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1.
Arthritis Rheumatol ; 71(11): 1969-1970, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31233293
2.
Arthritis Rheumatol ; 71(3): 451-459, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30225949

RESUMO

OBJECTIVE: To determine the relationship between serum levels of S100A8/A9 and S100A12 and the maintenance of clinically inactive disease during anti-tumor necrosis factor (anti-TNF) therapy and the occurrence of disease flare following withdrawal of anti-TNF therapy in patients with polyarticular forms of juvenile idiopathic arthritis (JIA). METHODS: In this prospective, multicenter study, 137 patients with polyarticular-course JIA whose disease was clinically inactive while receiving anti-TNF therapy were enrolled. Patients were observed for an initial 6-month phase during which anti-TNF treatment was continued. For those patients who maintained clinically inactive disease over the 6 months, anti-TNF was withdrawn and they were followed up for 8 months to assess for the occurrence of flare. Serum S100 levels were measured at baseline and at the time of anti-TNF withdrawal. Spearman's rank correlation test, Mann-Whitney U test, Kruskal-Wallis test, receiver operating characteristic (ROC) curve, and Kaplan-Meier survival analyses were used to assess the relationship between serum S100 levels and maintenance of clinically inactive disease and occurrence of disease flare after anti-TNF withdrawal. RESULTS: Over the 6-month initial phase with anti-TNF therapy, the disease state reverted from clinically inactive to clinically active in 24 (18%) of the 130 evaluable patients with polyarticular-course JIA; following anti-TNF withdrawal, 39 (37%) of the 106 evaluable patients experienced a flare. Serum levels of S100A8/A9 and S100A12 were elevated in up to 45% of patients. Results of the ROC analysis revealed that serum S100 levels did not predict maintenance of clinically inactive disease during anti-TNF therapy nor did they predict disease flare after treatment withdrawal. Elevated levels of S100A8/A9 were not predictive of the occurrence of a disease flare within 30 days, 60 days, 90 days, or 8 months following anti-TNF withdrawal, and elevated S100A12 levels had a modest predictive ability for determining the risk of flare within 30, 60, and 90 days after treatment withdrawal. Serum S100A12 levels at the time of anti-TNF withdrawal were inversely correlated with the time to disease flare (r = -0.36). CONCLUSION: Serum S100 levels did not predict maintenance of clinically inactive disease or occurrence of disease flare in patients with polyarticular-course JIA, and S100A12 levels were only moderately, and inversely, correlated with the time to disease flare.


Assuntos
Antirreumáticos/uso terapêutico , Artrite Juvenil/sangue , Artrite Juvenil/tratamento farmacológico , Calgranulina A/sangue , Calgranulina B/sangue , Proteína S100A12/sangue , Adolescente , Biomarcadores/sangue , Criança , Pré-Escolar , Feminino , Humanos , Quimioterapia de Manutenção/métodos , Masculino , Exacerbação dos Sintomas , Fatores de Tempo , Resultado do Tratamento , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Suspensão de Tratamento
3.
J Clin Invest ; 128(9): 3957-3975, 2018 08 31.
Artigo em Inglês | MEDLINE | ID: mdl-29969437

RESUMO

Biallelic loss-of-function (LOF) mutations of the NCF4 gene, encoding the p40phox subunit of the phagocyte NADPH oxidase, have been described in only 1 patient. We report on 24 p40phox-deficient patients from 12 additional families in 8 countries. These patients display 8 different in-frame or out-of-frame mutations of NCF4 that are homozygous in 11 of the families and compound heterozygous in another. When overexpressed in NB4 neutrophil-like cells and EBV-transformed B cells in vitro, the mutant alleles were found to be LOF, with the exception of the p.R58C and c.120_134del alleles, which were hypomorphic. Particle-induced NADPH oxidase activity was severely impaired in the patients' neutrophils, whereas PMA-induced dihydrorhodamine-1,2,3 (DHR) oxidation, which is widely used as a diagnostic test for chronic granulomatous disease (CGD), was normal or mildly impaired in the patients. Moreover, the NADPH oxidase activity of EBV-transformed B cells was also severely impaired, whereas that of mononuclear phagocytes was normal. Finally, the killing of Candida albicans and Aspergillus fumigatus hyphae by neutrophils was conserved in these patients, unlike in patients with CGD. The patients suffer from hyperinflammation and peripheral infections, but they do not have any of the invasive bacterial or fungal infections seen in CGD. Inherited p40phox deficiency underlies a distinctive condition, resembling a mild, atypical form of CGD.


