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1.
Pediatr Rheumatol Online J ; 17(1): 41, 2019 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-31299993

RESUMO

BACKGROUND: The pathology of juvenile dermatomyositis (JDM) is characterized by prominent vessel wall and perivascular inflammation. This feature of the disease has remained unexplained and under-investigated. We have hypothesized that plasma exosomes, which play an important role in inter-cellular communication, may play a role in the vascular injury associated with JDM. OBJECTIVE: To characterize the circulating exosomes of children with JDM and determine whether the small RNA cargoes within those exosomes are capable of altering transcriptional programs within endothelial cells. DESIGN/METHODS: We purified exosomes from plasma samples of children with active, untreated JDM (n = 6) and healthy controls (n = 9). We characterized the small RNA cargoes in JDM and control exosomes by RNA sequencing using the Illumina HiSeq 2500 platform. We then incubated isolated exosomes from healthy controls and children with JDM with cultured human aortic endothelial cells (HAEC) for 24 h. Fluorescence microscopy was used to confirm that both control and JDM exosomes were taken up by HAEC. RNA was then purified from HAEC that had been incubated with either control or JDM exosomes and sequenced on the Illumina platform. Differential expression of mRNAs from HAEC incubated with control or JDM exosomes was ascertained using standard computational methods. Finally, we assessed the degree to which differential gene expression in HAEC could be attributed to the different small RNA cargoes in JDM vs control exosomes using conventional and novel analytic methods. RESULTS: We identified 10 small RNA molecules that showed differential abundance when we compared JDM and healthy control exosomes. Fluorescence microscopy of labeled exosomes confirmed that both JDM and control exosomes were taken up by HAEC. Differential gene expression analysis revealed 59 genes that showed differential expression between HAEC incubated with JDM exosomes vs HAEC incubated with exosomes from controls. Statistical analysis of gene expression data demonstrated that multiple miRNAs exerted transcriptional control on multiple genes with HAEC. CONCLUSIONS: Plasma exosomes from children with active, untreated JDM are taken up by HAEC and are associated with alterations in gene expression in those cells. These findings provide new insight into potential mechanisms leading to the targeting of vascular tissue by the immune system in JDM.


Assuntos
Dermatomiosite/genética , Células Endoteliais/metabolismo , Exossomos/metabolismo , MicroRNAs/genética , Adolescente , Aorta/citologia , Estudos de Casos e Controles , Células Cultivadas , Criança , Pré-Escolar , Dermatomiosite/metabolismo , Feminino , Expressão Gênica , Regulação da Expressão Gênica/genética , Humanos , Masculino , Análise de Sequência de RNA
2.
J Rheumatol ; 45(12): 1680-1688, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30219769

RESUMO

OBJECTIVE: To identify clinical features that define disease activity in pediatric localized scleroderma (LS), and determine their specificity and importance. METHODS: We conducted a multicenter prospective study of patients with active and inactive LS skin lesions. A standardized evaluation of a single designated study lesion per subject was performed at 3 visits. We evaluated the pattern and correlation between assessed features and physician's global assessments of activity (PGA-A). RESULTS: Ninety of 103 subjects had evaluable data; 66 had active and 24 inactive disease. Subjects had similar age of onset, sex, and disease patterns. Linear scleroderma was the most common subtype. Features specific for active disease included erythema, violaceous color, tactile warmth, abnormal skin texture, and disease extension. Scores for these variables changed over time and correlated with PGA-A of the lesion. Active and inactive lesions could not be distinguished by the presence or level of skin thickening, either of lesion edge or center. However, in active lesions, skin thickening scores did correlate with PGA-A scores. Regression analysis identified the combination of erythema, disease extension, violaceous color, skin thickening, and abnormal texture as predictive of PGA-A at study entry. Damage features were common irrespective of activity status. CONCLUSION: We identified variables strongly associated with disease activity, expanding upon those used in current measures, and determined their relative importance in physician activity scoring. Skin thickening was found to lack specificity for disease activity. These results will help guide development of a sensitive, responsive activity tool to improve care of patients with LS.


Assuntos
Esclerodermia Localizada/diagnóstico , Pele/patologia , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Estudos Prospectivos , Esclerodermia Localizada/patologia , Índice de Gravidade de Doença , Avaliação de Sintomas/métodos
3.
Pediatr Clin North Am ; 65(4): 711-737, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-30031495

RESUMO

Juvenile systemic lupus erythematosus (jSLE), mixed connective tissue disease (jMCTD), and Sjögren syndrome (jSS) are systemic autoimmune and inflammatory disorders with distinct patterns of organ involvement. All are characterized by autoantibody formation, with antinuclear (ANA) and anti-double-stranded DNA common in jSLE, ANA with high-titer ribonucleoprotein antibody in jMCTD, and Sjögren syndrome A and Sjögren syndrome B antibodies + ANA in jSS. Recognition, monitoring, and management for primary care providers are discussed, focusing on the role of primary physicians in recognizing and helping maintain optimal health in children with these potentially life-threatening diseases.


