Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 115
Filtrar
1.
Proc Natl Acad Sci U S A ; 117(3): 1722-1730, 2020 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-31919284

RESUMO

Viruses activate inflammasomes but then subvert resulting inflammatory responses to avoid elimination. We asked whether viruses could instead use such activated or primed inflammasomes to directly aid their propagation and spread. Since herpesviruses are experts at coopting cellular functions, we investigated whether Epstein-Barr virus (EBV), an oncoherpesvirus, exploits inflammasomes to activate its replicative or lytic phase. Indeed, our experiments reveal that EBV exploits several inflammasome sensors to actually activate its replicative phase from quiescence/latency. In particular, TXNIP, a key inflammasome intermediary, causes assembly of the NLRP3 inflammasome, resulting in caspase-1-mediated depletion of the heterochromatin-inducing epigenetic repressor KAP1/TRIM28 in a subpopulation of cells. As a result, only TXNIPhiKAP1lo cells, that is, in a primed/prolytic state, turn expression of the replication/lytic/reactivation switch protein on to enter the replicative phase. Our findings 1) demonstrate that EBV dovetails its escape strategy to a key cellular danger-sensing mechanism, 2) indicate that transcription may be regulated by KAP1 abundance aside from canonical regulation through its posttranslational modification, 3) mechanistically link diabetes, which frequently activates the NLRP3 inflammasome, to deregulation of a tumor virus, and 4) demonstrate that B lymphocytes from NOMID (neonatal onset multisystem inflammatory disease) patients who have NLRP3 mutations and suffer from hyperactive innate responses are defective in controlling a herpesvirus.

2.
Pediatr Res ; 2019 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-31641281

RESUMO

OBJECTIVE: To develop a set of clinical criteria that identifies patients with a potential autoinflammatory IFNopathy. METHODS: Based on a literature review, a set of clinical criteria identifying genetically confirmed monogenic IFNopathies was selected. For validation, the clinical score was assessed in healthy controls (HCs) and 18 disease controls, including 2 known autoimmune IFNopathies, juvenile systemic lupus erythematosus (JSLE, n = 4) and dermatomyositis (JDM, n = 4); adenosine deaminase 2 deficiency (DADA2, n = 4); and oligoarticular juvenile idiopathic arthritis (oJIA, n = 6). We assessed an IFN score (IRG-S) in whole blood by NanoString using a previously published 28-gene-IRG-S and a reduced 6-gene-IRG-S. RESULTS: The 12 patients with a possible IFNopathy had higher clinical scores (3-5) than the patients with sJLE, JDM, DADA2, and oJIA and in HCs. Both the 28-IRG-S and 6-IRG-S were significantly higher in the autoinflammatory IFNopathy patients compared to HCs and oJIA and DADA2 patients but not different from patients with JSLE and JDM. Subsequently, genetic analysis revealed mutations in genes previously reported in genes related to the IFN pathway in 9 of the 12 patients. CONCLUSION: We developed a clinical score to identify patients with possible autoinflammatory IFNopathies. A clinical score was associated with a high IRG-S and may serve to identify patients with an autoinflammatory IFNopathy.

3.
Clin Immunol ; : 108273, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31626957

RESUMO

Stimulator of interferon genes associated vasculopathy with onset in infancy (SAVI), caused by heterozygote gain-of-function mutations in TMEM173, is characterized by fever attacks with ulcerating cutaneous manifestations on cold-sensitive areas and interstitial lung disease. A six-month-old boy was admitted to our hospital with fever, cough, and rash on the external surface of both upper and lower extremities. Respiratory symptoms consistent with ILD developed and skin lesions evolved to eschar formation particularly on acral regions. Ultimately, diagnosis of SAVI was confirmed at the age of 10 months due to the high level of interferon-score and a heterozygous N154S mutation in TMEM173. Since systemic corticosteroid and ruxolitinib were not effective, baricitinib was initiated at the age of 15 months, resulting in alleviation of fever attacks, cutaneous manifestations and respiratory symptoms within 2 months. In conclusion, we reported an infant diagnosed with SAVI at the age of 10 months and treated with baricitinib.

