRCSG research network. CONCLUSIONS AND RELEVANCE: Specialized research networks in pediatric rheumatology, such as the PRCSG, have changed the landscape of available therapies and improved overall disease outcomes for children with pediatric rheumatic diseases.
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Antirreumáticos/uso terapêutico , Pesquisa Biomédica/organização & administração , Doenças Reumáticas/tratamento farmacológico , Reumatologia/organização & administração , Criança , Ensaios Clínicos como Assunto/métodos , Aprovação de Drogas/métodos , Aprovação de Drogas/organização & administração , Humanos , Projetos de PesquisaRESUMO
OBJECTIVE: To investigate the pharmacokinetics, effectiveness, and safety of subcutaneous (SC) abatacept treatment over 24 months in patients with polyarticular-course juvenile idiopathic arthritis (JIA). METHODS: In this phase III, open-label, international, multicenter, single-arm study, patients with polyarticular JIA (cohort 1, ages 6-17 years and cohort 2, ages 2-5 years) in whom treatment with ≥1 disease-modifying antirheumatic drug was unsuccessful received weight-tiered SC abatacept weekly: 10 to <25 kg (50 mg), 25 to <50 kg (87.5 mg), ≥50 kg (125 mg). Patients who had met the JIA-American College of Rheumatology 30% improvement criteria (achieved a JIA-ACR 30 response) at month 4 were given the option to continue SC abatacept to month 24. The primary end point was the abatacept steady-state serum trough concentration (Cminss ) in cohort 1 at month 4. Other outcome measures included JIA-ACR 30, 50, 70, 90, 100, and inactive disease status, the median Juvenile Arthritis Disease Activity Score in 71 joints using the C-reactive protein level (JADAS-71-CRP) over time, safety, and immunogenicity. RESULTS: The median abatacept Cminss at month 4 (primary end point) and at month 24 was above the target therapeutic exposure (10 µg/ml) in both cohorts. The percentage of patients who had achieved JIA-ACR 30, 50, 70, 90, or 100 responses or had inactive disease responses at month 4 (intent-to-treat population) was 83.2%, 72.8%, 52.6%, 28.3%, 14.5%, and 30.1%, respectively, in cohort 1 (n = 173) and 89.1%, 84.8%, 73.9%, 58.7%, 41.3%, and 50.0%, respectively, in cohort 2 (n = 46); the responses were maintained to month 24. The median (interquartile range) JADAS-71-CRP improved from baseline to month 4: cohort 1, from 21.0 (13.5, 30.3) to 4.6 (2.1, 9.4); cohort 2, from 18.1 (14.0, 23.1) to 2.1 (0.3, 4.4). Improvements were sustained to month 24, at which time 27 of 173 patients (cohort 1) and 11 of 22 patients (cohort 2) had achieved JADAS-71-CRP remission. No unexpected adverse events were reported; 4 of 172 patients (2.3%) in cohort 1 and 4 of 46 (8.7%) in cohort 2 developed anti-abatacept antibodies, with no clinical effects. CONCLUSION: Weight-stratified SC abatacept yielded target therapeutic exposures across age and weight groups, was well tolerated, and improved polyarticular JIA symptoms over 24 months.
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Abatacepte/administração & dosagem , Artrite Juvenil/tratamento farmacológico , Imunossupressores/administração & dosagem , Adolescente , Artrite Juvenil/imunologia , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Humanos , Injeções Subcutâneas , Masculino , Resultado do TratamentoRESUMO
BACKGROUND: Juvenile idiopathic arthritis (JIA) is the most common pediatric rheumatic disease and a leading cause of childhood disability. The objective of this study was to characterize the PK, safety, and taste acceptability of tofacitinib in patients with JIA. METHODS: This Phase 1, open-label, multiple-dose (twice daily [BID] for 5 days) study of tofacitinib in patients with active (≥ 5 joints) polyarticular course JIA was conducted from March 2013-December 2015. Patients were allocated to one of three age-based cohorts: Cohort 1, 12 to < 18 years; Cohort 2, 6 to < 12 years; and Cohort 3, 2 to < 6 years. Tofacitinib was administered according to age and body weight as tablets or oral solution (grape flavor). PK were assessed on Day 5; safety was assessed at screening, Day 1, and Day 5. Taste acceptability of the oral solution was evaluated. RESULTS: Twenty-six patients (age range 2-17 years) were enrolled: Cohort 1, N = 8; Cohort 2, N = 9; Cohort 3, N = 9; median tofacitinib doses were 5.0, 2.5, and 3.0 mg BID, respectively. The higher median tofacitinib dose in Cohort 3 versus Cohort 2 reflected implementation of an amended dosing scheme following an interim PK analysis after Cohort 2 recruitment. Geometric mean AUC at steady state (AUCtau) was 156.6 ngâ¢h/mL in Cohort 1, 118.8 ngâ¢h/mL in Cohort 2, and 142.5 ngâ¢h/mL in Cohort 3; Cmax (ng/mL) was 47.0, 41.7, and 66.2, respectively. Ctrough, Cmin, and t1/2 were similar in Cohorts 2 and 3, but higher in Cohort 1. Median time to Cmax (Tmax) was similar between cohorts. Apparent clearance and volume of distribution decreased with decreasing age. Tofacitinib was well tolerated, with no serious adverse events or discontinuations due to adverse events reported. Taste acceptability was confirmed. CONCLUSIONS: PK findings from this study in children with polyarticular course JIA established dosing regimens and acceptable taste for use in subsequent studies within the tofacitinib pediatric development program. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01513902 .