Assuntos
Doença Granulomatosa Crônica/genética , Mutação com Perda de Função , Fosfoproteínas/deficiência , Fosfoproteínas/genética , Adolescente , Adulto , Alelos , Criança , Pré-Escolar , Feminino , Técnicas de Inativação de Genes , Doença Granulomatosa Crônica/diagnóstico , Doença Granulomatosa Crônica/metabolismo , Células HEK293 , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas Mutantes/genética , Proteínas Mutantes/metabolismo , NADPH Oxidases/genética , NADPH Oxidases/metabolismo , Linhagem , Fagócitos/imunologia , Fagócitos/metabolismo , Fagócitos/microbiologia , Fenótipo , Fosfoproteínas/metabolismo , Prognóstico , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Transdução Genética , Adulto Jovem
4.
Pediatr Rheumatol Online J ; 16(1): 40, 2018 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-29940960

RESUMO

BACKGROUND: Juvenile dermatomyositis (JDM) is the most common inflammatory myopathy in childhood and a major cause of morbidity among children with pediatric rheumatic diseases. The management of JDM is very heterogeneous. The JDM working group of the Society for Pediatric Rheumatology (GKJR) aims to define consensus- and practice-based strategies in order to harmonize diagnosis, treatment and monitoring of JDM. METHODS: The JDM working group was established in 2015 consisting of 23 pediatric rheumatologists, pediatric neurologists and dermatologists with expertise in the management of JDM. Current practice patterns of management in JDM had previously been identified via an online survey among pediatric rheumatologists and neurologists. Using a consensus process consisting of online surveys and a face-to-face consensus conference statements were defined regarding the diagnosis, treatment and monitoring of JDM. During the conference consensus was achieved via nominal group technique. Voting took place using an electronic audience response system, and at least 80% consensus was required for individual statements. RESULTS: Overall 10 individual statements were developed, finally reaching a consensus of 92 to 100% regarding (1) establishing a diagnosis, (2) case definitions for the application of the strategies (moderate and severe JDM), (3) initial diagnostic testing, (4) monitoring and documentation, (5) treatment targets within the context of a treat-to-target strategy, (6) supportive therapies, (7) explicit definition of a treat-to-target strategy, (8) various glucocorticoid regimens, including intermittent intravenous methylprednisolone pulse and high-dose oral glucocorticoid therapies with tapering, (9) initial glucocorticoid-sparing therapy and (10) management of refractory disease. CONCLUSION: Using a consensus process among JDM experts, statements regarding the management of JDM were defined. These statements and the strategies aid in the management of patients with moderate and severe JDM.


Assuntos
Dermatomiosite/tratamento farmacológico , Antirreumáticos/uso terapêutico , Áustria , Criança , Consenso , Dermatomiosite/diagnóstico , Gerenciamento Clínico , Alemanha , Glucocorticoides/uso terapêutico , Humanos , Inquéritos e Questionários
5.
Pediatr Rheumatol Online J ; 16(1): 38, 2018 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-29925381

