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1.
Clin Immunol ; 194: 9-18, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29928998

RESUMO

Systemic juvenile idiopathic arthritis (sJIA) is a childhood rheumatic disease of unknown origin. Dysregulated innate immunity is implicated in disease pathology. We investigated if IL-1 inhibition affects circulating cytokines and monocyte gene expression. CD14+ monocytes from patients in the RAPPORT trial were analyzed by RT-PCR for expression of IL1B and transcription factors associated with monocyte activation. Serum IL-1ra decreased with treatment, and IL-18BP transiently increased. Serum levels of IL-1ß, IL-6, IL-10 and IL-18 were unchanged. IRF5 and STAT6 were decreased, and PPARG was increased, independent of clinical response, and may represent a skew toward a PPARG-driven M2-like phenotype. IL1B expression was decreased in early clinical responders. A transient increase in STAT1, and a decrease in SOCS1 preceded the reduction in IL1B in early clinical responders. Changes in IL1B/STAT1/SOCS1 could be associated with crosstalk between IL-1 and IFN pathways in sJIA. These transcriptional changes might be useful as drug response biomarkers.


Assuntos
Artrite Juvenil/tratamento farmacológico , Interleucina-1/antagonistas & inibidores , Monócitos/efeitos dos fármacos , Proteínas Recombinantes de Fusão/uso terapêutico , Artrite Juvenil/imunologia , Ensaios Clínicos como Assunto , Humanos , Imunidade Inata/efeitos dos fármacos , Imunidade Inata/imunologia , Interleucina-1/imunologia , Interleucina-1beta/imunologia , Monócitos/imunologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Fator de Transcrição STAT1/imunologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Proteína 1 Supressora da Sinalização de Citocina/imunologia
2.
Proc Natl Acad Sci U S A ; 112(52): 15970-5, 2015 Dec 29.
Artigo em Inglês | MEDLINE | ID: mdl-26598658

RESUMO

Systemic juvenile idiopathic arthritis (sJIA) is an often severe, potentially life-threatening childhood inflammatory disease, the pathophysiology of which is poorly understood. To determine whether genetic variation within the MHC locus on chromosome 6 influences sJIA susceptibility, we performed an association study of 982 children with sJIA and 8,010 healthy control subjects from nine countries. Using meta-analysis of directly observed and imputed SNP genotypes and imputed classic HLA types, we identified the MHC locus as a bona fide susceptibility locus with effects on sJIA risk that transcended geographically defined strata. The strongest sJIA-associated SNP, rs151043342 [P = 2.8 × 10(-17), odds ratio (OR) 2.6 (2.1, 3.3)], was part of a cluster of 482 sJIA-associated SNPs that spanned a 400-kb region and included the class II HLA region. Conditional analysis controlling for the effect of rs151043342 found that rs12722051 independently influenced sJIA risk [P = 1.0 × 10(-5), OR 0.7 (0.6, 0.8)]. Meta-analysis of imputed classic HLA-type associations in six study populations of Western European ancestry revealed that HLA-DRB1*11 and its defining amino acid residue, glutamate 58, were strongly associated with sJIA [P = 2.7 × 10(-16), OR 2.3 (1.9, 2.8)], as was the HLA-DRB1*11-HLA-DQA1*05-HLA-DQB1*03 haplotype [6.4 × 10(-17), OR 2.3 (1.9, 2.9)]. By examining the MHC locus in the largest collection of sJIA patients assembled to date, this study solidifies the relationship between the class II HLA region and sJIA, implicating adaptive immune molecules in the pathogenesis of sJIA.


Assuntos
Artrite Juvenil/genética , Predisposição Genética para Doença/genética , Cadeias HLA-DRB1/genética , Antígenos de Histocompatibilidade Classe II/genética , Polimorfismo de Nucleotídeo Único , Criança , Frequência do Gene , Genótipo , Haplótipos , Humanos , Desequilíbrio de Ligação , Metanálise como Assunto , Razão de Chances , Fatores de Risco
3.
Ann Rheum Dis ; 76(5): 906-913, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-27927641