Assuntos
Artrite Juvenil/tratamento farmacológico , Piperidinas/farmacocinética , Inibidores de Proteínas Quinases/farmacocinética , Pirimidinas/farmacocinética , Pirróis/farmacocinética , Administração Oral , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Piperidinas/administração & dosagem , Piperidinas/efeitos adversos , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Pirimidinas/administração & dosagem , Pirimidinas/efeitos adversos , Pirróis/administração & dosagem , Pirróis/efeitos adversos , Paladar , Resultado do TratamentoRESUMO
The objective of this study was to assess the safety of adalimumab in patients aged 2 to <4 years old or ≥4 years old weighing <15 kg with moderately to severely active polyarticular juvenile idiopathic arthritis (JIA). Clinical effectiveness and pharmacokinetics (PK) of adalimumab were also evaluated. This was an international, multicenter, open-label, phase 3b study in 32 patients with active JIA that were treated with adalimumab 24 mg/m(2) (maximum = 20 mg/dose) every other week up to 120 weeks, with or without concomitant methotrexate. Adverse events (AEs) were summarized for completed visits. Efficacy endpoints included American College of Rheumatology pediatric (PedACR) 30/50/70/90 responses and JIA core components. Adalimumab serum trough concentrations were measured in a subset of patients. Among the patients, 88 % were female. Baseline mean age, weight, and JIA duration were 3 years, 13 kg, and 12 months, respectively; 39 % had elevated C-reactive protein. AE incidence rates included any AEs (29/32, 91 %), serious AEs (5/32, 16 %), infectious AEs (25/32, 78 %), and serious infections (3/32, 9 %). No deaths, malignancies, or opportunistic infections were reported. Growth was not adversely impacted. At week 96, 92 % of patients achieved PedACR30, and 77 % achieved PedACR70. Improvements in JIA core components were observed. Mean steady-state serum adalimumab trough concentrations were 7-8 µg/mL at weeks 12 and 24. Adalimumab was well tolerated in JIA patients aged 2 to <4 years old or ≥4 years old weighing <15 kg. The efficacy and PK of adalimumab were comparable to those seen in older JIA patients.
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Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/uso terapêutico , Antirreumáticos/efeitos adversos , Antirreumáticos/uso terapêutico , Artrite Juvenil/tratamento farmacológico , Adalimumab , Anticorpos Monoclonais Humanizados/farmacocinética , Antirreumáticos/farmacocinética , Artrite Juvenil/sangue , Biomarcadores/sangue , Proteína C-Reativa/metabolismo , Pré-Escolar , Relação Dose-Resposta a Droga , Quimioterapia Combinada , Europa (Continente) , Feminino , Humanos , Cooperação Internacional , Masculino , Metotrexato/uso terapêutico , Resultado do Tratamento , Estados UnidosRESUMO
OBJECTIVE: There are no validated tools for measuring disease activity in pediatric vasculitis. The Birmingham Vasculitis Activity Score (BVAS) is a valid disease activity tool in adult vasculitis. Version 3 (BVAS v.3) correlates well with physician's global assessment (PGA), treatment decision, and C-reactive protein in adults. The utility of BVAS v.3 in pediatric vasculitis is not known. We assessed the association of BVAS v.3 scores with PGA, treatment decision, and erythrocyte sedimentation rate (ESR) at diagnosis in pediatric antineutrophil cytoplasmic antibody-associated vasculitis (AAV). METHODS: Children with AAV diagnosed between 2004 and 2010 at all ARChiVe centers were eligible. BVAS v.3 scores were calculated with a standardized online tool (www.vasculitis.org). Spearman's rank correlation coefficient (r(s)) was used to test the strength of association between BVAS v.3 and PGA, treatment decision, and ESR. RESULTS: A total of 152 patients were included. The physician diagnosis of these patients was predominantly granulomatosis with polyangiitis (n = 99). The median BVAS v.3 score was 18.0 (range 0-40). The BVAS v.3 correlations were r(s) = 0.379 (95% CI 0.233 to 0.509) with PGA, r(s) = 0.521 (95% CI 0.393 to 0.629) with treatment decision, and r(s) = 0.403 (95% CI 0.253 to 0.533) with ESR. CONCLUSION: Applied to children with AAV, BVAS v.3 had a weak correlation with PGA and moderate correlation with both ESR and treatment decision. Prospective evaluation of BVAS v.3 and/or pediatric-specific modifications to BVAS v.3 may be required before it can be formalized as a disease activity assessment tool in pediatric AAV.