RESUMO

BACKGROUND: Juvenile Dermatomyositis (JDM) is a rare pediatric autoimmune disease with broad variations of the individual course. Data on the optimal management are mostly lacking. Currently treatment decisions are often based on experts' opinions. In order to develop consensus-based treatment strategies for JDM in Germany a survey was pursued to analyze the current clinical practice. METHODS: An online survey addressing all members of the Society for Pediatric Rheumatology (GKJR) in Germany and Austria and pediatric neurologists with expertise in JDM was performed in February/March of 2016. The questionnaire consisted of 5 case scenarios including diagnostic criteria, treatment of moderate, severe and refractory JDM, using either multiple choice or a 5-point Likert scale. Basic descriptive statistics were used to analyze the findings. RESULTS: The survey was completed by 60 pediatric rheumatologists and 7 pediatric neurologists experienced in the management of JDM. Typical findings allowing a diagnosis were considered to be: typical skin changes, proximal muscle weakness, MRI findings, elevated muscle enzymes, nailfold capillary changes, presence of calcinosis and muscle biopsy. Regarding induction treatment of moderate/severe JDM: 59%/74% opted for intermittent intravenous methylprednisolone (IVMP) pulse therapy, and 21%/40% for conventional high-dose oral glucocorticoids. Methotrexate (MTX) was the preferred disease-modifying conventional anti-rheumatic drug (cDMARD) for moderate and severe JDM. Regarding the management of refractory moderate or severe JDM, intravenous immune globulins, mycophenolate mofetil and rituximab were preferred treatment options. CONCLUSION: There is consensus about the diagnosis of JDM strongly supported by classic clinical and MRI findings. There is great variety in the treatment of JDM in Germany regarding both induction and maintenance therapy. The development of consensus-based treatment strategies for JDM based on harmonization of current clinical practice is essential in order to allow comparative effectiveness research in the future.


Assuntos
Dermatomiosite/tratamento farmacológico , Padrões de Prática Médica/estatística & dados numéricos , Antirreumáticos/uso terapêutico , Áustria , Criança , Consenso , Dermatomiosite/diagnóstico , Alemanha , Glucocorticoides/uso terapêutico , Humanos , Imunoglobulinas Intravenosas , Neurologistas , Reumatologistas , Inquéritos e Questionários
6.
Pediatr Rheumatol Online J ; 16(1): 15, 2018 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-29499726

RESUMO

BACKGROUND: The goal of this study was to apply the varicella zoster virus (VZV) vaccine to patients with pediatric rheumatic diseases (PRD) at risk for severe chickenpox, without interrupting their current immunosuppression, including biological agents, using an immunological-based pre-vaccination checklist to assure safety. A pre-vaccination checklist was implemented to ensure adequate immune competence prior to immunization. METHODS: This prospective study included seronegative patients (VZV-IgG ≤200 mIU/ml) and patients who had previously received only a single dose of VZV vaccine. All vaccinees demonstrated clinically inactive PRD. Patients were categorized according to their actual treatment in low-intensity IS (LIIS) and high-intensity IS (HIIS) including biological therapy. The pre-vaccination checklist defined thresholds for the following basic laboratory tests: white blood cell count ≥3000/mm3, lymphocytes ≥1200/mm3, serum IgG ≥500 mg/dl, IgM ≥20 mg/dl, tetanus toxoid antibody ≥0.1 IU/ml. In case of HIIS additional specifications included a CD4+ lymphocyte count ≥200/mm3 and a positive T-cell function (via analyzable positive control of a standard tuberculosis interferon-gamma-release-assay (TB-IGRA) indicating mitogen-induced T cell proliferation). Patients who met the criteria of the pre-vaccination checklist received the first and/or second VZV vaccination. Immunologic response and side effects were monitored. RESULTS: Twenty-three patients were recruited of whom nine had already received one VZV immunization before initiating IS. All patients met the pre-vaccination checklist criteria despite ongoing IS. There was no overall difference in VZV-IgG levels when comparing the LIIS (n=9) and HIIS (n=14) groups. In total, 21 patients (91%) showed a positive vaccination response, after the first immunization the median VZV-IgG across all patients was 224 (59-1219) mIU/ml (median (range)), after booster immunization it increased to 882 (30-4685) mIU/ml. Two patients in the HIIS group failed to raise positive VZV-IgG, despite booster immunization. All nine patients receiving only the second immunization on IS reached high titers of VZV-IgG >500 mIU/ml (1117 (513-4685) mIU/ml). There were no cases of rash or other vaccine-induced varicella disease symptoms and no evidence of PRD flare. CONCLUSIONS: VZV vaccination is safe and largely immunogenic in children with ongoing IS fulfilling an immunological based pre-vaccination checklist. This new approach is based on immunologic function rather than on type of medications. TRIAL REGISTRATION NUMBER: ISRCRTN trial registration number 21654693 , date of registration February 12, 2018, retrospectively registered.