RESUMO

OBJECTIVES: Juvenile idiopathic arthritis (JIA) is a heterogeneous group of conditions unified by the presence of chronic childhood arthritis without an identifiable cause. Systemic JIA (sJIA) is a rare form of JIA characterised by systemic inflammation. sJIA is distinguished from other forms of JIA by unique clinical features and treatment responses that are similar to autoinflammatory diseases. However, approximately half of children with sJIA develop destructive, long-standing arthritis that appears similar to other forms of JIA. Using genomic approaches, we sought to gain novel insights into the pathophysiology of sJIA and its relationship with other forms of JIA. METHODS: We performed a genome-wide association study of 770 children with sJIA collected in nine countries by the International Childhood Arthritis Genetics Consortium. Single nucleotide polymorphisms were tested for association with sJIA. Weighted genetic risk scores were used to compare the genetic architecture of sJIA with other JIA subtypes. RESULTS: The major histocompatibility complex locus and a locus on chromosome 1 each showed association with sJIA exceeding the threshold for genome-wide significance, while 23 other novel loci were suggestive of association with sJIA. Using a combination of genetic and statistical approaches, we found no evidence of shared genetic architecture between sJIA and other common JIA subtypes. CONCLUSIONS: The lack of shared genetic risk factors between sJIA and other JIA subtypes supports the hypothesis that sJIA is a unique disease process and argues for a different classification framework. Research to improve sJIA therapy should target its unique genetics and specific pathophysiological pathways.


Assuntos
Artrite Juvenil/genética , Cromossomos Humanos Par 1/genética , Complexo Principal de Histocompatibilidade/genética , Artrite Juvenil/tratamento farmacológico , Estudos de Casos e Controles , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Polimorfismo de Nucleotídeo Único , Fatores de Risco
4.
Ann Rheum Dis ; 75(3): 481-9, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26865703

RESUMO

To develop criteria for the classification of macrophage activation syndrome (MAS) in patients with systemic juvenile idiopathic arthritis (JIA). A multistep process, based on a combination of expert consensus and analysis of real patient data, was conducted. A panel of 28 experts was first asked to classify 428 patient profiles as having or not having MAS, based on clinical and laboratory features at the time of disease onset. The 428 profiles comprised 161 patients with systemic JIA-associated MAS and 267 patients with a condition that could potentially be confused with MAS (active systemic JIA without evidence of MAS, or systemic infection). Next, the ability of candidate criteria to classify individual patients as having MAS or not having MAS was assessed by evaluating the agreement between the classification yielded using the criteria and the consensus classification of the experts. The final criteria were selected in a consensus conference. Experts achieved consensus on the classification of 391 of the 428 patient profiles (91.4%). A total of 982 candidate criteria were tested statistically. The 37 best-performing criteria and 8 criteria obtained from the literature were evaluated at the consensus conference. During the conference, 82% consensus among experts was reached on the final MAS classification criteria. In validation analyses, these criteria had a sensitivity of 0.73 and a specificity of 0.99. Agreement between the classification (MAS or not MAS) obtained using the criteria and the original diagnosis made by the treating physician was high (κ=0.76). We have developed a set of classification criteria for MAS complicating systemic JIA and provided preliminary evidence of its validity. Use of these criteria will potentially improve understanding of MAS in systemic JIA and enhance efforts to discover effective therapies, by ensuring appropriate patient enrollment in studies.


Assuntos
Artrite Juvenil/complicações , Síndrome de Ativação Macrofágica/classificação , Criança , Técnica Delphi , Europa (Continente) , Humanos , Modelos Logísticos , Síndrome de Ativação Macrofágica/complicações , Síndrome de Ativação Macrofágica/diagnóstico , Reprodutibilidade dos Testes , Reumatologia , Sociedades Médicas , Estados Unidos
5.
Ann Rheum Dis ; 73(3): 557-66, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23436914