Assuntos
Lúpus Eritematoso Sistêmico , Doença Mista do Tecido Conjuntivo , Síndrome de Sjogren , Adolescente , Anti-Inflamatórios não Esteroides/uso terapêutico , Criança , Diagnóstico Diferencial , Humanos , Imunossupressores/uso terapêutico , Lúpus Eritematoso Sistêmico/complicações , Lúpus Eritematoso Sistêmico/diagnóstico , Lúpus Eritematoso Sistêmico/terapia , Doença Mista do Tecido Conjuntivo/diagnóstico , Doença Mista do Tecido Conjuntivo/terapia , Pediatras , Prognóstico , Síndrome de Sjogren/diagnóstico , Síndrome de Sjogren/terapia
4.
PLoS One ; 13(3): e0193749, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29538431

RESUMO

OBJECTIVE: Endothelial dysfunction is central to the pathogenesis of many rheumatic diseases, typified by vascular inflammation and damage. Immunosuppressive drugs induce disease remission and lead to improved patient survival. However, there remains a higher incidence of cardiovascular disease in these patients even after adequate disease control. The purpose of this study was to determine the effect of mycophenolic acid (MPA), a commonly used immunosuppressive drug in rheumatology, on blood vessel or circulating endothelial colony forming cell number and function. METHODS: We tested whether mycophenolic acid exerts an inhibitory effect on proliferation, clonogenic potential and vasculogenic function of endothelial colony forming cell. We also studied potential mechanisms involved in the observed effects. RESULTS: Treatment with MPA decreased endothelial colony forming cell proliferation, clonogenic potential and vasculogenic function in a dose-dependent fashion. MPA increased senescence-associated ß-galactosidase expression, p21 gene expression and p53 phosphorylation, indicative of activation of cellular senescence. Exogenous guanosine supplementation rescued diminished endothelial colony forming cell proliferation and indices of senescence, consistent with the known mechanism of action of MPA. CONCLUSION: Our findings show that clinically relevant doses of MPA have potent anti-angiogenic and pro-senescent effects on vascular precursor cells in vitro, thus indicating that treatment with MPA can potentially affect vascular repair and regeneration. This warrants further studies in vivo to determine how MPA therapy contributes to vascular dysfunction and increased cardiovascular disease seen in patients with inflammatory rheumatic disease.


Assuntos
Senescência Celular/efeitos dos fármacos , Ácido Micofenólico/farmacologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Inibidor p16 de Quinase Dependente de Ciclina/genética , Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , Inibidor de Quinase Dependente de Ciclina p21/genética , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Células Endoteliais/citologia , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Galactosidases/metabolismo , Guanosina/farmacologia , Humanos , Fosforilação/efeitos dos fármacos , Proteína Supressora de Tumor p53/metabolismo , Cordão Umbilical/citologia
5.
J Rheumatol ; 44(10): 1484-1486, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28765255

RESUMO

OBJECTIVE: To determine cancer incidence in a large pediatric-onset systemic lupus erythematosus (SLE) population. METHODS: Data were examined from 12 pediatric SLE registries in North America. Patients were linked to their regional cancer registries to detect cancers observed after cohort entry, defined as date first seen in the clinic. The expected number of malignancies was obtained by multiplying the person-years in the cohort (defined from cohort entry to end of followup) by the geographically matched age-, sex-, and calendar year-specific cancer rates. The standardized incidence ratio (SIR; ratio of cancers observed to expected) was generated, with 95% CI. RESULTS: A total of 1168 patients were identified from the registries. The mean age at cohort entry was 13 years (SD 3.3), and 83.7% of the subjects were female. The mean duration of followup was 7.6 years, resulting in a total observation period of 8839 years spanning the calendar period 1974-2009. During followup, fourteen invasive cancers occurred (1.6 cancers per 1000 person-yrs, SIR 4.13, 95% CI 2.26-6.93). Three of these were hematologic (all lymphomas), resulting in an SIR for hematologic cancers of 4.68 (95% CI 0.96-13.67). SIR were increased for both male and female patients, and across age groups. CONCLUSION: Although cancer remains a relatively rare outcome in pediatric-onset SLE, our data do suggest an increase in cancer for patients followed an average of 7.6 years. About one-fifth of the cancers were hematologic. Longer followup, and study of drug effects and disease activity, is warranted.


