RESUMO
BACKGROUND: Etanercept (ETN) is widely used tumour necrosis factor (TNF) blocker in the treatment of juvenile idiopathic arthritis (JIA) when traditional synthetic disease modifying antirheumatic drug (sDMARD) therapy is not sufficient. There is limited information about the effects of methotrexate (MTX) on serum ETN concentration in children with JIA. We aimed to investigate whether ETN dose and concomitant MTX would effect ETN serum trough levels in JIA patients, and whether concomitant MTX have an influence on the clinical response in patients with JIA receiving ETN. METHODS: In this study, we collected the medical record data of 180 JIA patients from eight Finnish pediatric rheumatological centres. All these patients were treated with ETN monotherapy or combination therapy with DMARD. To evaluate the ETN concentrations, blood samples of the patients were collected between injections right before the subsequent drug. Free ETN level was measured from serum. RESULTS: Ninety-seven (54%) of the patients used concomitant MTX, and 83 (46%) received either ETN monotherapy or used sDMARDs other than MTX. A significant correlation was noted between ETN dose and drug level [r = 0.45 (95% CI: 0.33-0.56)]. The ETN dose and serum drug level were correlated (p = 0.030) in both subgroups - in MTX group [r = 0.35 (95% CI: 0.14-0.52)] and in non-MTX group [r = 0.54 (95% CI: 0.39-0.67)]. CONCLUSION: In the present study, we found that concomitant MTX had no effect on serum ETN concentration or on clinical response. In addition, a significant correlation was detected between ETN dose and ETN concentration.
Assuntos
Antirreumáticos , Artrite Juvenil , Criança , Humanos , Etanercepte/uso terapêutico , Metotrexato , Artrite Juvenil/tratamento farmacológico , Resultado do Tratamento , Quimioterapia CombinadaRESUMO
INTRODUCTION: The prevalence of immune-mediated diseases has increased in the past decades and despite the use of biological treatments all patients do not achieve remission. The aim of this study was to characterise the reasons for short interruptions during treatment with two commonly used TNF-inhibitors infliximab and adalimumab and to analyse the possible effects of the interruptions on immunisation and switching the treatment. MATERIAL AND METHODS: This case-control study was based on retrospective analyses of patient records and a questionnaire survey to clinicians. A total of 370 patients (194 immunised cases and 172 non-immunised controls, 4 excluded) were enrolled from eight hospitals around Finland. Eleven different diagnoses were represented, and the largest patient groups were those with inflammatory bowel or rheumatic diseases. RESULTS: Treatment interruptions were associated with immunisation in patients using infliximab (p < .001) or adalimumab (p < .000001). Patients with treatment interruptions were more likely to have been treated with more than one biological agent compared to those without treatment interruptions. This was particularly prominent among patients with a rheumatic disease (p < .00001). The most frequent reason for a treatment interruption among the cases was an infection, whereas among the control patients it was remission. The median length of one interruption was one month (interquartile range 1-3 months). CONCLUSION: Our results suggest that the interruptions of the treatment with TNF-inhibitors expose patients to immunisation and increase the need for drug switching. These findings stress the importance of careful judgement of the need for a short interruption in the biological treatment in clinical work, especially during non-severe infections.