Assuntos
Lista de Checagem/métodos , Vacina contra Varicela/administração & dosagem , Varicela/imunologia , Herpesvirus Humano 3/imunologia , Doenças Reumáticas/imunologia , Adolescente , Fatores Biológicos/administração & dosagem , Fatores Biológicos/efeitos adversos , Vacina contra Varicela/efeitos adversos , Criança , Pré-Escolar , Feminino , Alemanha , Humanos , Hospedeiro Imunocomprometido/imunologia , Imunoglobulina G/sangue , Masculino , Estudos Prospectivos , Vacinação/efeitos adversos , Vacinação/métodos
7.
Pediatr Rheumatol Online J ; 16(1): 7, 2018 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-29357887

RESUMO

BACKGROUND: Systemic juvenile idiopathic arthritis (SJIA) is an autoinflammatory disease associated with chronic arthritis. Early diagnosis and effective therapy of SJIA is desirable, so that complications are avoided. The PRO-KIND initiative of the German Society for Pediatric Rheumatology (GKJR) aims to define consensus-based strategies to harmonize diagnostic and therapeutic approaches in Germany. METHODS: We analyzed data on patients diagnosed with SJIA from 3 national registries in Germany. Subsequently, via online surveys and teleconferences among pediatric rheumatologists with a special expertise in the treatment of SJIA, we identified current diagnostic and treatment approaches in Germany. Those were harmonized via the formulation of statements and, supported by findings from a literature search. Finally, an in-person consensus conference using nominal group technique was held to further modify and consent the statements. RESULTS: Up to 50% of patients diagnosed with SJIA in Germany do not fulfill the International League of Associations for Rheumatology (ILAR) classification criteria, mostly due to the absence of chronic arthritis. Our findings suggest that chronic arthritis is not obligatory for the diagnosis and treatment of SJIA, allowing a diagnosis of probable SJIA. Malignant, infectious and hereditary autoinflammatory diseases should be considered before rendering a diagnosis of probable SJIA. There is substantial variability in the initial treatment of SJIA. Based on registry data, most patients initially receive systemic glucocorticoids, however, increasingly substituted or accompanied by biological agents, i.e. interleukin (IL)-1 and IL-6 blockade (up to 27.2% of patients). We identified preferred initial therapies for probable and definitive SJIA, including step-up patterns and treatment targets for the short-term (resolution of fever, decrease in C-reactive protein by 50% within 7 days), the mid-term (improvement in physician global and active joint count by at least 50% or a JADAS-10 score of maximally 5.4 within 4 weeks) and the long-term (glucocorticoid-free clinically inactive disease within 6 to 12 months), and an explicit treat-to-target strategy. CONCLUSIONS: We developed consensus-based strategies regarding the diagnosis and treatment of probable or definitive SJIA in Germany.


Assuntos
Artrite Juvenil/diagnóstico , Padrões de Prática Médica/estatística & dados numéricos , Antirreumáticos/uso terapêutico , Artrite Juvenil/tratamento farmacológico , Fatores Biológicos/uso terapêutico , Criança , Pré-Escolar , Consenso , Bases de Dados Factuais , Alemanha , Glucocorticoides/uso terapêutico , Humanos , Sistema de Registros
9.
Pediatr Rheumatol Online J ; 14(1): 52, 2016 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-27623619

RESUMO

BACKGROUND: High-dose intravenous immune globulins (IVIg) are frequently used in refractory juvenile dermatomyositis (JDM) but are often poorly tolerated. High-dose recombinant human hyaluronidase-facilitated subcutaneous immune globulins (fSCIg) allow the administration of much higher doses of immune globulins than conventional subcutaneous immune globulin therapy and may be an alternative to IVIg. The safety and efficacy of fSCIg therapy in JDM is unknown. CASE PRESENTATION: In this retrospective case series, five patients with steroid-refractory severe JDM were treated with high-dose fSCIg due to IVIg adverse effects (severe headaches, nausea, vomiting, difficult venous access). Peak serum IgG levels, muscle enzymes, the childhood myositis assessment scale and adverse effects were retrieved for at least 6 months following intiation of fSCIg. Data were analyzed by descriptive statistics. Patients initially received fSCIg 1 g/kg every 14 days, resulting in median IgG peak levels of 1901 mg/dl (1606-2719 mg/dl), compared to median IgG peak and trough levels while previously receiving IVIg of 2741 mg/dl (2429-2849 mg/dl) and 1351 mg/dl (1156-1710 mg/dl). Additional antirheumatic therapies consisted of low-dose glucocorticoid therapy, methotrexate, mycophenolate mofetil and/or rituximab. Two patients maintained clinically inactive disease and three patients had only a partial treatment response. In the three patients with partial treatment response, fSCIg 1 g/kg was then given on days 1 and 6 of every 28-day cycle resulting in IgG peak levels of between 2300-2846 mg/dl (previously 1606-1901 mg/dl on the biweekly regimen), resulting in clinically inactive disease in two of the three patients. There were no relevant adverse effects that limited continuation of fSCIg treatment. CONCLUSIONS: High-dose fSCIg is well-tolerated in patients with JDM and high peak serum IgG levels can be achieved which may be important for treatment success. High-dose fSCIg may therefore be an alternative to high-dose IVIg and deserves further study. TRIAL REGISTRATION: This is a case series and data were retrospectively registered.