RESUMO

OBJECTIVE: Participants in the Atherosclerosis Prevention in Paediatric Lupus Erythematosus (APPLE) trial were randomised to placebo or atorvastatin for 36 months. The primary endpoint, reduced carotid intima medial thickness (CIMT) progression, was not met but atorvastatin-treated participants showed a trend of slower CIMT progression. Post-hoc analyses were performed to assess subgroup benefit from atorvastatin therapy. METHODS: Subgroups were prespecified and defined by age (> or ≤15.5 years), systemic lupus erythematosus (SLE) duration (> or ≤24 months), pubertal status (Tanner score≥4 as post-pubertal or <4 as pre-pubertal), low density lipoprotein cholesterol (LDL) (≥ or <110 mg/dl) and high-sensitivity C reactive protein (hsCRP) (≥ or <1.5 mg/l). A combined subgroup (post-pubertal and hsCRP≥1.5 mg/l) was compared to all others. Longitudinal linear mixed-effects models were developed using 12 CIMT and other secondary APPLE outcomes (lipids, hsCRP, disease activity and damage, and quality of life). Three way interaction effects were assessed for models. RESULTS: Significant interaction effects with trends of less CIMT progression in atorvastatin-treated participants were observed in pubertal (3 CIMT segments), high hsCRP (2 CIMT segments), and the combined high hsCRP and pubertal group (5 CIMT segments). No significant treatment effect trends were observed across subgroups defined by age, SLE duration, LDL for CIMT or other outcome measures. CONCLUSIONS: Pubertal status and higher hsCRP were linked to lower CIMT progression in atorvastatin-treated subjects, with most consistent decreases in CIMT progression in the combined pubertal and high hsCRP group. While secondary analyses must be interpreted cautiously, results suggest further research is needed to determine whether pubertal lupus patients with high CRP benefit from statin therapy. TRIAL REGISTRATION: Clinical Trials.gov Identifier: NCT00065806.


Assuntos
Aterosclerose/prevenção & controle , Proteína C-Reativa/metabolismo , Ácidos Heptanoicos/uso terapêutico , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Pirróis/uso terapêutico , Adolescente , Fatores Etários , Aterosclerose/diagnóstico por imagem , Aterosclerose/etiologia , Atorvastatina , Biomarcadores/sangue , Artérias Carótidas/diagnóstico por imagem , Artérias Carótidas/patologia , Espessura Intima-Media Carotídea , LDL-Colesterol/sangue , Progressão da Doença , Método Duplo-Cego , Feminino , Humanos , Lúpus Eritematoso Sistêmico/sangue , Lúpus Eritematoso Sistêmico/complicações , Masculino , Estudos Prospectivos , Puberdade , Resultado do Tratamento
6.
Arthritis Rheum ; 64(6): 2012-21, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22183975

RESUMO

OBJECTIVE: To determine whether aggressive treatment initiated early in the course of rheumatoid factor (RF)-positive or RF-negative polyarticular juvenile idiopathic arthritis (JIA) can induce clinical inactive disease within 6 months. METHODS: Between May 2007 and October 2010, a multicenter, prospective, randomized, double-blind, placebo-controlled trial of 2 aggressive treatments was conducted in 85 children ages 2-16 years with polyarticular JIA of <12 months' duration. Patients received either methotrexate (MTX) 0.5 mg/kg/week (maximum 40 mg) subcutaneously, etanercept 0.8 mg/kg/week (maximum 50 mg), and prednisolone 0.5 mg/kg/day (maximum 60 mg) tapered to 0 by 17 weeks (arm 1), or MTX (same dosage as arm 1), etanercept placebo, and prednisolone placebo (arm 2). The primary outcome measure was clinical inactive disease at 6 months. An exploratory phase determined the rate of clinical remission on medication (6 months of continuous clinical inactive disease) at 12 months. RESULTS: By 6 months, clinical inactive disease had been achieved in 17 (40%) of 42 patients in arm 1 and 10 (23%) of 43 patients in arm 2 (χ(2) = 2.91, P = 0.088). After 12 months, clinical remission on medication was achieved in 9 patients in arm 1 and 3 patients in arm 2 (P = 0.053). There were no significant interarm differences in adverse events. CONCLUSION: Although this study did not meet its primary end point, early aggressive therapy in this cohort of children with recent-onset polyarticular JIA resulted in clinical inactive disease by 6 months and clinical remission on medication within 12 months of treatment in substantial proportions of patients in both arms.


Assuntos
Antirreumáticos/uso terapêutico , Artrite Juvenil/tratamento farmacológico , Imunoglobulina G/uso terapêutico , Metotrexato/uso terapêutico , Prednisolona/uso terapêutico , Receptores do Fator de Necrose Tumoral/uso terapêutico , Adolescente , Antirreumáticos/administração & dosagem , Criança , Pré-Escolar , Método Duplo-Cego , Esquema de Medicação , Etanercepte , Feminino , Humanos , Imunoglobulina G/administração & dosagem , Estudos Longitudinais , Masculino , Metotrexato/administração & dosagem , Prednisolona/administração & dosagem , Estudos Prospectivos , Receptores do Fator de Necrose Tumoral/administração & dosagem , Indução de Remissão , Resultado do Tratamento
7.
Arthritis Rheum ; 63(2): 545-55, 2011 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-21280009