Assuntos
Doenças Reumáticas , Inibidores do Fator de Necrose Tumoral , Adalimumab/uso terapêutico , Estudos de Casos e Controles , Substituição de Medicamentos , Finlândia , Humanos , Infliximab/uso terapêutico , Estudos Retrospectivos , Doenças Reumáticas/tratamento farmacológico , Falha de Tratamento , Inibidores do Fator de Necrose Tumoral/uso terapêuticoRESUMO
OBJECTIVES: To evaluate the patterns of usage, efficacy and safety of tocilizumab in polyarticular JIA. METHODS: An observational study of 56 consecutive polyarticular JIA patients was conducted using patient charts and electronic JIA databases. Efficacy was assessed by tocilizumab survival, rates of low disease activity (LDA) and of inactive disease by 10-joint Juvenile Arthritis Disease Activity Score (JADAS-10), and of clinically inactive disease according to Wallace's preliminary criteria. Efficacy and rate of adverse events (AEs) were evaluated during a 24-month period after tocilizumab commencement. RESULTS: Tocilizumab was started on average as third-line biological agent (median, range first- to fourth-line) at a median disease duration of 5.2 years (interquartile range 3.0-7.7). Survival rates were 82% at 12 months and 64% at 24 months. The reasons for discontinuation were inadequate treatment effect in 50%, AE plus inadequate treatment effect in 37.5% and AE alone in 12.5%. LDA (JADAS-10 ⩽3.9) was reached in 58% at 12 months and in 84% at 24 months, inactive disease (JADAS-10 ⩽0.7) in 19% and 44%, and clinically inactive disease in 28% and 46%, respectively. The rate of AEs was 200.9/100 patient years and of serious AEs 12.9/100 patient years. CONCLUSION: Survival of tocilizumab was high and a large proportion of the treatment-resistant patients reached LDA at 12 months of treatment. The LDA rate continued to increase throughout 24 months. The rates of AEs and serious AEs were higher than in register studies but lower than in the originator study of tocilizumab.
Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antirreumáticos/uso terapêutico , Artrite Juvenil/tratamento farmacológico , Adolescente , Alanina Transaminase/metabolismo , Artrite Juvenil/fisiopatologia , Criança , Pré-Escolar , Estudos de Coortes , Quimioterapia Combinada , Feminino , Glucocorticoides/uso terapêutico , Humanos , Leflunomida/uso terapêutico , Masculino , Adesão à Medicação , Metotrexato/uso terapêutico , Neutropenia/induzido quimicamente , Prednisolona/uso terapêutico , Falha de Tratamento , Resultado do Tratamento , Inibidores do Fator de Necrose Tumoral/uso terapêuticoRESUMO
BACKGROUND: MONA, which stands for a spectrum of Multicentric Osteolysis, subcutaneous Nodulosis, and Athropathia, is an ultra rare autosomal recessive disorder caused by mutations in the matrix metallopeptidase 2 (MMP2) gene. To date only 44 individuals, carrying 22 different mutations have been reported. Here we report on two brothers with identical homozygous MMP2 gene mutations, but with clearly different phenotypes. METHODS: Genomic DNA was isolated from the affected brothers and the parents. An iliac crest bone biopsy was taken from the younger patient (index case). The level of matrix metallopeptidase 2 enzyme (MMP2) in serum and synovial fluid of the younger patient was analyzed using gelatin zymography. RESULTS: The DNA analysis revealed a homozygous c.1188C>A transversion on exon 8 of the gene. The affected brothers had the same homozygous variant and the parents were heterozygous to this variant. This variant has been reported as a compound heterozygous mutation on one individual resulting in scleroderma like skin thickening. Bone histomorphometry indicated increased trabecular bone remodeling and turnover. The zymography revealed that the level of MMP2 was completely nonmeasurable in the serum and only a minor gelatinolytic protein band of about similar molecular weight as MMP2 was found in the synovial fluid. CONCLUSIONS: Both the age at the onset and the phenotypic severity of the syndrome in these two brothers were different despite identical genotypes. The younger patients had corneal opacities leading to deteriorating visual acuity. For the first time in this disease, opacities were successfully treated with corneal transplantations.