Assuntos
Dermatomiosite , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/prevenção & controle , Hialuronoglucosaminidase , Imunoglobulinas Intravenosas , Tela Subcutânea , Permeabilidade da Membrana Celular/efeitos dos fármacos , Criança , Dermatomiosite/tratamento farmacológico , Dermatomiosite/imunologia , Dermatomiosite/fisiopatologia , Relação Dose-Resposta a Droga , Monitoramento de Medicamentos/métodos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/etiologia , Feminino , Humanos , Hialuronoglucosaminidase/administração & dosagem , Hialuronoglucosaminidase/farmacocinética , Imunoglobulinas Intravenosas/administração & dosagem , Imunoglobulinas Intravenosas/efeitos adversos , Fatores Imunológicos/administração & dosagem , Fatores Imunológicos/efeitos adversos , Imunomodulação , Masculino , Monitorização Imunológica/métodos , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/farmacocinética , Tela Subcutânea/efeitos dos fármacos , Tela Subcutânea/imunologia , Resultado do Tratamento
10.
Pediatr Dermatol ; 27(5): 500-3, 2010.
Artigo em Inglês | MEDLINE | ID: mdl-20807363

RESUMO

We report an 11-year-old boy with a longstanding history of recurrent pyoderma gangrenosum and abnormal wound healing who eventually developed a fatal invasive fungal infection. This article emphasizes the importance to consider leukocyte adhesion deficiency type 1 in the differential diagnosis of patients with recurrent skin ulcers.


Assuntos
Cicatriz/patologia , Pioderma Gangrenoso/complicações , Pioderma Gangrenoso/patologia , Biópsia , Criança , Cicatriz/etiologia , Cicatriz/imunologia , Evolução Fatal , Humanos , Síndrome da Aderência Leucocítica Deficitária/complicações , Síndrome da Aderência Leucocítica Deficitária/imunologia , Síndrome da Aderência Leucocítica Deficitária/patologia , Masculino , Pioderma Gangrenoso/imunologia , Recidiva , Pele/imunologia , Pele/patologia
11.
Arthritis Res Ther ; 12(3): R123, 2010.
Artigo em Inglês | MEDLINE | ID: mdl-20576155

RESUMO

INTRODUCTION: Previous observations suggest that active systemic juvenile idiopathic arthritis (sJIA) is associated with a prominent erythropoiesis gene-expression signature. The aim of this study was to determine the association of this signature with peripheral blood mononuclear cell (PBMC) subpopulations and its specificity for sJIA as compared with related conditions. METHODS: The 199 patients with JIA (23 sJIA and 176 non-sJIA) and 38 controls were studied. PBMCs were isolated and analyzed for multiple surface antigens with flow cytometry and for gene-expression profiles. The proportions of different PBMC subpopulations were compared among sJIA, non-sJIA patients, and controls and subsequently correlated with the strength of the erythropoiesis signature. Additional gene-expression data from patients with familial hemophagocytic lymphohistiocytosis (FHLH) and from a published sJIA cohort were analyzed to determine whether the erythropoiesis signature was present. RESULTS: Patients with sJIA had significantly increased proportions of immature cell populations, including CD34+ cells, correlating highly with the strength of the erythropoiesis signature. The erythropoiesis signature strongly overlapped with the gene-expression pattern in purified immature erythroid precursors. The expansion of immature cells was most prominently seen in patients with sJIA and anemia, even in the absence of reticulocytosis. Patients with non-sJIA and anemia did not exhibit the erythropoiesis signature. The erythropoiesis signature was found to be prominent in patients with FHLH and in a published cohort of patients with active sJIA, but not in patients with inactive sJIA. CONCLUSIONS: An erythropoiesis signature in active sJIA is associated with the expansion of CD34+ cells, also is seen in some patients with FHLH and infection, and may be an indicator of ineffective erythropoiesis and hemophagocytosis due to hypercytokinemia.