6.
Ann Rheum Dis ; 78(8): 1025-1032, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31018962

RESUMO

BACKGROUND: Different diagnostic and classification criteria are available for hereditary recurrent fevers (HRF)-familial Mediterranean fever (FMF), tumour necrosis factor receptor-associated periodic fever syndrome (TRAPS), mevalonate kinase deficiency (MKD) and cryopyrin-associated periodic syndromes (CAPS)-and for the non-hereditary, periodic fever, aphthosis, pharyngitis and adenitis (PFAPA). We aimed to develop and validate new evidence-based classification criteria for HRF/PFAPA. METHODS: Step 1: selection of clinical, laboratory and genetic candidate variables; step 2: classification of 360 random patients from the Eurofever Registry by a panel of 25 clinicians and 8 geneticists blinded to patients' diagnosis (consensus ≥80%); step 3: statistical analysis for the selection of the best candidate classification criteria; step 4: nominal group technique consensus conference with 33 panellists for the discussion and selection of the final classification criteria; step 5: cross-sectional validation of the novel criteria. RESULTS: The panellists achieved consensus to classify 281 of 360 (78%) patients (32 CAPS, 36 FMF, 56 MKD, 37 PFAPA, 39 TRAPS, 81 undefined recurrent fever). Consensus was reached for two sets of criteria for each HRF, one including genetic and clinical variables, the other with clinical variables only, plus new criteria for PFAPA. The four HRF criteria demonstrated sensitivity of 0.94-1 and specificity of 0.95-1; for PFAPA, criteria sensitivity and specificity were 0.97 and 0.93, respectively. Validation of these criteria in an independent data set of 1018 patients shows a high accuracy (from 0.81 to 0.98). CONCLUSION: Eurofever proposes a novel set of validated classification criteria for HRF and PFAPA with high sensitivity and specificity.

8.
J Rheumatol ; 46(4): 429-436, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30385706

RESUMO

OBJECTIVE: Provisional evidence-based classification criteria for hereditary periodic fever (HPF) have been recently developed. However, no consensus on how to combine clinical criteria, laboratory tests, and results of molecular analysis has been reached. The objective of this study is to understand which variables physicians consider important for the classification of patients with HPF. METHODS: Two Delphi surveys were sent to health professionals in the field of autoinflammation. In the first open survey, 124 researchers could list all the variables they consider useful for the diagnosis of each monogenic periodic fever. The variables could be of any type and each researcher could complete the survey for 1 or more diseases. In the second survey, 162 researchers were asked to select, from a list of items coming from the first survey, the 10 top variables and to rank them by assigning a score from 10 to 1. RESULTS: The response rates to the Delphi surveys were 85% for the first session and 87% for the second. The variables selected for each disease (corresponding to the third quartile, considering the total score obtained by the variables after the second Delphi survey) were 21 for mevalonate kinase deficiency, 22 for cryopyrinopathies, 18 for familial Mediterranean fever, and 20 for tumor necrosis factor receptor-associated periodic fever syndrome. A positive genetic test reached the top rank in all the HPF. CONCLUSION: Our process led to the identification of those features considered the most important as candidate variables to be included in a new set of evidence-based classification criteria for HPF.

10.
J Clin Immunol ; 39(1): 75-80, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30574673

RESUMO

PURPOSE: Singleton-Merten syndrome manifests as dental dysplasia, glaucoma, psoriasis, aortic calcification, and skeletal abnormalities including tendon rupture and arthropathy. Pathogenic variants in IFIH1 have previously been associated with the classic Singleton-Merten syndrome, while variants in DDX58 has been described in association with a milder phenotype, which is suggested to have a better prognosis. We studied a family with severe, "classic" Singleton-Merten syndrome. METHODS: We undertook clinical phenotyping, next-generation sequencing, and functional studies of type I interferon production in patient whole blood and assessed the type I interferon promoter activity in HEK293 cells transfected with wild-type or mutant DDX58 stimulated with Poly I:C. RESULTS: We demonstrate a DDX58 autosomal dominant gain-of-function mutation, with constitutive upregulation of type I interferon. CONCLUSIONS: DDX58 mutations may be associated with the classic features of Singleton-Merten syndrome including dental dysplasia, tendon rupture, and severe cardiac sequela.