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Anticorpos Anticitoplasma de Neutrófilos/imunologia , Sistema de Registros/normas , Índice de Gravidade de Doença , Vasculite/diagnóstico , Vasculite/fisiopatologia , Adulto , Fatores Etários , Sedimentação Sanguínea , Proteína C-Reativa/metabolismo , Criança , Estudos de Coortes , Feminino , Granulomatose com Poliangiite/diagnóstico , Granulomatose com Poliangiite/imunologia , Granulomatose com Poliangiite/fisiopatologia , Humanos , Masculino , Pediatria/normas , Reprodutibilidade dos Testes , Estudos Retrospectivos , Reumatologia/normas , Vasculite/imunologiaRESUMO
OBJECTIVE: Granulomatosis with polyangiitis (Wegener's; GPA) and other antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV) are rare in childhood and are sometimes difficult to discriminate. We compared use of adult-derived classification schemes for GPA against validated pediatric criteria in the ARChiVe (A Registry for Childhood Vasculitis e-entry) cohort, a Childhood Arthritis and Rheumatology Research Alliance initiative. METHODS: Time-of-diagnosis data for children with physician (MD) diagnosis of AAV and unclassified vasculitis (UCV) from 33 US/Canadian centers were analyzed. The European Medicines Agency (EMA) classification algorithm and European League Against Rheumatism/Paediatric Rheumatology International Trials Organisation/Paediatric Rheumatology European Society (EULAR/PRINTO/PRES) and American College of Rheumatology (ACR) criteria for GPA were applied to all patients. Sensitivity and specificity were calculated (MD-diagnosis as reference). RESULTS: MD-diagnoses for 155 children were 100 GPA, 25 microscopic polyangiitis (MPA), 6 ANCA-positive pauciimmune glomerulonephritis, 3 Churg-Strauss syndrome, and 21 UCV. Of these, 114 had GPA as defined by EMA, 98 by EULAR/PRINTO/PRES, and 87 by ACR. Fourteen patients were identified as GPA by EULAR/PRINTO/PRES but not by ACR; 3 were identified as GPA by ACR but not EULAR/PRINTO/PRES. Using the EMA algorithm, 135 (87%) children were classifiable. The sensitivity of the EMA algorithm, the EULAR/PRINTO/PRES, and ACR criteria for classifying GPA was 90%, 77%, and 69%, respectively, with specificities of 56%, 62%, and 67%. The relatively poor sensitivity of the 2 criteria related to their inability to discriminate patients with MPA. CONCLUSION: EULAR/PRINTO/PRES was more sensitive than ACR criteria in classifying pediatric GPA. Neither classification system has criteria for MPA; therefore usefulness in discriminating patients in ARChiVe was limited. Even when using the most sensitive EMA algorithm, many children remained unclassified.