Assuntos
Predisposição Genética para Doença/genética , Síndrome de Hajdu-Cheney/genética , Metaloproteinase 2 da Matriz/genética , Mutação , Sequência de Bases , Osso e Ossos/patologia , Criança , Pré-Escolar , DNA/análise , Análise Mutacional de DNA , Estudos de Associação Genética , Genótipo , Síndrome de Hajdu-Cheney/patologia , Síndrome de Hajdu-Cheney/fisiopatologia , Homozigoto , Humanos , Masculino , Metaloproteinase 2 da Matriz/sangue , Anormalidades Musculoesqueléticas , Osteólise , Fenótipo , Pele/patologia , Líquido SinovialRESUMO
Lean body mass (LM) has been positively associated with bone mineral density (BMD) in children and adolescents, but the relationship between body fat mass (FM) and BMD remains controversial. Several biomarkers secreted by adipose tissue, skeletal muscle, or bone may affect bone metabolism and BMD. We investigated the associations of LM, FM, and such biomarkers with BMD in children. We studied a population sample of 472 prepubertal Finnish children (227 girls, 245 boys) aged 6-8years. We assessed BMD, LM, and FM using whole-body dual-energy x-ray absorptiometry and analysed several biomarkers from fasting blood samples. We studied the associations of LM, FM, and the biomarkers with BMD of the whole body excluding the head using linear regression analysis. LM (standardized regression coefficient ß=0.708, p<0.001), FM (ß=0.358, p<0.001), and irisin (ß=0.079, p=0.048) were positive correlates for BMD adjusted for age, sex, and height in all children. These associations remained statistically significant after further adjustment for LM or FM. The positive associations of dehydroepiandrosterone sulphate (DHEAS), insulin, homeostatic model assessment for insulin resistance (HOMA-IR), leptin, free leptin index, and high-sensitivity C-reactive protein and the negative association of leptin receptor with BMD were explained by FM. The positive associations of DHEAS and HOMA-IR with BMD were also explained by LM. Serum 25-hydroxyvitamin D was a positive correlate for BMD adjusted for age, sex, and height and after further adjustment for FM but not for LM. LM and FM were positive correlates for BMD also in girls and boys separately. In girls, insulin, HOMA-IR, leptin, and free leptin index were positively and leptin receptor was negatively associated with BMD adjusted for age, height, and LM. After adjustment for age, height, and FM, none of the biomarkers was associated with BMD. In boys, leptin and free leptin index were positively and leptin receptor was negatively associated with BMD adjusted for age, height, and LM. After adjustment for age, height and FM, 25(OH)D was positively and IGF-1 and leptin were negatively associated with BMD. FM strongly modified the association between leptin and BMD. LM but also FM were strong, independent positive correlates for BMD in all children, girls, and boys. Irisin was positively and independently associated with BMD in all children. The associations of other biomarkers with BMD were explained by LM or FM.
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Tecido Adiposo/fisiologia , Biomarcadores/metabolismo , Densidade Óssea/fisiologia , Fenômenos Fisiológicos da Nutrição Infantil , Exercício Físico/fisiologia , Criança , Feminino , Humanos , MasculinoRESUMO
Cryopyrin-associated periodic syndrome (CAPS) is caused by a mutation in the NLRP3 gene encoding cryopyrin production. Overproduction of interleukin-1 (IL-1) leads to symptoms that are associated with elevated inflammatory markers, including periodic fever and a rash. We provide a clinical overview of CAPS in children, including three Finnish case studies. CONCLUSION: When CAPS has been diagnosed, an IL-1 blockade with biological should be introduced to lessen the symptoms and to prevent the progression of organ damage.
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Síndromes Periódicas Associadas à Criopirina/tratamento farmacológico , Interleucina-1/antagonistas & inibidores , Anti-Inflamatórios/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados , Antirreumáticos/uso terapêutico , Pré-Escolar , Síndromes Periódicas Associadas à Criopirina/diagnóstico , Feminino , Humanos , Lactente , Proteína Antagonista do Receptor de Interleucina 1/uso terapêutico , Masculino , Proteínas Recombinantes de Fusão/uso terapêuticoRESUMO
Chronic nonbacterial osteomyelitis is an autoinflammatory disease occurring mainly in children and adolescents, typically involving recurrent or persistent osteitic foci. The symptom is bone pain, possibly accompanied by soft tissue tenderness. Some patients exhibit symptoms of systemic inflammation. The. precise etiology of the disease is not known, but an imbalance of inflammatory and anti-inflammatory cytokines is presumed to play a role in the development of the disease. While an anti-inflammatory analgesic is in most cases sufficient to calm down the osteitis, the use of corticosteroids, anti- TNF-a inhibitors or bisphosphonates is required in some cases.