Assuntos
Doenças da Aorta/genética , Proteína DEAD-box 58/genética , Hipoplasia do Esmalte Dentário/genética , Metacarpo/anormalidades , Doenças Musculares/genética , Odontodisplasia/genética , Osteoporose/genética , Calcificação Vascular/genética , Adulto , Linhagem Celular , Feminino , Mutação com Ganho de Função/genética , Células HEK293 , Humanos , Interferon Tipo I/genética , Masculino , Pessoa de Meia-Idade , Fenótipo , Regiões Promotoras Genéticas/genética
11.
Curr Opin Immunol ; 55: 97-105, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30453204

RESUMO

Autoinflammatory diseases are hyperinflammatory, immune dysregulatory diseases caused by innate immune cells dysregulation that present typically in the perinatal period with systemic and organ-targeted inflammation, but with improved genetic testing and the development of diagnostic criteria, milder and later-onset forms are being detected in adulthood. While the discovery of gain-of-function mutations in innate sensors linked to the production of proinflammatory cytokines provided the bases for anti-cytokine therapies that changed disease and patient outcomes, the field is expanding with the increasing discovery of disease-causing loss-of-function mutations in genes with cellular house-keeping functions that affect cell homeostasis and when dysregulated trigger innate inflammatory pathways. This review focuses on updates on molecular pathways and diseases that cause predominantly IL-1ß and Type-I IFN-mediated autoinflammatory diseases.


Assuntos
Doenças Autoimunes/imunologia , Inflamação/imunologia , Animais , Doenças Autoimunes/patologia , Humanos , Imunidade Inata/imunologia , Inflamação/patologia , Interferon Tipo I/imunologia
12.
Proc Natl Acad Sci U S A ; 115(33): E7768-E7775, 2018 08 14.
Artigo em Inglês | MEDLINE | ID: mdl-30061387

RESUMO

The adaptor molecule stimulator of IFN genes (STING) is central to production of type I IFNs in response to infection with DNA viruses and to presence of host DNA in the cytosol. Excessive release of type I IFNs through STING-dependent mechanisms has emerged as a central driver of several interferonopathies, including systemic lupus erythematosus (SLE), Aicardi-Goutières syndrome (AGS), and stimulator of IFN genes-associated vasculopathy with onset in infancy (SAVI). The involvement of STING in these diseases points to an unmet need for the development of agents that inhibit STING signaling. Here, we report that endogenously formed nitro-fatty acids can covalently modify STING by nitro-alkylation. These nitro-alkylations inhibit STING palmitoylation, STING signaling, and subsequently, the release of type I IFN in both human and murine cells. Furthermore, treatment with nitro-fatty acids was sufficient to inhibit production of type I IFN in fibroblasts derived from SAVI patients with a gain-of-function mutation in STING. In conclusion, we have identified nitro-fatty acids as endogenously formed inhibitors of STING signaling and propose for these lipids to be considered in the treatment of STING-dependent inflammatory diseases.


Assuntos
Ácidos Graxos/metabolismo , Herpes Simples/metabolismo , Herpesvirus Humano 2/metabolismo , Proteínas de Membrana/metabolismo , Transdução de Sinais , Animais , Doenças Autoimunes do Sistema Nervoso/genética , Doenças Autoimunes do Sistema Nervoso/metabolismo , Doenças Autoimunes do Sistema Nervoso/patologia , Herpes Simples/genética , Herpes Simples/patologia , Humanos , Interferon Tipo I/genética , Interferon Tipo I/metabolismo , Lipoilação , Lúpus Eritematoso Sistêmico/genética , Lúpus Eritematoso Sistêmico/metabolismo , Lúpus Eritematoso Sistêmico/patologia , Proteínas de Membrana/genética , Camundongos , Camundongos Knockout , Malformações do Sistema Nervoso/genética , Malformações do Sistema Nervoso/metabolismo , Malformações do Sistema Nervoso/patologia , Células RAW 264.7
13.
Nat Commun ; 9(1): 3506, 2018 08 29.
Artigo em Inglês | MEDLINE | ID: mdl-30158636