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Síndrome de Churg-Strauss/diagnóstico , Granulomatose com Poliangiite/classificação , Granulomatose com Poliangiite/diagnóstico , Poliangiite Microscópica/diagnóstico , Algoritmos , Criança , Síndrome de Churg-Strauss/classificação , Diagnóstico Diferencial , Feminino , Humanos , Masculino , Poliangiite Microscópica/classificação , Sistema de Registros , Sensibilidade e EspecificidadeRESUMO
OBJECTIVE: To determine whether adult disease severity subclassification systems for antineutrophil cytoplasmic antibody-associated vasculitis (AAV) are concordant with the decision to treat pediatric patients with cyclophosphamide (CYC). METHODS: We applied the European Vasculitis Study (EUVAS) and Wegener's Granulomatosis Etanercept Trial (WGET) disease severity subclassification systems to pediatric patients with AAV in A Registry for Childhood Vasculitis (ARChiVe). Modifications were made to the EUVAS and WGET systems to enable their application to this cohort of children. Treatment was categorized into 2 groups, "cyclophosphamide" and "no cyclophosphamide." Pearson's chi-square and Kendall's rank correlation coefficient statistical analyses were used to determine the relationship between disease severity subgroup and treatment at the time of diagnosis. RESULTS: In total, 125 children with AAV were studied. Severity subgroup was associated with treatment group in both the EUVAS (chi-square 45.14, p < 0.001, Kendall's tau-b 0.601, p < 0.001) and WGET (chi-square 59.33, p < 0.001, Kendall's tau-b 0.689, p < 0.001) systems; however, 7 children classified by both systems as having less severe disease received CYC, and 6 children classified as having severe disease by both systems did not receive CYC. CONCLUSION: In this pediatric AAV cohort, the EUVAS and WGET adult severity subclassification systems had strong correlation with physician choice of treatment. However, a proportion of patients received treatment that was not concordant with their assigned severity subclass.
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Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/tratamento farmacológico , Antirreumáticos/uso terapêutico , Ciclofosfamida/uso terapêutico , Imunossupressores/uso terapêutico , Adolescente , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/classificação , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/diagnóstico , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Padrões de Prática Médica , Índice de Gravidade de DoençaRESUMO
Characteristic features of the 12q14 microdeletion syndrome include low birth weight, failure to thrive, short stature, learning disabilities and Buschke-Ollendorff lesions in bone and skin. This report on two additional patients with this microdeletion syndrome emphasizes the rather constant and uniform phenotype encountered in this disorder and refines the critical region to a 2.61 Mb interval on 12q14.3, encompassing 10 RefSeq genes. We have previously shown that LEMD3 haploinsufficiency is responsible for the Buschke-Ollendorff lesions and now provide strong evidence that a heterozygous deletion of HMGA2 is causing the growth failure observed in this disorder. The identification of an intragenic HMGA2 deletion in a boy with proportionate short stature and the cosegregation of this deletion with reduced adult height in the extended family of the boy further underscore the role of HMGA2 in regulating human linear growth.
Assuntos
Estatura/genética , Transtornos Cromossômicos/genética , Cromossomos Humanos Par 12 , Proteína HMGA2/genética , Adolescente , Criança , Pré-Escolar , Deleção Cromossômica , Feminino , Deleção de Genes , Transtornos do Crescimento/genética , Humanos , Masculino , Fenótipo , SíndromeRESUMO
OBJECTIVE: To compare the criteria for Wegener's granulomatosis (WG) of the American College of Rheumatology (ACR) with those of the European League Against Rheumatism/Pediatric Rheumatology European Society (EULAR/PRES) in a cohort of children with WG and other antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAVs), and to describe the interval to diagnosis, presenting features, and initial treatment for WG. METHODS: Eligible patients had been diagnosed by site rheumatologists (termed the "MD diagnosis") since 2004. This diagnosis was used as a reference standard for sensitivity and specificity testing of the 2 WG classification criteria. Descriptive analyses were confined to ACR-classified WG patients. RESULTS: MD diagnoses of 117 patients (82 of whom were female) were WG (n = 76), microscopic polyangiitis (n = 17), ANCA-positive pauci-immune glomerulonephritis (n = 5), Churg-Strauss syndrome (n = 2), and unclassified vasculitis (n = 17). The sensitivities of the ACR and EULAR/PRES classification criteria for WG among the spectrum of AAVs were 68.4% and 73.6%, respectively, and the specificities were 68.3% and 73.2%, respectively. Two more children were identified as having WG by the EULAR/PRES criteria than by the ACR criteria. For the 65 ACR-classified WG patients, the median age at diagnosis was 14.2 years (range 4-17 years), and the median interval from symptom onset to diagnosis was 2.7 months (range 0-49 months). The most frequent presenting features by organ system were constitutional (89.2%), pulmonary (80.0%), ear, nose, and throat (80.0%), and renal (75.4%). Fifty-four patients (83.1%) commenced treatment with the combination of corticosteroids and cyclophosphamide, with widely varying regimens; the remainder received methotrexate alone (n = 1), corticosteroids alone (n = 4), or a combination (n = 6). CONCLUSION: The EULAR/PRES criteria minimally improved diagnostic sensitivity and specificity for WG among a narrow spectrum of children with AAVs. Diagnostic delays may result from poor characterization of childhood WG. Initial therapy varied considerably among participating centers.