RESUMO

OBJECTIVE: To examine the safety and efficacy of the interleukin-1 (IL-1) receptor antagonist anakinra as first-line therapy for systemic juvenile idiopathic arthritis (JIA). METHODS: Patients with systemic JIA receiving anakinra as part of initial disease-modifying antirheumatic drug (DMARD) therapy were identified from 11 centers in 4 countries. Medical records were abstracted using a standardized instrument, and resulting data were analyzed to characterize concomitant therapies, clinical course, adverse events, and predictors of outcome. RESULTS: Among 46 patients meeting inclusion criteria, anakinra monotherapy was used in 10 patients (22%), while 67% received corticosteroids and 33% received additional DMARDs. Outcomes were evaluated at a median followup interval of 14.5 months. Fever and rash resolved within 1 month in >95% of patients, while C-reactive protein and ferritin normalized within this interval in >80% of patients. Active arthritis persisted at 1 month in 39% of patients, at 3 months in 27%, and at >6 months of followup in 11%. Approximately 60% of patients, including 8 of 10 receiving anakinra monotherapy, attained a complete response without escalation of therapy. Disease characteristics and treatment were similar in partial and complete responders, except that partial responders were markedly younger at onset (median age 5.2 years versus 10.2 years; P = 0.004). Associated adverse events included documented bacterial infection in 2 patients and hepatitis in 1 patient. Tachyphylaxis was not observed. CONCLUSION: Anakinra as first-line therapy for systemic JIA was associated with rapid resolution of systemic symptoms and prevention of refractory arthritis in almost 90% of patients during the interval examined. These results justify further study of IL-1 inhibition as first-line, rather than rescue, therapy in systemic JIA.


Assuntos
Antirreumáticos/uso terapêutico , Artrite Juvenil/tratamento farmacológico , Proteína Antagonista do Receptor de Interleucina 1/uso terapêutico , Adolescente , Artrite Juvenil/sangue , Artrite Juvenil/fisiopatologia , Sedimentação Sanguínea , Proteína C-Reativa/análise , Criança , Pré-Escolar , Quimioterapia Combinada , Feminino , Glucocorticoides/uso terapêutico , Humanos , Lactente , Cooperação Internacional , Articulações/efeitos dos fármacos , Articulações/fisiopatologia , Masculino , Resultado do Tratamento
8.
Arthritis Rheum ; 62(11): 3259-64, 2010 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-20669280

RESUMO

OBJECTIVE: To evaluate the effects of long-term etanercept treatment, with or without methotrexate, on growth in children with selected categories of juvenile idiopathic arthritis (JIA). METHODS: We conducted a 3-year, open-label, nonrandomized registry of 594 patients with polyarticular or systemic JIA treated with etanercept only, etanercept plus methotrexate, or methotrexate only. Height, weight, and body mass index (BMI) were assessed at baseline and at years 1, 2, and 3, using percentiles derived from US Centers for Disease Control and Prevention standardized growth charts. RESULTS: Statistically significant increases in the mean height percentiles from baseline were observed in etanercept-treated patients at year 3 (4.8 percentile points) and in patients treated with etanercept plus methotrexate at years 1, 2, and 3 (2.4, 3.3, and 5.6 percentile points, respectively). Statistically significant increases from baseline in the mean weight percentiles were observed at years 1, 2, and 3 in both the etanercept group (7.4, 10.0, and 13.0 percentile points) and the etanercept-plus-methotrexate group (2.9, 6.9, and 8.4 percentile points, respectively). Statistically significant increases from baseline in the mean BMI percentiles were observed in both the etanercept group (range 9.6-13.8 percentile points) and the etanercept-plus-methotrexate group (range 2.1-5.2 percentile points). The mean height, weight, and BMI percentiles did not change significantly in patients in the methotrexate-only group. CONCLUSION: Etanercept treatment, with or without methotrexate, may contribute to the restoration of normal growth in children with JIA.