Assuntos
Artrite Juvenil/genética , Artrite Juvenil/patologia , Eritropoese/genética , Perfilação da Expressão Gênica , Leucócitos Mononucleares/patologia , Adolescente , Anemia/genética , Anemia/metabolismo , Antígenos CD/metabolismo , Antígenos CD34/metabolismo , Artrite Juvenil/metabolismo , Estudos de Casos e Controles , Criança , Pré-Escolar , Citocinas/sangue , Feminino , Humanos , Leucócitos Mononucleares/imunologia , Lúpus Eritematoso Sistêmico/genética , Lúpus Eritematoso Sistêmico/metabolismo , Linfo-Histiocitose Hemofagocítica/genética , Linfo-Histiocitose Hemofagocítica/metabolismo , Masculino , Estudos Prospectivos , Receptores da Transferrina/metabolismo
12.
Pediatr Infect Dis J ; 28(10): 927-8, 2009 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-19738512

RESUMO

Kawasaki disease (KD) characteristically presents with prolonged, remittent fever in addition to other clinical findings. We report the case of a 3-month-old boy who developed characteristic manifestations of KD and coronary aneurysms in the absence of fever. This case report underlines the difficulty to diagnose KD in young infants.


Assuntos
Febre , Síndrome de Linfonodos Mucocutâneos/diagnóstico , Aneurisma Coronário/etiologia , Humanos , Lactente , Masculino , Síndrome de Linfonodos Mucocutâneos/patologia , Síndrome de Linfonodos Mucocutâneos/fisiopatologia
13.
Arthritis Rheum ; 60(9): 2772-81, 2009 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-19714584

RESUMO

OBJECTIVE: To determine whether neutrophil gelatinase-associated lipocalin (NGAL) can predict worsening of global and renal disease activity in childhood-onset systemic lupus erythematosus (SLE). METHODS: One hundred eleven patients with childhood-onset SLE were enrolled in a longitudinal, prospective study with quarterly study visits and had at least 3 study visits. At each visit, global disease activity was measured using 3 external standards: the numerically converted British Isles Lupus Assessment Group (BILAG) index, the SLE Disease Activity Index 2000 update score, and the physician's assessment of global disease activity. Renal and extrarenal disease activity were measured by the respective domain scores. The disease course over time was categorized at the most recent visit (persistently active, persistently inactive, improved, or worsening). Plasma and urinary NGAL levels were measured by enzyme-linked immunosorbent assay, and urinary NGAL levels were standardized to the urinary creatinine concentration. The longitudinal changes in NGAL levels were compared with the changes in SLE disease activity using mixed-effect models. RESULTS: Significant increases in standardized urinary NGAL levels of up to 104% were detected up to 3 months before worsening of lupus nephritis (as measured by all 3 external standards). Plasma NGAL levels increased significantly by as much as 26% up to 3 months before worsening of global SLE disease activity as measured by all 3 external standards. Plasma NGAL levels increased significantly by 26% as early as 3 months prior to worsening of lupus nephritis as measured by the BILAG renal score. CONCLUSION: Serial measurement of urinary and plasma NGAL levels may be valuable in predicting impending worsening of global and renal childhood-onset SLE disease activity.


Assuntos
Proteínas da Fase Aguda/urina , Nefropatias/diagnóstico , Nefropatias/metabolismo , Lipocalinas/sangue , Lipocalinas/urina , Lúpus Eritematoso Sistêmico/diagnóstico , Lúpus Eritematoso Sistêmico/metabolismo , Proteínas Proto-Oncogênicas/sangue , Proteínas Proto-Oncogênicas/urina , Índice de Gravidade de Doença , Adolescente , Biomarcadores/sangue , Biomarcadores/urina , Criança , Creatinina/urina , Progressão da Doença , Feminino , Humanos , Nefropatias/complicações , Lipocalina-2 , Estudos Longitudinais , Lúpus Eritematoso Sistêmico/complicações , Masculino , Valor Preditivo dos Testes , Prognóstico , Estudos Prospectivos
14.
Arthritis Rheum ; 60(7): 2113-23, 2009 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-19565504

RESUMO

OBJECTIVE: To determine whether peripheral blood mononuclear cells (PBMCs) from children with recent-onset polyarticular juvenile idiopathic arthritis (JIA) exhibit biologically or clinically informative gene expression signatures. METHODS: Peripheral blood samples were obtained from 59 healthy children and 61 children with polyarticular JIA prior to treatment with second-line medications, such as methotrexate or biologic agents. RNA was extracted from isolated mononuclear cells, fluorescence labeled, and hybridized to commercial gene expression microarrays (Affymetrix HG-U133 Plus 2.0). Data were analyzed using analysis of variance at a 5% false discovery rate threshold after robust multichip analysis preprocessing and distance-weighted discrimination normalization. RESULTS: Initial analysis revealed 873 probe sets for genes that were differentially expressed between polyarticular JIA patients and healthy controls. Hierarchical clustering of these probe sets distinguished 3 subgroups within the polyarticular JIA group. Prototypical patients within each subgroup were identified and used to define subgroup-specific gene expression signatures. One of these signatures was associated with monocyte markers, another with transforming growth factor beta-inducible genes, and a third with immediate early genes. Correlation of gene expression signatures with clinical and biologic features of JIA subgroups suggested relevance to aspects of disease activity and supported the division of polyarticular JIA into distinct subsets. CONCLUSION: Gene expression signatures in PBMCs from patients with recent-onset polyarticular JIA reflect discrete disease processes and offer a molecular classification of disease.


Assuntos
Artrite Juvenil/classificação , Artrite Juvenil/genética , Artrite/classificação , Artrite/genética , Perfilação da Expressão Gênica , Adolescente , Anticorpos Antinucleares/genética , Antirreumáticos/uso terapêutico , Artrite/tratamento farmacológico , Artrite Juvenil/tratamento farmacológico , Estudos de Casos e Controles , Criança , Pré-Escolar , Feminino , Genes Precoces/genética , Humanos , Leucócitos Mononucleares/metabolismo , Leucócitos Mononucleares/patologia , Masculino , Metotrexato/uso terapêutico , Família Multigênica/genética , Fator Reumatoide/genética , Fator de Crescimento Transformador beta/genética
15.
Arthritis Rheum ; 60(7): 2102-12, 2009 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-19565513

RESUMO

OBJECTIVE: To identify differences in peripheral blood gene expression between patients with different subclasses of juvenile idiopathic arthritis (JIA) and healthy controls in a multicenter study of patients with recent-onset JIA prior to treatment with disease-modifying antirheumatic drugs (DMARDs) or biologic agents. METHODS: Peripheral blood mononuclear cells (PBMCs) from 59 healthy children and 136 patients with JIA (28 with enthesitis-related arthritis [ERA], 42 with persistent oligoarthritis, 45 with rheumatoid factor [RF]-negative polyarthritis, and 21 with systemic disease) were isolated from whole blood. Poly(A) RNA was labeled using a commercial RNA amplification and labeling system (NuGEN Ovation), and gene expression profiles were obtained using commercial expression microarrays (Affymetrix HG-U133 Plus 2.0). RESULTS: A total of 9,501 differentially expressed probe sets were identified among the JIA subtypes and controls (by analysis of variance; false discovery rate 5%). Specifically, 193, 1,036, 873, and 7,595 probe sets were different in PBMCs from the controls compared with those from the ERA, persistent oligoarthritis, RF-negative polyarthritis, and systemic JIA patients, respectively. In patients with persistent oligoarthritis, RF-negative polyarthritis, and systemic JIA subtypes, up-regulation of genes associated with interleukin-10 (IL-10) signaling was prominent. A hemoglobin cluster was identified that was underexpressed in ERA patients but overexpressed in systemic JIA patients. The influence of JAK/STAT, ERK/MAPK, IL-2, and B cell receptor signaling pathways was evident in patients with persistent oligoarthritis. In systemic JIA, up-regulation of innate immune pathways, including IL-6, Toll-like receptor/IL-1 receptor, and peroxisome proliferator-activated receptor signaling, were noted, along with down-regulation of gene networks related to natural killer cells and T cells. Complement and coagulation pathways were up-regulated in systemic JIA, with a subset of these genes being differentially expressed in other subtypes as well. CONCLUSION: Expression analysis identified differentially expressed genes in PBMCs obtained early in the disease from patients with different subtypes of JIA and in healthy controls, providing evidence of immunobiologic differences between these forms of childhood arthritis.