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Osteomielite/diagnóstico , Osteomielite/tratamento farmacológico , Corticosteroides/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Doença Crônica , Citocinas/imunologia , Diagnóstico Diferencial , Difosfonatos/uso terapêutico , Humanos , Osteomielite/etiologia , Osteomielite/imunologia , Fator de Necrose Tumoral alfa/antagonistas & inibidoresRESUMO
Systemic onset juvenile idiopathic arthritis is a rare form of juvenile arthritis in which, contrary to autoimmune diseases in general, no association with a certain tissue type has been detected. Together with this fact, the lack of autoantibodies and the general symptoms belonging to the diagnostic criteria of the illness such as high fever, rather speak for its classification into autoinflammatory diseases. Treatment is usually started with anti-inflammatory drugs, often requiring combination with a systemic glucocorticoid. Recognition of interleukins 1 and 6 as central mediators in the pathogenesis of the disease has brought new possibilities for its treatment.
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Artrite Juvenil/diagnóstico , Artrite Juvenil/tratamento farmacológico , Anti-Inflamatórios/uso terapêutico , Criança , Glucocorticoides/uso terapêutico , Humanos , Interleucina-1/antagonistas & inibidores , Interleucina-6/antagonistas & inibidoresRESUMO
Although etiology of juvenile idiopathic arthritis (JIA) is currently not known, better understanding of immunologic pathways of inflammation and the development of new therapies with biologic agents have remarkably improved the treatment of JIA. However, approximately 30% of the patients with JIA do not seem to response adequately to conventional anti-rheumatic drugs but the arthritis runs a continuously active course and may lead to the evolution of erosions. Such patients benefit from biologic agents, of which the longest clinical experience comes from anti-TNF therapies. Molecules targeting IL-1, IL-6 and B- and T-lymphocytes are also used in the treatment of severe JIA.
Assuntos
Antirreumáticos/uso terapêutico , Artrite Juvenil/tratamento farmacológico , Artrite Juvenil/imunologia , Progressão da Doença , Humanos , Interleucina-1/antagonistas & inibidores , Interleucina-6/antagonistas & inibidores , Fator de Necrose Tumoral alfa/antagonistas & inibidoresRESUMO
OBJECTIVES: In juvenile idiopathic arthritis (JIA), the efficacy of very early disease-modifying drug therapy, synthetic or biological, is not well known. Three alternative strategies were compared for treating recent-onset polyarticular JIA. METHODS: In a 54-week multicentre open-label clinical trial, 60 disease-modifying antirheumatic drug (DMARD)-naive patients aged 4-15 years were randomly assigned into three treatment arms. The efficacy of infliximab plus methotrexate (TNF) was compared to that of two synthetic therapies: methotrexate alone (MTX) and DMARD methotrexate, sulphasalazine and hydroxychloroquine in combination (COMBO). Primary endpoint was American College of Rheumatology paediatric 75% improvement (ACR Pedi 75). Secondary endpoints were inactive disease and safety. RESULTS: In 59 patients, mean (±SE) age at baseline was 9.6±0.4 years, duration of JIA 1.9±0.2 months and number of active joints 18±1. ACR Pedi 75 was achieved in 100% (19/19) of patients receiving TNF, 65% (13/20) on COMBO (95% CI 44% to 86%) and 50% (10/20) on methotrexate (95% CI 28% to 72%) p<0.0001. Thirteen patients receiving TNF (68%; 95% CI 47% to 89%) achieved inactive disease, whereas eight (40%; 95% CI 22% to 63%) on COMBO and five (25%; 95% CI 6% to 44%) on methotrexate did (p=0.002). Patients on TNF spent a mean 26 weeks (95% CI 18 to 34) with inactive disease, longer than did those receiving COMBO (13 weeks; 95% CI 6 to 20), or methotrexate (6 weeks; 95% CI 2 to 10). Serious adverse events were rare. CONCLUSION: In early polyarticular JIA, targeting to achieve minimally active or inactive disease, infliximab plus methotrexate was superior to synthetic DMARD in combination and strikingly superior to methotrexate alone.