Assuntos
Artrite Juvenil/terapia , Estatura/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Imunoglobulina G/efeitos adversos , Adolescente , Antirreumáticos/efeitos adversos , Antirreumáticos/uso terapêutico , Índice de Massa Corporal , Criança , Quimioterapia Combinada , Etanercepte , Feminino , Humanos , Imunoglobulina G/uso terapêutico , Masculino , Metotrexato/uso terapêutico , Receptores do Fator de Necrose Tumoral/antagonistas & inibidores , Receptores do Fator de Necrose Tumoral/uso terapêutico , Sistema de Registros , Resultado do Tratamento
10.
J Rheumatol ; 46(2): 190-197, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30275259

RESUMO

OBJECTIVE: To revise the current juvenile idiopathic arthritis (JIA) International League of Associations for Rheumatology (ILAR) classification criteria with an evidence-based approach, using clinical and routine laboratory measures available worldwide, to identify homogeneous clinical groups and to distinguish those forms of chronic arthritis typically seen only in children from the childhood counterpart of adult diseases. METHODS: The overall project consists of 4 steps. This work represents Step 1, a Delphi Web-based consensus and Step 2, an international nominal group technique (NGT) consensus conference for the new provisional Pediatric Rheumatology International Trials Organization JIA classification criteria. A future large data collection of at least 1000 new-onset JIA patients (Step 3) followed by analysis and NGT consensus (Step 4) will provide data for the evidence-based validation of the JIA classification criteria. RESULTS: In Step 1, three Delphi rounds of interactions were implemented to revise the 7 ILAR JIA categories. In Step 2, forty-seven questions with electronic voting were implemented to derive the new proposed criteria. Four disorders were proposed: (a) systemic JIA; (b) rheumatoid factor-positive JIA; (c) enthesitis/spondylitis-related JIA; and (d) early-onset antinuclear antibody-positive JIA. The other forms were gathered under the term "others." These will be analyzed during the prospective data collection using a list of descriptors to see whether the clustering of some of them could identify homogeneous entities. CONCLUSION: An international consensus was reached to identify different proposed homogeneous chronic disorders that fall under the historical term JIA. These preliminary criteria will be formally validated with a dedicated project.


Assuntos
Artrite Juvenil/classificação , Consenso , Reumatologia/métodos , Adulto , Anticorpos Antinucleares , Criança , Coleta de Dados , Humanos , Agências Internacionais , Fator Reumatoide , Sociedades Médicas , Espondilite , Terminologia como Assunto
11.
Curr Opin Rheumatol ; 20(5): 613-8, 2008 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-18698187

RESUMO

PURPOSE OF REVIEW: The purpose of this review is to summarize the recent data on biologic therapies in juvenile rheumatoid arthritis. The armamentarium for treatment of juvenile idiopathic arthritis is expanding at a rapid rate, and improved physical and functional outcomes are anticipated. New data from large prospective randomized trials have demonstrated efficacy of anti-tumor necrosis factor agents and a costimulator signal inhibitor. RECENT FINDINGS: The results of a pivotal trial of infliximab in polyarticular juvenile idiopathic arthritis suggested efficacy, but the primary outcome was not significantly different from placebo. Important information regarding dosing in children was obtained, however. A pivotal trial of adalimumab did prove efficacy, and resulted in U.S. Food and Drug Administration (FDA) approval. The monoclonal antibodies to tumor necrosis factor appear to be more effective in treating chronic uveitis associated with juvenile idiopathic arthritis than etanercept. Anti-IL-1 and anti-IL-6 therapy, particularly for systemic disease patients, looks very promising, as well. The costimulation modifier abatacept was shown to be effective and relatively well tolerated in the short term, also resulting in FDA approval this year. Continued experience with these agents and appropriate systems-based methods such as formal registries, to complement existing FDA procedures for monitoring safety, will improve our ability to identify short-term and long-term toxicities of these new agents. SUMMARY: As experience is gained, and longer-term safety is demonstrated, it is likely that biologics will be introduced as therapy earlier in the course of patients who inadequately respond to conventional disease-modifying antirheumatic drugs.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Antirreumáticos/uso terapêutico , Artrite Juvenil/tratamento farmacológico , Produtos Biológicos/uso terapêutico , Criança , Humanos
12.
Arthritis Care Res (Hoboken) ; 70(3): 420-427, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-28544820

RESUMO

OBJECTIVE: Prompt treatment for lupus is important to prevent morbidity. A potential barrier to early treatment of pediatric lupus is delayed presentation to a pediatric rheumatologist. To better understand factors contributing to delayed presentation among pediatric lupus patients, we examined differences in demographic and clinical characteristics of lupus patients within the Childhood Arthritis and Rheumatology Research Alliance (CARRA) Legacy Registry with regard to time between symptom onset and presentation to a pediatric rheumatologist. METHODS: We analyzed data from 598 CARRA Legacy Registry participants for differences between those who presented early (within <1 month of symptom onset), between 1-3 months (typical presentation), with moderate delays (3-12 months), and with severe delays (≥1 year). Factors associated with early presentation, moderate delay, and severe delay were determined by multinomial logistic regression. RESULTS: Forty-four percent of patients presented early, while 23% had moderate delays and 9% had severe delays. Family history of lupus, absence of discoid rash, and location in a state with a higher density of pediatric rheumatologists were associated with earlier presentation. Younger age, low household income (<$25,000 per year), and a family history of lupus were associated with severe delay. CONCLUSION: Delays to care ≥1 year exist in a notable minority of pediatric lupus patients from the CARRA Legacy Registry. In this large and diverse sample of patients, access to care and family resources played an important role in predicting time to presentation to a pediatric rheumatologist.