Assuntos
Artrite Juvenil/genética , Artrite Juvenil/metabolismo , Perfilação da Expressão Gênica , Leucócitos Mononucleares/metabolismo , Adolescente , Antirreumáticos/uso terapêutico , Artrite/tratamento farmacológico , Artrite/genética , Artrite/metabolismo , Artrite Juvenil/tratamento farmacológico , Estudos de Casos e Controles , Criança , Pré-Escolar , Feminino , Regulação da Expressão Gênica/fisiologia , Humanos , Lactente , Interleucina-6/metabolismo , Leucócitos Mononucleares/citologia , Leucócitos Mononucleares/patologia , Masculino , Receptores Ativados por Proliferador de Peroxissomo/metabolismo , Receptores de Interleucina-1/metabolismo , Receptores Toll-Like/metabolismo
16.
J Pediatr ; 155(1): 136-9, 2009 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-19559299

RESUMO

To report on the efficacy of rituximab (RTX) therapy in standard treatment-refractory, chronic Henoch-Schönlein purpura, a retrospective chart review of 3 pediatric patients treated with RTX for severe refractory chronic Henoch-Schönlein purpura was performed. All 3 patients responded to 1 or 2 courses of RTX without serious adverse events.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Fatores Imunológicos/uso terapêutico , Púrpura de Schoenlein-Henoch/tratamento farmacológico , Adolescente , Corticosteroides/uso terapêutico , Anticorpos Monoclonais Murinos , Criança , Resistência a Medicamentos , Feminino , Humanos , Masculino , Estudos Retrospectivos , Rituximab , Índice de Gravidade de Doença
17.
Clin Rev Allergy Immunol ; 34(3): 372-9, 2008 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-18172780

RESUMO

Wegener's granulomatosis (WG) is a chronic, relapsing, systemic necrotizing vasculitis with typical pathologic findings of granulomatous inflammation and pauci-immune vasculitis. Untreated, the condition has a very high mortality, and contemporary treatment strategies carry a high risk of treatment-related morbidity. Antineutrophil cytoplasmic antibodies (ANCA) play a central role in the pathogenesis of the disease. It is unclear how ANCA develop, but B cells are of major importance in the disease pathogenesis as precursors of ANCA-producing plasma cells and, possibly, also as antigen-presenting and cytokine-producing cells. Therefore, the use of B-cell depletion therapy, e.g., with rituximab appears to be an attractive treatment option in WG. Several small clinical trials and case reports show promising results with a high rate of clinical remissions achieved in patients that were refractory to or intolerant of conventional treatment regimens. However, granulomatous manifestations seemed to be less responsive to B-cell depletion therapy. B-cell depletion therapy was generally well tolerated. A large prospective, randomized, double-blind clinical trial evaluating the efficacy of B-cell depletion therapy in WG is pending.


Assuntos
Anticorpos Anticitoplasma de Neutrófilos/imunologia , Anticorpos Monoclonais/uso terapêutico , Linfócitos B , Granulomatose com Poliangiite/terapia , Imunossupressores/uso terapêutico , Depleção Linfocítica/métodos , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais Murinos , Linfócitos B/imunologia , Doença Crônica , Granulomatose com Poliangiite/imunologia , Granulomatose com Poliangiite/fisiopatologia , Humanos , Imunossupressores/efeitos adversos , Depleção Linfocítica/efeitos adversos , Rituximab
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