Assuntos
Antirreumáticos/uso terapêutico , Artrite Juvenil/tratamento farmacológico , Adolescente , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/uso terapêutico , Antirreumáticos/efeitos adversos , Criança , Pré-Escolar , Combinação de Medicamentos , Métodos Epidemiológicos , Feminino , Glucocorticoides/administração & dosagem , Humanos , Hidroxicloroquina/efeitos adversos , Hidroxicloroquina/uso terapêutico , Infliximab , Injeções Intra-Articulares , Masculino , Metotrexato/efeitos adversos , Metotrexato/uso terapêutico , Sulfassalazina/efeitos adversos , Sulfassalazina/uso terapêutico , Resultado do Tratamento , Fator de Necrose Tumoral alfa/antagonistas & inibidoresRESUMO
Down syndrome is associated with the risk of various structural abnormalities or functional disturbances of organ systems, and with several abnormalities of the immune system. Screening and monitoring of congenital heart defects or orthopedic problems are managed and the increased risk to develop leukemia, diabetes of hypothyroidism is well known. The 3 to 6-fold incidence of juvenile idiopathic arthritis in Down syndrome compared with the general juvenile population is, however, less known. We describe a patient, for whom the diagnostic delay of juvenile idiopathic arthritis was eight years.
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Artrite Juvenil/etiologia , Síndrome de Down/complicações , Artrite Juvenil/diagnóstico por imagem , Criança , Humanos , RadiografiaRESUMO
OBJECTIVE: To study the incidence of inflammatory joint diseases in a defined population in Finland. METHODS: We collected data for the year 2000 on a population of 87,000 inhabitants of Kuopio, Finland, of whom 20% were < 16 years of age. Information about the study was given through a local newspaper, and subjects attended one health center and 2 local hospitals for study. Inclusion criteria were that subjects have at least one peripheral joint with synovitis or signs of inflammation in sacroiliac, glenohumeral, or hip joints on the first visit. Incidence rates were calculated according to the diagnosis on the first visit, except for children, for whom diagnoses were established after 3 months' followup. RESULTS: A total of 188 adult incident cases (138 women, 50 men) and 11 children (8 girls, 3 boys) satisfied the inclusion criteria. The incidence of all arthritides was 230/100,000 (95% confidence interval 198.9-263.9) for the whole population; 271/100,000 (95% CI 233.7-312.7) for adults and 64/100,000 (95% CI 31.7-113.8) for children. Among adults the annual incidence of rheumatoid arthritis (RA), ankylosing spondylitis (AS), psoriatic arthritis (PsA), reactive arthritis (ReA), other spondyloarthropathies (SpA), connective tissue disease (CTD), crystalline arthritis, viral arthritis, and undifferentiated arthritis were 36, 7, 23, 10, 13, 9, 19, 7, and 149/100,000, respectively. The mean age at diagnosis was 49.4 +/- 16.3 years for all cases of arthritis among adults, about the same for both women and men. The mean age at diagnosis was 59.7 years in RA, 31.5 years in AS, 48.7 years in PsA, 38.0 years in ReA, 36.5 years in other SpA, 36.1 years in CTD, 65.0 years in crystalline arthritis, 53.3 years in viral arthritis, and 48.3 years in undifferentiated arthritis. Four of 11 children had juvenile idiopathic arthritis (JIA). The incidence of JIA was 23/100,000 in the population < 16 years of age. Of the remaining cases, 3 children had antibodies against Sindbis (Pogosta) virus and 4 had a transient monoarthritis. CONCLUSION: The overall incidence of arthritides among adults was slightly higher than previously reported from Finland. The incidence rates in the child population are in agreement with previous figures. These data are useful in planning the provision of health care.