Assuntos
Lúpus Eritematoso Sistêmico/terapia , Pediatria/métodos , Reumatologia/métodos , Tempo para o Tratamento , Adolescente , Idade de Início , Criança , Diagnóstico Tardio , Feminino , Humanos , Lúpus Eritematoso Sistêmico/diagnóstico , Lúpus Eritematoso Sistêmico/epidemiologia , Masculino , América do Norte/epidemiologia , Valor Preditivo dos Testes , Sistema de Registros , Estudos Retrospectivos , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento
13.
Arthritis Rheumatol ; 70(8): 1319-1330, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29609200

RESUMO

OBJECTIVE: To determine whether systemic juvenile idiopathic arthritis (JIA) susceptibility loci that were identified by candidate gene studies demonstrate association with systemic JIA in the largest study population assembled to date. METHODS: Single-nucleotide polymorphisms (SNPs) from 11 previously reported systemic JIA risk loci were examined for association in 9 populations, including 770 patients with systemic JIA and 6,947 controls. The effect of systemic JIA-associated SNPs on gene expression was evaluated in silico in paired whole genome and RNA sequencing data from the lymphoblastoid cell lines (LCLs) of 373 European subjects from the 1000 Genomes Project. Responses of systemic JIA-associated SNPs to anakinra treatment were evaluated in 38 US patients for whom treatment response data were available. RESULTS: We found no association between the previously reported 26 SNPs and systemic JIA. Expanded analysis of the regions containing the 26 SNPs revealed only 1 significant association: the promoter region of IL1RN (P < 1 × 10-4 ). Systemic JIA-associated SNPs correlated with IL1RN expression in LCLs, with an inverse correlation between systemic JIA risk and IL1RN expression. The presence of homozygous IL1RN high expression alleles correlated strongly with a lack of response to anakinra therapy (odds ratio 28.7 [95% confidence interval 3.2-255.8]). CONCLUSION: In our study, IL1RN was the only candidate locus associated with systemic JIA. The implicated SNPs are among the strongest known determinants of IL1RN and interleukin-1 receptor antagonist levels, linking low expression with increased systemic JIA risk. Homozygous high expression alleles predicted nonresponsiveness to anakinra therapy, making them ideal candidate biomarkers to guide systemic JIA treatment. This study is an important first step toward the personalized treatment of systemic JIA.


Assuntos
Antirreumáticos/farmacologia , Artrite Juvenil/genética , Predisposição Genética para Doença/genética , Proteína Antagonista do Receptor de Interleucina 1/farmacologia , Alelos , Artrite Juvenil/tratamento farmacológico , Estudos de Casos e Controles , Criança , Feminino , Estudo de Associação Genômica Ampla , Humanos , Proteína Antagonista do Receptor de Interleucina 1/efeitos dos fármacos , Proteína Antagonista do Receptor de Interleucina 1/genética , Masculino , Razão de Chances , Variantes Farmacogenômicos/efeitos dos fármacos , Variantes Farmacogenômicos/genética , Polimorfismo de Nucleotídeo Único/efeitos dos fármacos , Polimorfismo de Nucleotídeo Único/genética , Regiões Promotoras Genéticas/genética
14.
Rheum Dis Clin North Am ; 33(3): 441-70, vi, 2007 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-17936173

RESUMO

Juvenile idiopathic arthritis (JIA), a term referring to a group of disorders characterized by chronic arthritis, is the most common chronic rheumatic illness in children and is a significant cause of short- and long-term disability. This article discusses the classification, differential diagnosis, and treatment of JIA.