RESUMO

The transcription factor Nrf2 is a critical regulator of inflammatory responses. If and how Nrf2 also affects cytosolic nucleic acid sensing is currently unknown. Here we identify Nrf2 as an important negative regulator of STING and suggest a link between metabolic reprogramming and antiviral cytosolic DNA sensing in human cells. Here, Nrf2 activation decreases STING expression and responsiveness to STING agonists while increasing susceptibility to infection with DNA viruses. Mechanistically, Nrf2 regulates STING expression by decreasing STING mRNA stability. Repression of STING by Nrf2 occurs in metabolically reprogrammed cells following TLR4/7 engagement, and is inducible by a cell-permeable derivative of the TCA-cycle-derived metabolite itaconate (4-octyl-itaconate, 4-OI). Additionally, engagement of this pathway by 4-OI or the Nrf2 inducer sulforaphane is sufficient to repress STING expression and type I IFN production in cells from patients with STING-dependent interferonopathies. We propose Nrf2 inducers as a future treatment option in STING-dependent inflammatory diseases.


Assuntos
Proteínas de Membrana/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Animais , Linhagem Celular Tumoral , Células Cultivadas , Vírus de DNA/metabolismo , Expressão Gênica/efeitos dos fármacos , Humanos , Interferon Tipo I/metabolismo , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/metabolismo , Proteínas de Membrana/genética , Camundongos , Fator 2 Relacionado a NF-E2/genética , Células RAW 264.7 , RNA Mensageiro/metabolismo , Succinatos/farmacologia
14.
Ann Rheum Dis ; 77(11): 1599-1605, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30077992

RESUMO

INTRODUCTION: Autoinflammatory diseases can cause irreversible tissue damage due to systemic inflammation. Recently, the Autoinflammatory Disease Damage Index (ADDI) was developed. The ADDI is the first instrument to quantify damage in familial Mediterranean fever, cryopyrin-associated periodic syndromes, mevalonate kinase deficiency and tumour necrosis factor receptor-associated periodic syndrome. The aim of this study was to validate this tool for its intended use in a clinical/research setting. METHODS: The ADDI was scored on paper clinical cases by at least three physicians per case, independently of each other. Face and content validity were assessed by requesting comments on the ADDI. Reliability was tested by calculating the intraclass correlation coefficient (ICC) using an 'observer-nested-within-subject' design. Construct validity was determined by correlating the ADDI score to the Physician Global Assessment (PGA) of damage and disease activity. Redundancy of individual items was determined with Cronbach's alpha. RESULTS: The ADDI was validated on a total of 110 paper clinical cases by 37 experts in autoinflammatory diseases. This yielded an ICC of 0.84 (95% CI 0.78 to 0.89). The ADDI score correlated strongly with PGA-damage (r=0.92, 95% CI 0.88 to 0.95) and was not strongly influenced by disease activity (r=0.395, 95% CI 0.21 to 0.55). After comments from disease experts, some item definitions were refined. The interitem correlation in all different categories was lower than 0.7, indicating that there was no redundancy between individual damage items. CONCLUSION: The ADDI is a reliable and valid instrument to quantify damage in individual patients and can be used to compare disease outcomes in clinical studies.


Assuntos
Doenças Hereditárias Autoinflamatórias/diagnóstico , Índice de Gravidade de Doença , Adolescente , Adulto , Criança , Simulação por Computador , Síndromes Periódicas Associadas à Criopirina/complicações , Síndromes Periódicas Associadas à Criopirina/diagnóstico , Febre Familiar do Mediterrâneo/complicações , Febre Familiar do Mediterrâneo/diagnóstico , Doenças Hereditárias Autoinflamatórias/complicações , Humanos , Deficiência de Mevalonato Quinase/complicações , Deficiência de Mevalonato Quinase/diagnóstico , Variações Dependentes do Observador , Sistema de Registros , Reprodutibilidade dos Testes , Adulto Jovem
15.
Nat Commun ; 9(1): 1758, 2018 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-29717110

RESUMO

Although the aetiology of systemic lupus erythematosus (SLE) is unclear, dysregulated B cell responses have been implicated. Here we show that an unusual CD11chiT-bet+ B cell subset, with a unique expression profile including chemokine receptors consistent with migration to target tissues, is expanded in SLE patients, present in nephrotic kidney, enriched for autoreactive specificities and correlates with defined clinical manifestations. IL-21 can potently induce CD11chiT-bet+ B cells and promote the differentiation of these cells into Ig-secreting autoreactive plasma cells. While murine studies have identified a role for T-bet-expressing B cells in autoimmunity, this study describes and exemplifies the importance of CD11chiT-bet+ B cells in human SLE.