Assuntos
Lúpus Eritematoso Sistêmico/epidemiologia , Neoplasias/epidemiologia , Adolescente , Criança , Comorbidade , Feminino , Seguimentos , Humanos , Incidência , Masculino , Sistema de Registros , Fatores Sexuais
6.
Pediatr Rheumatol Online J ; 15(1): 61, 2017 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-28784150

RESUMO

BACKGROUND: Because pediatric antineutrophil cytoplasmic antibody-associated vasculitis is rare, management generally relies on adult data. We assessed treatment practices, uptake of existing clinical assessment tools, and interest in pediatric treatment protocols among rheumatologists caring for children with granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA). METHODS: A needs-assessment survey developed by an international working group of pediatric rheumatologists and two nephrologists was circulated internationally. Data were summarized with descriptive statistics. Pearson's chi-square tests were used in inferential univariate analyses. RESULTS: The 209 respondents from 36 countries had collectively seen ~1600 children with GPA/MPA; 144 had seen more than two in the preceding 5 years. Standardized and validated clinical assessment tools to score disease severity, activity, and damage were used by 59, 63, and 36%, respectively; barriers to use included lack of knowledge and limited perceived utility. Therapy varied significantly: use of rituximab rather than cyclophosphamide was more common among respondents from the USA (OR = 2.7 [1.3-5.5], p = 0.0190, n = 139), those with >5 years of independent practice experience (OR = 3.8 [1.3-12.5], p = 0.0279, n = 137), and those who had seen >10 children with GPA/MPA in their careers (OR = 4.39 [2.1-9.1], p = 0.0011, n = 133). Respondents who had treated >10 patients were also more likely to continue maintenance therapy for at least 24 months (OR = 3.0 [1.4-6.4], p = 0.0161, n = 127). Ninety six percent of respondents believed in a need for pediatric-specific treatment guidelines; 46% supported adaptation of adult guidelines while 69% favoured guidelines providing a limited range of treatment options to allow comparison of effectiveness through a registry. CONCLUSIONS: These data provide a rationale for developing pediatric-specific consensus treatment guidelines for GPA/MPA. While pediatric rheumatologist uptake of existing clinical tools has been limited, guideline uptake may be enhanced if outcomes of consensus-derived treatment options are evaluated within the framework of an international registry.


Assuntos
Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/tratamento farmacológico , Conhecimentos, Atitudes e Prática em Saúde , Padrões de Prática Médica/estatística & dados numéricos , Criança , Guias como Assunto , Inquéritos Epidemiológicos , Humanos , Pediatria , Reumatologistas
7.
Rheumatology (Oxford) ; 56(9): 1542-1551, 2017 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-28582527

RESUMO

Objective: The mechanisms that determine the efficacy or inefficacy of MTX in JIA are ill-defined. The objective of this study was to identify a gene expression transcriptional signature associated with poor response to MTX in patients with JIA. Methods: RNA sequencing was used to measure gene expression in peripheral blood mononuclear cells collected from 47 patients with JIA prior to MTX treatment and 14 age-matched controls. Differentially expressed baseline genes between responders and non-responders were evaluated. Biological differences between all JIA patients and controls were explored by constructing a signature of differentially expressed genes. Unsupervised clustering and pathway analysis was performed. Results: A signature of 99 differentially expressed genes (Bonferroni-corrected P < 0.05) capturing the biological differences between all JIA patients and controls was identified. Unsupervised clustering of samples based on this list of 99 genes produced subgroups enriched for MTX response status. Comparing this gene signature with reference signatures from sorted cell populations revealed high concordance between the expression signatures of monocytes and of MTX non-responders. CXCL8 (IL-8) was the most significantly differentially expressed gene transcript comparing all JIA patients with controls (Bonferroni-corrected P = 4.12 × 10-10). Conclusion: Variability in clinical response to MTX in JIA patients is associated with differences in gene transcripts modulated in monocytes. These gene expression profiles may provide a basis for biomarkers predictive of treatment response.