15.
Pediatr Rheumatol Online J ; 15(1): 30, 2017 Apr 17.
Artigo em Inglês | MEDLINE | ID: mdl-28416023

RESUMO

BACKGROUND: Herein we describe the history, design, and rationale of the new Childhood Arthritis and Rheumatology Research Alliance (CARRA) Registry and present the characteristics of patients with juvenile idiopathic arthritis (JIA) enrolled in the first 12 months of operation. METHODS: The CARRA Registry began prospectively collecting data in the United States and Canada in July 2015 to evaluate the safety of therapeutic agents in persons with childhood-onset rheumatic disease, initially restricted to JIA. Secondary objectives include the evaluation of disease outcomes and their associations with medication use and other factors. Data are collected every 6 months and include clinical assessments, detailed medication use, patient-reported outcomes, and safety events. Follow-up is planned for at least 10 years for each participant and is facilitated by a telephone call center. RESULTS: As of July 2016, 1192 patients with JIA were enrolled in the CARRA Registry at 49 clinical sites. At enrollment, their median age was 12.4 years old and median disease duration was 2.6 years. Owing to preferential enrollment, patients with systemic JIA (13%) and with a polyarticular course (75%) were over-represented compared to patients in typical clinical practice. Approximately 49% were currently using biologic agents and ever use of oral glucocorticoids was common (47%). The CARRA Registry provides safety surveillance data to pharmaceutical companies to satisfy their regulatory requirements, and several independently-funded sub-studies that use the Registry infrastructure are underway. CONCLUSION: The new CARRA Registry successfully enrolled nearly 1200 participants with JIA in the first 12 months of its operation. Sustainable funding has been secured from multiple sources. The CARRA Registry may serve as a model for the study of other uncommon diseases.


Assuntos
Antirreumáticos/uso terapêutico , Artrite Juvenil/tratamento farmacológico , Sistema de Registros , Adolescente , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Canadá , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Medidas de Resultados Relatados pelo Paciente , Estudos Prospectivos , Doenças Reumáticas/tratamento farmacológico , Resultado do Tratamento , Estados Unidos
17.
Expert Rev Clin Pharmacol ; 9(8): 1015-24, 2016 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-27367267

RESUMO

INTRODUCTION: Canakinumab, a fully human monoclonal antibody against interleukin-1ß, is a relatively new medication approved for treatment of systemic juvenile idiopathic arthritis (SJIA). Here, we review data supporting use of canakinumab for patients with active SJIA, as compared to other available biologic medications. AREAS COVERED: This article provides an overview of chemistry of canakinumab as well as the phase II and phase III trials that led to approval for treatment of active SJIA. To undertake this review, the authors performed literature search using Pubmed, with keywords 'canakinumab,' 'biologic,' 'anti-IL-1B,' and 'systemic juvenile idiopathic arthritis,' focusing on publications within the last 5 years. Expert commentary: Canakinumab has shown efficacy in treatment of SJIA with active systemic features including fever. There is no evidence to suggest increased risk of macrophage activation syndrome. Its use in the treatment of chronic arthritis without active systemic features has not been approved and warrants further study.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Artrite Juvenil/tratamento farmacológico , Interleucina-1beta/antagonistas & inibidores , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais Humanizados , Artrite Juvenil/imunologia , Febre/tratamento farmacológico , Febre/etiologia , Humanos , Interleucina-1beta/imunologia
18.
Arthritis Rheumatol ; 68(1): 218-28, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26314396

RESUMO

OBJECTIVE: In pivotal trials, canakinumab has been shown to be effective in the treatment of systemic juvenile idiopathic arthritis (JIA), but reported adverse events have included macrophage activation syndrome (MAS). This study was undertaken to assess the impact of canakinumab on MAS incidence. METHODS: An independent MAS Adjudication Committee (MASAC), consisting of 3 of the authors, was convened, and a search of databases from clinical studies of canakinumab treatment in systemic JIA was performed using MASAC-specified adverse event terms to identify potential MAS events. These were then adjudicated as "probable MAS," "possible MAS," or "MAS unlikely," using criteria developed by the MASAC. MAS rates were expressed as numbers of cases per 100 patient-years. RESULTS: Of 72 potential MAS cases identified, 21 events (19 with canakinumab treatment; 2 with placebo treatment) in 19 patients were adjudicated as being probable MAS and 10 events in 9 patients as being possible MAS. Systemic JIA was well controlled in the majority of canakinumab-treated patients at the time of MAS. The time period between initiation of canakinumab treatment and onset of MAS ranged from 3 to 1,358 days (median 292 days). When the rates of probable MAS events were compared between canakinumab-treated patients (2.8 per 100 patient-years) and placebo-treated patients (7.7 per 100 patient-years), the difference was not significant (-4.9 [95% confidence interval -15.6, 5.9]). There were 3 deaths due to MAS-related complications (2 in patients receiving canakinumab; 1 in a patient receiving placebo); full recovery was reported in all other patients. Infections were the most common trigger of MAS, and the clinical features of MAS were not modified by canakinumab. CONCLUSION: Canakinumab does not have a significant effect on MAS risk or its clinical features in patients with systemic JIA. Infections are the most common trigger, and MAS occurs even in patients whose systemic JIA is well controlled with this treatment.