Assuntos
Linfócitos B/imunologia , Antígeno CD11c/imunologia , Diferenciação Celular/fisiologia , Interleucinas/fisiologia , Lúpus Eritematoso Sistêmico/metabolismo , Plasmócitos/citologia , Proteínas com Domínio T/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Subpopulações de Linfócitos B , Linfócitos B/metabolismo , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Plasmócitos/imunologia , Adulto Jovem
16.
J Interferon Cytokine Res ; 38(4): 171-185, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29638206

RESUMO

Chronic elevation of interferon (IFN)-response genes (IRG) in a subset of patients with systemic immune-dysregulatory diseases, including the Mendelian Type-I IFN-mediated autoinflammatory diseases and some autoimmune diseases suggest a causative role of excessive IFN signaling in the disease pathogenesis and as target for treatment. We developed a 28-IFN response gene scoring system to calculate either a standardized or geomean score by customizing a NanoString assay to quantify the expression of putative IRGs. The gene targets were selected in patients with the IFN-mediated disease chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE) and an adult patient with chronic hepatitis C who received the first dose of pegylated interferon alpha-2a. The putative target genes were validated in patients with STING-associated vasculopathy with onset in infancy (SAVI), a monogenic autoinflammatory disease caused by gain-of-function mutations in TMEM173 that encodes the viral sensor stimulator of IFN genes (STING), and had low expression in clinically active patients with the monogenic IL-1-mediated autoinflammatory disease, neonatal-onset multisystem inflammatory disease (NOMID) and in healthy controls. The score calculation on the NanoString assay is rapid and showed high reproducibility and low intra-, and interassay variability. The utility of this 28-gene IFN score may be explored in the diagnosis of patients with presumed interferonopathies and as a biomarker to assess disease activity, long-term outcome, and treatment responses.


Assuntos
Doenças Autoimunes/diagnóstico , Doenças Autoimunes/genética , Interferons/imunologia , Técnicas de Amplificação de Ácido Nucleico , Adolescente , Adulto , Doenças Autoimunes/imunologia , Doenças Autoimunes/fisiopatologia , Biomarcadores/análise , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Interferons/metabolismo , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Adulto Jovem
18.
Blood ; 131(13): 1442-1455, 2018 03 29.
Artigo em Inglês | MEDLINE | ID: mdl-29326099

RESUMO

Hemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS) are life-threatening hyperferritinemic systemic inflammatory disorders. Although profound cytotoxic impairment causes familial HLH (fHLH), the mechanisms driving non-fHLH and MAS are largely unknown. MAS occurs in patients with suspected rheumatic disease, but the mechanistic basis for its distinction is unclear. Recently, a syndrome of recurrent MAS with infantile enterocolitis caused by NLRC4 inflammasome hyperactivity highlighted the potential importance of interleukin-18 (IL-18). We tested this association in hyperferritinemic and autoinflammatory patients and found a dramatic correlation of MAS risk with chronic (sometimes lifelong) elevation of mature IL-18, particularly with IL-18 unbound by IL-18 binding protein, or free IL-18. In a mouse engineered to carry a disease-causing germ line NLRC4T337S mutation, we observed inflammasome-dependent, chronic IL-18 elevation. Surprisingly, this NLRC4T337S-induced systemic IL-18 elevation derived entirely from intestinal epithelia. NLRC4T337S intestines were histologically normal but showed increased epithelial turnover and upregulation of interferon-γ-induced genes. Assessing cellular and tissue expression, classical inflammasome components such as Il1b, Nlrp3, and Mefv predominated in neutrophils, whereas Nlrc4 and Il18 were distinctly epithelial. Demonstrating the importance of free IL-18, Il18 transgenic mice exhibited free IL-18 elevation and more severe experimental MAS. NLRC4T337S mice, whose free IL-18 levels were normal, did not. Thus, we describe a unique connection between MAS risk and chronic IL-18, identify epithelial inflammasome hyperactivity as a potential source, and demonstrate the pathogenicity of free IL-18. These data suggest an IL-18-driven pathway, complementary to the cytotoxic impairment of fHLH, with potential as a distinguishing biomarker and therapeutic target in MAS.