Assuntos
Antirreumáticos/uso terapêutico , Artrite Juvenil/tratamento farmacológico , Artrite Juvenil/genética , Metotrexato/uso terapêutico , Transcrição Genética , Adolescente , Estudos de Casos e Controles , Criança , Análise por Conglomerados , Feminino , Perfilação da Expressão Gênica/métodos , Humanos , Masculino , Monócitos/metabolismo , Análise de Sequência de RNA/métodos , Índice de Gravidade de Doença , Transcriptoma , Falha de Tratamento
8.
Curr Opin Rheumatol ; 29(5): 516-522, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28632503

RESUMO

PURPOSE OF REVIEW: To review the difficult syndrome of catastrophic antiphospholipid syndrome, emphasizing new developments in the diagnosis, pathogenesis and treatment. RECENT FINDINGS: Few recent publications directly address pediatric catastrophic antiphospholipid syndrome (CAPS). Most articles are case reports or are data from adult and pediatric registries. The major factors contributing to most pediatric catastrophic antiphospholipid syndrome include infection and the presence of antiphospholipid antibodies, but complement activation also is important in creating diffuse thrombosis in the microcirculation. Treatment of the acute emergency requires anticoagulation, suppression of the hyperinflammatory state and elimination of the triggering infection. Inhibition of complement activation appears to improve outcome in limited studies, and suppression of antiphospholipid antibody formation may be important in long-term management. SUMMARY: CAPS, an antibody-mediated diffuse thrombotic disease of microvasculature, is rare in childhood but has high mortality (33-50%). It requires prompt recognition and aggressive multimodality treatment, including anticoagulation, anti-inflammatory therapy and elimination of inciting infection and pathogenic autoantibodies.


Assuntos
Anticorpos Antifosfolipídeos/imunologia , Síndrome Antifosfolipídica , Autoimunidade , Gerenciamento Clínico , Síndrome Antifosfolipídica/diagnóstico , Síndrome Antifosfolipídica/imunologia , Síndrome Antifosfolipídica/terapia , Doença Catastrófica , Criança , Humanos
9.
RMD Open ; 2(1): e000212, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27175293

RESUMO

OBJECTIVE: To determine cancer incidence in a large clinical juvenile-onset arthritis population. METHODS: We combined data from 6 existing North American juvenile-onset arthritis cohorts. Patients with juvenile-onset arthritis were linked to regional cancer registries to detect incident cancers after cohort entry, defined as first date seen in the paediatric rheumatology clinic. The expected number of malignancies was obtained by multiplying the person-years observed (defined from cohort entry to end of follow-up) by the geographically matched age, sex and calendar year-specific cancer rates. The standardised incidence ratios (SIR; ratio of cancers observed to expected) were generated, with 95% CIs. RESULTS: The 6 juvenile arthritis registries provided a total of 5294 patients. The mean age at cohort entry was 8.9 (SD 5.0) years and 68% of participants were female. The mean duration of follow-up was 6.8 years with a total of 36 063 person-years spanning 1978-2012. During follow-up, 9 invasive cancers occurred, compared with 10.9 expected (SIR 0.82, 95% CI 0.38 to 1.5). 3 of these were haematological (Hodgkin's, non-Hodgkin's lymphoma and leukaemia). 6 of the patients with cancer were exposed to disease-modifying drugs; 5 of these had also been exposed to biological agents. CONCLUSIONS: We did not clearly demonstrate an increase in overall malignancy risk in patients with juvenile-onset arthritis followed for an average of almost 7 years. 3 of the 9 observed cancers were haematological. 5 of the cancers arose in children exposed to biological agents. Longer follow-up of this population is warranted, with further study of drug effects.

10.
Arthritis Rheumatol ; 68(10): 2514-26, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27111558

RESUMO

OBJECTIVE: To uniquely classify children with microscopic polyangiitis (MPA), to describe their demographic characteristics, presenting clinical features, and initial treatments in comparison to patients with granulomatosis with polyangiitis (Wegener's) (GPA). METHODS: The European Medicines Agency (EMA) classification algorithm was applied by computation to categorical data from patients recruited to the ARChiVe (A Registry for Childhood Vasculitis: e-entry) cohort, with the data censored to November 2015. The EMA algorithm was used to uniquely distinguish children with MPA from children with GPA, whose diagnoses had been classified according to both adult- and pediatric-specific criteria. Descriptive statistics were used for comparisons. RESULTS: In total, 231 of 440 patients (64% female) fulfilled the classification criteria for either MPA (n = 48) or GPA (n = 183). The median time to diagnosis was 1.6 months in the MPA group and 2.1 months in the GPA group (ranging to 39 and 73 months, respectively). Patients with MPA were significantly younger than those with GPA (median age 11 years versus 14 years). Constitutional features were equally common between the groups. In patients with MPA compared to those with GPA, pulmonary manifestations were less frequent (44% versus 74%) and less severe (primarily, hemorrhage, requirement for supplemental oxygen, and pulmonary failure). Renal pathologic features were frequently found in both groups (75% of patients with MPA versus 83% of patients with GPA) but tended toward greater severity in those with MPA (primarily, nephrotic-range proteinuria, requirement for dialysis, and end-stage renal disease). Airway/eye involvement was absent among patients with MPA, because these GPA-defining features preclude a diagnosis of MPA within the EMA algorithm. Similar proportions of patients with MPA and those with GPA received combination therapy with corticosteroids plus cyclophosphamide (69% and 78%, respectively) or both drugs in combination with plasmapheresis (19% and 22%, respectively). Other treatments administered, ranging in decreasing frequency from 13% to 3%, were rituximab, methotrexate, azathioprine, and mycophenolate mofetil. CONCLUSION: Younger age at disease onset and, perhaps, both gastrointestinal manifestations and more severe kidney disease seem to characterize the clinical profile in children with MPA compared to those with GPA. Delay in diagnosis suggests that recognition of these systemic vasculitides is suboptimal. Compared with adults, initial treatment regimens in children were comparable, but the complete reversal of female-to-male disease prevalence ratios is a provocative finding.


Assuntos
Granulomatose com Poliangiite/fisiopatologia , Hemorragia/fisiopatologia , Falência Renal Crônica/fisiopatologia , Pneumopatias/fisiopatologia , Poliangiite Microscópica/fisiopatologia , Síndrome Nefrótica/fisiopatologia , Insuficiência Respiratória/fisiopatologia , Adolescente , Corticosteroides/uso terapêutico , Distribuição por Idade , Anticorpos Anticitoplasma de Neutrófilos , Ásia/epidemiologia , Azatioprina/uso terapêutico , Canadá/epidemiologia , Criança , Pré-Escolar , Estudos de Coortes , Ciclofosfamida/uso terapêutico , Quimioterapia Combinada , Europa (Continente)/epidemiologia , Feminino , Granulomatose com Poliangiite/complicações , Granulomatose com Poliangiite/epidemiologia , Granulomatose com Poliangiite/terapia , Hemorragia/etiologia , Humanos , Imunossupressores/uso terapêutico , Lactente , Falência Renal Crônica/etiologia , Falência Renal Crônica/terapia , Pneumopatias/etiologia , Masculino , Metotrexato/uso terapêutico , Poliangiite Microscópica/complicações , Poliangiite Microscópica/epidemiologia , Poliangiite Microscópica/terapia , Ácido Micofenólico/uso terapêutico , Síndrome Nefrótica/etiologia , Oxigenoterapia , Plasmaferese , Proteinúria/etiologia , Diálise Renal , Insuficiência Respiratória/etiologia , Insuficiência Respiratória/terapia , Rituximab/uso terapêutico , Estados Unidos/epidemiologia
11.
Arthritis Care Res (Hoboken) ; 68(7): 1003-11, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-26473509

RESUMO

OBJECTIVE: Noninvasive estimation of the degree of inflammation seen on kidney biopsy with lupus nephritis (LN) remains difficult. The objective of this study was to develop a Renal Activity Index for Lupus (RAIL) that, based solely on laboratory measures, accurately reflects histologic LN activity. METHODS: We assayed traditional LN laboratory tests and 16 urine biomarkers (UBMs) in children (n = 47) at the time of kidney biopsy. Histologic LN activity was measured by the National Institutes of Health activity index (NIH-AI) and the tubulointerstitial activity index (TIAI). High LN-activity status (versus moderate/low) was defined as NIH-AI scores >10 (versus ≤10) or TIAI scores >5 (versus ≤5). RAIL algorithms that predicted LN-activity status for both NIH-AI and TIAI were derived by stepwise multivariate logistic regression, considering traditional biomarkers and UBMs as candidate components. The accuracy of the RAIL for discriminating by LN-activity status was determined. RESULTS: The differential excretion of 6 UBMs (neutrophil gelatinase-associated lipocalin, monocyte chemotactic protein 1, ceruloplasmin, adiponectin, hemopexin, and kidney injury molecule 1) standardized by urine creatinine was considered in the RAIL. These UBMs predicted LN-activity (NIH-AI) status with >92% accuracy and LN-activity (TIAI) status with >80% accuracy. RAIL accuracy was minimally influenced by concomitant LN damage. Accuracies between 71% and 85% were achieved without standardization of the UBMs. The strength of these UBMs to reflect LN-activity status was confirmed by principal component and linear discriminant analyses. CONCLUSION: The RAIL is a robust and highly accurate noninvasive measure of LN activity. The measurement properties of the RAIL, which reflect the degree of inflammatory changes as seen on kidney biopsy, will require independent validation.


Assuntos
Biomarcadores/urina , Nefrite Lúpica/diagnóstico , Nefrite Lúpica/urina , Adolescente , Adulto , Criança , Estudos Transversais , Feminino , Humanos , Masculino , Índice de Gravidade de Doença , Adulto Jovem
12.
Ann Intern Med ; 162(12): 860-5, 2015 Jun 16.
Artigo em Inglês | MEDLINE | ID: mdl-26075757

RESUMO

The National Institutes of Health (NIH) Pathways to Prevention Workshop: Advancing the Research on Myalgic Encephalomyelitis/Chronic Fatigue Syndrome was cosponsored by the NIH Office of Disease Prevention and the Trans-NIH Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Research Working Group. A multidisciplinary working group developed the agenda, and an Evidence-based Practice Center prepared an evidence report through a contract with the Agency for Healthcare Research and Quality to facilitate the discussion. During the 1.5-day workshop, invited experts discussed the body of evidence and attendees had the opportunity to comment during open discussions. After weighing evidence from the evidence report, expert presentations, and public comments, an unbiased, independent panel prepared a draft report that identified research gaps and future research priorities. The report was posted on the NIH Office of Disease Prevention Web site for 4 weeks for public comment.


Assuntos
Pesquisa Biomédica , Encefalomielite/terapia , Síndrome de Fadiga Crônica/terapia , Mialgia/terapia , Adulto , Criança , Educação Médica Continuada , Encefalomielite/diagnóstico , Encefalomielite/epidemiologia , Síndrome de Fadiga Crônica/diagnóstico , Síndrome de Fadiga Crônica/epidemiologia , Feminino , Educação em Saúde , Humanos , Incidência , Masculino , Mialgia/diagnóstico , Mialgia/epidemiologia , Equipe de Assistência ao Paciente , Prevalência , Apoio à Pesquisa como Assunto , Estados Unidos/epidemiologia
13.
J Rheumatol ; 41(12): 2459-65, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25179849

RESUMO

OBJECTIVE: To follow children with juvenile idiopathic arthritis (JIA) who had completed at least 6 months of the TRial of Early Aggressive Therapy (TREAT) clinical study for an additional 2 years, describing safety of early aggressive treatment, disease activity, function, and duration of clinical inactive disease (CID) during followup. METHODS: Children were treated as per provider's discretion. Physician, patient/parent, and laboratory measures of disease status as well as safety information were collected at clinic visits every 3 months for up to 2 years. RESULTS: Forty-eight children were followed for a mean of 28 months (range 12-42) beyond the end of the TREAT study. Half of patients were in CID for > 50% of their followup time. Overall, 88% of patients achieved CID at > 1 study visit and 54% achieved clinical remission while taking medication. Six patients were in CID for the duration of the study, and, of those, 2 achieved a full year of clinical remission while not taking medication. Active disease was mild: mean physician's global assessment 2.4, active joint count 3.5, parent global evaluation 2.4, Childhood Health Assessment Questionnaire 0.32, erythrocyte sedimentation rate 19 mm/h, and morning stiffness 23 min. There were no serious adverse events or adverse events reported at grade 3 or higher of Common Terminology Criteria for Adverse Events. CONCLUSION: Early aggressive therapy in this cohort of patients with polyarticular JIA who had high initial disease activity was associated with prolonged periods of CID in the majority of patients during followup. Those not in CID had low levels of disease activity.


Assuntos
Artrite Juvenil/diagnóstico , Artrite Juvenil/tratamento farmacológico , Avaliação da Deficiência , Imunoglobulina G/uso terapêutico , Metotrexato/uso terapêutico , Prednisolona/uso terapêutico , Receptores do Fator de Necrose Tumoral/uso terapêutico , Artrite Juvenil/sangue , Sedimentação Sanguínea , Criança , Quimioterapia Combinada , Etanercepte , Seguimentos , Humanos , Estudos Longitudinais , Estudos Prospectivos , Indução de Remissão , Estudos Retrospectivos , Índice de Gravidade de Doença , Inquéritos e Questionários , Resultado do Tratamento
14.
J Rheumatol ; 41(6): 1163-70, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24786928

RESUMO

OBJECTIVE: To determine the elapsed time while receiving aggressive therapy to the first observation of clinically inactive disease (CID), total duration of CID and potential predictors of this response in a cohort of children with recent onset of polyarticular juvenile idiopathic arthritis (poly-JIA). METHODS: Eighty-five children were randomized blindly to methotrexate (MTX), etanercept, and rapidly tapered prednisolone (MEP) or MTX monotherapy and assessed for CID over 1 year of treatment. Patients who failed to achieve intermediary endpoints were switched to open-label MEP treatment. RESULTS: Fifty-eight (68.2%) of the 85 patients achieved CID at 1 or more visits including 18 who received blinded MEP, 11 while receiving MTX monotherapy, and 29 while receiving open-label MEP. Patients starting on MEP achieved CID earlier and had more study days in CID compared to those starting MTX, but the differences were not significantly different. Patients given MEP (more aggressive therapy) earlier in the disease course were statistically more likely to have a higher proportion of followup visits in CID than those with longer disease course at baseline. Those who achieved American College of Rheumatology Pediatric 70 response at 4 months had a significantly greater proportion of followup visits in CID, compared to those who failed to achieve this improvement (p < 0.0001). Of the 32 patients who met criteria for CID and then lost CID status, only 3 fulfilled the definition of disease flare. CONCLUSION: Shorter disease duration prior to treatment, a robust response at 4 months, and more aggressive therapy result in a higher likelihood and longer duration of CID in patients with poly-JIA. The original trial from which data for this analysis were obtained is registered on www.clinicaltrials.gov NCT 00443430.


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 , Criança , Pré-Escolar , Progressão da Doença , Método Duplo-Cego , Quimioterapia Combinada , Etanercepte , Feminino , Humanos , Masculino , Indução de Remissão , Resultado do Tratamento
15.
Ann Rheum Dis ; 73(2): 401-6, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23345596

RESUMO

OBJECTIVES: This study tested the concurrent validity of the systemic lupus erythematosus responder index (SRI) in assessing improvement in juvenile-onset systemic lupus erythematosus (jSLE). METHODS: The SRI considers changes in the SELENA-SLEDAI, BILAG and a 3-cm visual analogue scale of physician-rated disease activity (PGA) to determine patient improvement. Using prospectively collected data from 760 unique follow-up visit intervals of 274 jSLE patients, we assessed the sensitivity and specificity of the SRI using these external standards: physician-rated improvement (MD-change), patient/parent-rated major improvement of wellbeing (patient-change) and decrease in prescribed systemic corticosteroids (steroid-change). Modifications of the SRI that considered different thresholds for the SELENA-SLEDAI, BILAG and 10-cm PGA were explored and agreement with the American College of Rheumatology/PRINTO provisional criteria for improvement of jSLE (PCI) was examined. RESULTS: The sensitivity/specificity in capturing major improvement by the MD-change were 78%/76% for the SRI and 83%/78% for the PCI, respectively. There was fair agreement between the SRI and PCI (kappa=0.35, 95% CI 0.02 to 0.73) in capturing major improvement by the MD-change. Select modified versions of the SRI had improved accuracy overall. All improvement criteria tested had lower sensitivity when considering patient-change and steroid-change as external standards compared to MD-change. CONCLUSIONS: The SRI and its modified versions based on meaningful changes in jSLE have high specificity but at most modest sensitivity for capturing jSLE improvement. When used as an endpoint of clinical trials in jSLE, the SRI will provide a conservative estimate regarding the efficacy of the therapeutic agent under investigation.


Assuntos
Lúpus Eritematoso Sistêmico/diagnóstico , Índice de Gravidade de Doença , Adolescente , Idade de Início , Criança , Esquema de Medicação , Feminino , Glucocorticoides/administração & dosagem , Glucocorticoides/uso terapêutico , Humanos , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Masculino , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Resultado do Tratamento
16.
Arthritis Res Ther ; 15(6): R198, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24267155

RESUMO

INTRODUCTION: The aim of this study was to assess cancer incidence in childhood-onset systemic lupus erythematosus (SLE). METHODS: We ascertained cancers within SLE registries at 10 pediatric centers. Subjects were linked to cancer registries for the observational interval, spanning 1974 to 2009. The ratio of observed to expected cancers represents the standardized incidence ratio (SIR) or relative cancer risk in childhood-onset SLE, versus the general population. RESULTS: There were 1020 patients aged <18 at cohort entry. Most (82%) were female and Caucasian; mean age at cohort entry was 12.6 years (standard deviation (SD) = 3.6). Subjects were observed for a total of 7,986 (average 7.8) patient-years. Within this interval, only three invasive cancers were expected. However, 14 invasive cancers occurred with an SIR of 4.7, 95% confidence interval (CI) 2.6 to 7.8. Three hematologic cancers were found (two non-Hodgkin's lymphoma, one leukemia), for an SIR of 5.2 (95% CI 1.1 to 15.2). The SIRs stratified by age group and sex, were similar across these strata. There was a trend for highest cancer occurrence 10 to 19 years after SLE diagnosis. CONCLUSIONS: These results suggest an increased cancer risk in pediatric onset SLE versus the general population. In absolute terms, this represents relatively few events. Of note, risk may be highest only after patients have transferred to adult care.


Assuntos
Lúpus Eritematoso Sistêmico/complicações , Neoplasias/complicações , Neoplasias/epidemiologia , Adolescente , Idade de Início , Criança , Feminino , Humanos , Incidência , Masculino , Sistema de Registros , Fatores de Risco
17.
Pediatr Rheumatol Online J ; 10(1): 31, 2012 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-22931206

RESUMO

BACKGROUND: The management of background corticosteroid therapy in rheumatology clinical trials poses a major challenge. We describe the consensus methodology used to design an algorithm to standardize changes in corticosteroid dosing during the Randomized Placebo Phase Study of Rilonacept in Systemic Juvenile Idiopathic Arthritis Trial (RAPPORT). METHODS: The 20 RAPPORT site principal investigators (PIs) and 4 topic specialists constituted an expert panel that participated in the consensus process. The panel used a modified Delphi Method consisting of an on-line questionnaire, followed by a one day face-to-face consensus conference. Consensus was defined as ≥ 75% agreement. For items deemed essential but when consensus on critical values was not achieved, simple majority vote drove the final decision. RESULTS: The panel identified criteria for initiating or increasing corticosteroids. These included the presence or development of anemia, myocarditis, pericarditis, pleuritis, peritonitis, and either complete or incomplete macrophage activation syndrome (MAS). The panel also identified criteria for tapering corticosteroids which included absence of fever for ≥ 3 days in the previous week, absence of poor physical functioning, and seven laboratory criteria. A tapering schedule was also defined. CONCLUSION: The expert panel established consensus regarding corticosteroid management and an algorithm for steroid dosing that was well accepted and used by RAPPORT investigators. Developed specifically for the RAPPORT trial, further study of the algorithm is needed before recommendation for more general clinical use.

18.
J Rheumatol ; 39(10): 2012-20, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-22859342

RESUMO

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.


Assuntos
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 Doença
19.
J Rheumatol ; 39(8): 1687-97, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22589257

RESUMO

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.


Assuntos
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 Especificidade
20.
Arthritis Care Res (Hoboken) ; 64(8): 1175-85, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22505322

RESUMO

OBJECTIVE: Juvenile localized scleroderma (LS) is a chronic inflammatory skin disorder associated with substantial morbidity and disability. Although a wide range of therapeutic strategies has been reported in the literature, a lack of agreement on treatment specifics and accepted methods for clinical assessment has made it difficult to compare approaches and identify optimal therapy. Our objective was to develop standardized treatment plans, clinical assessments, and response criteria for active, moderate to high severity juvenile LS. METHODS: A core group of pediatric rheumatologists, dermatologists, and a lay advisor was engaged by the Childhood Arthritis and Rheumatology Research Alliance (CARRA) to develop standardized treatment plans and assessment parameters for juvenile LS using consensus methods/nominal group techniques. Recommendations were validated in 2 face-to-face conferences with a larger group of practitioners with expertise in juvenile LS and with the full membership of CARRA, which encompasses the majority of pediatric rheumatologists in the US and Canada. RESULTS: Consensus was achieved on standardized treatment plans that reflect the prevailing treatment practices of CARRA members. Standardized clinical assessment methods and provisional treatment response criteria were also developed. Greater than 90% of pediatric rheumatologists responding to a survey (66% of CARRA membership) affirmed the final recommendations and agreed to utilize these consensus plans to treat patients with juvenile LS. CONCLUSION: Using consensus methodology, we have developed standardized treatment plans and assessment methods for juvenile LS. The high level of support among pediatric rheumatologists will support future comparative effectiveness studies and enable the development of evidence-based guidelines for the treatment of juvenile LS.


Assuntos
Consenso , Guias de Prática Clínica como Assunto/normas , Desenvolvimento de Programas/normas , Adolescente , Quimioterapia Combinada , Feminino , Humanos , Masculino , Metotrexato/administração & dosagem , Metilprednisolona/administração & dosagem , Desenvolvimento de Programas/métodos , Ensaios Clínicos Controlados Aleatórios como Assunto/métodos , Ensaios Clínicos Controlados Aleatórios como Assunto/normas , Esclerodermia Localizada/diagnóstico , Esclerodermia Localizada/epidemiologia , Esclerodermia Localizada/terapia , Escleroderma Sistêmico/diagnóstico , Escleroderma Sistêmico/epidemiologia , Escleroderma Sistêmico/terapia , Resultado do Tratamento , Adulto Jovem
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