Assuntos
Anticorpos Monoclonais/efeitos adversos , Antirreumáticos/uso terapêutico , Artrite Juvenil/tratamento farmacológico , Síndrome de Ativação Macrofágica/induzido quimicamente , Adolescente , Anticorpos Monoclonais Humanizados , Criança , Pré-Escolar , Bases de Dados Factuais , Feminino , Humanos , Infecções/epidemiologia , Síndrome de Ativação Macrofágica/epidemiologia , Masculino , Fatores de Risco , Adulto Jovem
19.
RMD Open ; 2(1): e000161, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26848401

RESUMO

OBJECTIVE: To identify which laboratory tests that change over time are most valuable for the timely diagnosis of macrophage activation syndrome (MAS) complicating systemic juvenile idiopathic arthritis (sJIA). METHODS: A multistep process, based on a combination of expert consensus and analysis of real patient data, was conducted. A panel of experts was first asked to evaluate 115 profiles of patients with MAS, which included the values of laboratory tests at the pre-MAS visit and at MAS onset, and the change in values between the two time points. The experts were asked to choose the 5 laboratory tests in which change was most important for the diagnosis of MAS and to rank the 5 selected tests in order of importance. The relevance of change in laboratory parameters was further discussed and ranked by the same experts at a consensus conference. RESULTS: Platelet count was the most frequently selected test, followed by ferritin level, aspartate aminotransferase (AST), white cell count, neutrophil count, and fibrinogen and erythrocyte sedimentation rate. Ferritin was most frequently assigned the highest score. At the end of the process, platelet count, ferritin level and AST were the laboratory tests in which the experts found change over time to be most important. CONCLUSIONS: We identified the laboratory tests in which change over time is most valuable for the early diagnosis of MAS in sJIA. The dynamics of laboratory values during the course of MAS should be further scrutinised in a prospective study in order to establish the optimal cut-off values for their variation.

20.
Arthritis Rheumatol ; 68(3): 566-76, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26314788

RESUMO

OBJECTIVE: To develop criteria for the classification of macrophage activation syndrome (MAS) in patients with systemic juvenile idiopathic arthritis (JIA). METHODS: A multistep process, based on a combination of expert consensus and analysis of real patient data, was conducted. A panel of 28 experts was first asked to classify 428 patient profiles as having or not having MAS, based on clinical and laboratory features at the time of disease onset. The 428 profiles comprised 161 patients with systemic JIA-associated MAS and 267 patients with a condition that could potentially be confused with MAS (active systemic JIA without evidence of MAS, or systemic infection). Next, the ability of candidate criteria to classify individual patients as having MAS or not having MAS was assessed by evaluating the agreement between the classification yielded using the criteria and the consensus classification of the experts. The final criteria were selected in a consensus conference. RESULTS: Experts achieved consensus on the classification of 391 of the 428 patient profiles (91.4%). A total of 982 candidate criteria were tested statistically. The 37 best-performing criteria and 8 criteria obtained from the literature were evaluated at the consensus conference. During the conference, 82% consensus among experts was reached on the final MAS classification criteria. In validation analyses, these criteria had a sensitivity of 0.73 and a specificity of 0.99. Agreement between the classification (MAS or not MAS) obtained using the criteria and the original diagnosis made by the treating physician was high (κ = 0.76). CONCLUSION: We have developed a set of classification criteria for MAS complicating systemic JIA and provided preliminary evidence of its validity. Use of these criteria will potentially improve understanding of MAS in systemic JIA and enhance efforts to discover effective therapies, by ensuring appropriate patient enrollment in studies.


Assuntos
Artrite Juvenil/complicações , Síndrome de Ativação Macrofágica/classificação , Consenso , Diagnóstico Diferencial , Humanos , Internet , Modelos Logísticos , Síndrome de Ativação Macrofágica/diagnóstico
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