Assuntos
Interleucina-18/imunologia , Síndrome de Ativação Macrofágica/imunologia , Transdução de Sinais/imunologia , Substituição de Aminoácidos , Animais , Proteínas Reguladoras de Apoptose/genética , Proteínas Reguladoras de Apoptose/imunologia , Proteínas Adaptadoras de Sinalização CARD/genética , Proteínas Adaptadoras de Sinalização CARD/imunologia , Proteínas de Ligação ao Cálcio/genética , Proteínas de Ligação ao Cálcio/imunologia , Humanos , Inflamassomos/genética , Inflamassomos/imunologia , Peptídeos e Proteínas de Sinalização Intercelular/genética , Peptídeos e Proteínas de Sinalização Intercelular/imunologia , Interleucina-18/genética , Interleucina-1beta/genética , Interleucina-1beta/imunologia , Mucosa Intestinal/imunologia , Mucosa Intestinal/patologia , Linfo-Histiocitose Hemofagocítica/genética , Linfo-Histiocitose Hemofagocítica/imunologia , Linfo-Histiocitose Hemofagocítica/patologia , Síndrome de Ativação Macrofágica/genética , Síndrome de Ativação Macrofágica/patologia , Camundongos , Camundongos Knockout , Mutação de Sentido Incorreto , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia , Pirina/genética , Pirina/imunologia , Transdução de Sinais/genética
20.
Clin Pharmacol Ther ; 104(2): 364-373, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29134648

RESUMO

Population pharmacokinetic (popPK) modeling was used to characterize the PK profile of the oral Janus kinase (JAK)1/JAK2 inhibitor, baricitinib, in 18 patients with Mendelian interferonopathies who are enrolled in a compassionate use program. Patients received doses between 0.1 to 17 mg per day. Covariates of weight and renal function significantly influenced volume-of-distribution and clearance, respectively. The half-life of baricitinib in patients less than 40 kg was substantially shorter than in adult populations, requiring the need for dosing up to 4 times daily. On therapeutic doses, the mean area-under-the-concentration-vs.-time curve was 2,388 nM*hr, which is 1.83-fold higher than mean baricitinib exposures in adult patients with rheumatoid arthritis receiving doses of 4 mg once-daily. Dose-dependent decreases in interferon (IFN) biomarkers confirmed an in vivo effect of baricitinib on type-1 IFN signaling. PopPK and pharmacodynamic data support a proposal for a weight- and estimated glomerular filtration rate-based dosing regimen in guiding baricitinib dosing in patients with rare interferonopathies.


Assuntos
Doenças Autoimunes/tratamento farmacológico , Azetidinas/administração & dosagem , Azetidinas/farmacocinética , Cálculos da Dosagem de Medicamento , Inflamação/tratamento farmacológico , Janus Quinase 1/antagonistas & inibidores , Janus Quinase 2/antagonistas & inibidores , Inibidores de Janus Quinases/administração & dosagem , Inibidores de Janus Quinases/farmacocinética , Modelos Biológicos , Sulfonamidas/administração & dosagem , Sulfonamidas/farmacocinética , Administração Oral , Adolescente , Fatores Etários , Doenças Autoimunes/diagnóstico , Doenças Autoimunes/enzimologia , Doenças Autoimunes/genética , Azetidinas/efeitos adversos , Peso Corporal , Criança , Pré-Escolar , Ensaios de Uso Compassivo , Feminino , Predisposição Genética para Doença , Taxa de Filtração Glomerular , Humanos , Lactente , Inflamação/diagnóstico , Inflamação/enzimologia , Inflamação/genética , Janus Quinase 1/metabolismo , Janus Quinase 2/metabolismo , Inibidores de Janus Quinases/efeitos adversos , Masculino , Sulfonamidas/efeitos adversos , Resultado do Tratamento , Adulto Jovem
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA