RESUMO
OBJECTIVE: The aim of this study was to analyse the role of circulating cleaved IL-1ß in patients with FMF. METHODS: We enrolled 20 patients with FMF (5 males and 15 females), 22 patients with RA (4 males and 18 females) and 22 healthy controls (6 males and 16 females). Serum levels of serum amyloid A (SAA) were measured by ELISA. We also determined whether IL-1ß was present as the cleaved form (p17) in the sera of FMF patients by immunoblotting using anti-cleaved IL-1ß antibody. RESULTS: Although SAA concentrations were elevated in the sera, there was no significant difference in these concentrations between FMF patients and RA patients. Immunoblot analysis demonstrated that the cleaved form of IL-1ß (p17) was present in sera from FMF patients during febrile attack periods, but not in healthy controls. Bands representing the cleaved form of IL-1ß were not detected in serum from FMF patients at non-febrile attack periods or remission periods under colchicine treatment. The amounts of cleaved IL-1ß (p17) were significantly higher in patients with FMF compared with those in patients with RA in the inflammatory phase. CONCLUSION: The cleaved form of IL-1ß is a valuable biomarker for monitoring disease activity and response to colchicine treatment in patients with FMF. It might be useful to discriminate FMF from other non-IL-1ß-mediated inflammatory disorders.
Assuntos
Febre Familiar do Mediterrâneo/metabolismo , Interleucina-1beta/metabolismo , Proteína Amiloide A Sérica/metabolismo , Adulto , Idoso , Artrite Reumatoide/metabolismo , Povo Asiático , Biomarcadores/metabolismo , Estudos de Casos e Controles , Feminino , Humanos , Immunoblotting , Masculino , Pessoa de Meia-IdadeRESUMO
We describe herein a patient who presented with immunoglobulin G4-related disease (IgG4-RD) involving the testis and prostate as well as the submandibular glands. Massive infiltration of IgG4-expressing plasma cells was observed in testis and prostate tissues. Serum concentrations of B cell activating factor belonging to the tumor necrosis factor family (BAFF) were elevated in parallel with serum IgG4 concentrations, and infiltration of BAFF-receptor (BAFF-R)-expressing B cells and BAFF-expressing lymphoid cells was observed around the ectopic lymphoid foci in the affected urogenital tissues. To date, testicular involvement in a patient diagnosed with IgG4-RD had not been reported, making this the first reported case of IgG4-related epididymo-orchitis. These findings suggest that the immune mechanism underlying ectopic lymphoneogenesis in IgG4-RD may involve enhanced BAFF/BAFF-R interactions among lymphoid cells.
Assuntos
Doenças Autoimunes/complicações , Imunoglobulina G/imunologia , Orquite/complicações , Neoplasias da Bexiga Urinária/complicações , Idoso , Doenças Autoimunes/imunologia , Receptor do Fator Ativador de Células B , Humanos , Masculino , Orquite/imunologia , Próstata/imunologia , Testículo/imunologia , Neoplasias da Bexiga Urinária/imunologiaRESUMO
Familial Mediterranean fever (FMF) is an autoinflammatory disorder characterized by recurrent febrile polyserositis and arthritis. Although accompanying seronegative spondyloarthropathy has been reported in FMF, coexistence with rheumatoid arthritis (RA) is very rare. This case report describes a Japanese female RA patient who presented with periodic fever. Genetic analysis revealed compound heterozygous mutations in exon 2 and 3 of the MEFV gene (E148Q/G304R/P369S/R408Q). The patient was successfully treated with colchicine with 3-year follow-up.
Assuntos
Artrite Reumatoide/complicações , Febre Familiar do Mediterrâneo/complicações , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/genética , Colchicina/uso terapêutico , Proteínas do Citoesqueleto/genética , Febre Familiar do Mediterrâneo/tratamento farmacológico , Febre Familiar do Mediterrâneo/genética , Feminino , Humanos , Pessoa de Meia-Idade , Mutação , Pirina , Resultado do TratamentoRESUMO
Familial Mediterranean fever (FMF) is an autosomal recessive disease affecting populations surrounding the Mediterranean area. In this case report, we report a Japanese female patient with polymyositis (PM) who presented with periodic fever. Genetic analysis revealed that she had compound heterozygous mutations in exon 2 of the MEFV gene (L110P/E148Q/R202Q). Treatment with colchicines (1.0 mg/day) successfully eliminated febrile attack and normalized the elevated levels of neutrophil CD64 expression, leading to the diagnosis of FMF. The association of FMF and PM has not previously been reported, so we discuss this rare association.
Assuntos
Febre Familiar do Mediterrâneo/complicações , Polimiosite/complicações , Adulto , Colchicina/uso terapêutico , Proteínas do Citoesqueleto/genética , Análise Mutacional de DNA , Febre Familiar do Mediterrâneo/tratamento farmacológico , Febre Familiar do Mediterrâneo/genética , Feminino , Heterozigoto , Humanos , Mutação , Polimiosite/tratamento farmacológico , Polimiosite/genética , Pirina , Resultado do TratamentoRESUMO
OBJECTIVE: Pentraxin 3 (PTX3) is an acute-phase reactant that is involved in amplification of the inflammatory response and innate immunity. In the present study, we evaluated the relationship between PTX3 and serum amyloid A (SAA), another acute-phase reactant, in rheumatoid synoviocytes. METHODS: PTX3 mRNA expression was examined by reverse transcription polymerase chain reaction, and PTX3 protein was measured by enzyme-linked immunosorbent assay. RESULTS: SAA induced PTX3 mRNA and PTX3 protein expression in rheumatoid synoviocytes. SAA-induced PTX3 expression was attenuated when rheumatoid synoviocytes were nucleofected with N-formyl peptide receptor ligand-1 (FPRL-1)-specific siRNA, suggesting the involvement of FPRL-1. Furthermore, SAA-induced PTX3 expression was inhibited by NF-κB or mitogen-activated protein kinase-specific inhibitors. Neither soluble TNF receptor (etanercept) nor recombinant IL-1 receptor antagonist affected PTX3 production by SAA-stimulated synoviocytes, suggesting that SAA directly induces PTX3. CONCLUSION: Our data suggest that SAA plays a role in the proinflammatory and immune responses in rheumatoid synovium by inducing PTX3. We provide the first evidence that the acute-phase reactant SAA, which is produced systemically by hepatocytes, perpetuates the rheumatoid inflammatory processes by inducing another proinflammatory molecule, PTX3, locally in rheumatoid synovial tissues.
Assuntos
Artrite Reumatoide/metabolismo , Proteína C-Reativa/metabolismo , Osteoartrite/metabolismo , Proteína Amiloide A Sérica/farmacologia , Componente Amiloide P Sérico/metabolismo , Membrana Sinovial/efeitos dos fármacos , Artrite Reumatoide/patologia , Proteína C-Reativa/antagonistas & inibidores , Proteína C-Reativa/genética , Inibidores Enzimáticos/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Inativação Gênica , Humanos , Quinases de Proteína Quinase Ativadas por Mitógeno/antagonistas & inibidores , NF-kappa B/antagonistas & inibidores , Osteoartrite/patologia , RNA Mensageiro/metabolismo , RNA Interferente Pequeno/farmacologia , Receptores de Formil Peptídeo/genética , Receptores de Formil Peptídeo/metabolismo , Receptores de Lipoxinas/genética , Receptores de Lipoxinas/metabolismo , Proteínas Recombinantes , Componente Amiloide P Sérico/antagonistas & inibidores , Componente Amiloide P Sérico/genética , Membrana Sinovial/metabolismo , Membrana Sinovial/patologia , TransfecçãoRESUMO
BACKGROUND/AIMS: Although the outcome of autoimmune hepatitis (AIH) is generally good, the natural course and likelihood of progression to cirrhosis or hepatocellular carcinoma (HCC) remain undefined, and may vary by region and population structure. Our aims were to evaluate risk factors that contribute to poor outcome and particularly development of HCC in a prospective multicentric cohort study of AIH. METHODS: The study group comprised 193 Japanese patients with AIH who were prospectively followed up at annual intervals between 1995 and 2008. The mean follow-up period was 8.0 ± 4.5 years. RESULTS: Twenty-one (10.9%) patients had cirrhosis at presentation and a further 15 (7.8%) developed cirrhosis during the follow-up period. Survival rates were 94.2% at 10 years and 89.3% at 15 years. HCC was diagnosed in seven of the 193 patients. The presence of cirrhosis at presentation was a risk factor for HCC according to a Cox proportional hazard model, and the HCC-free survival rate was significantly lower in those with cirrhosis compared to those without cirrhosis according to Kaplan-Meier analysis. CONCLUSIONS: Although the outcome of AIH is as good if not better among Japanese than for other populations, there was an increased risk of HCC in these patients. Cirrhosis at presentation was predictive of development of HCC in AIH in Japan.
Assuntos
Carcinoma Hepatocelular/mortalidade , Hepatite Autoimune/mortalidade , Neoplasias Hepáticas/mortalidade , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Hepatocelular/patologia , Comorbidade , Progressão da Doença , Feminino , Hepatite Autoimune/patologia , Humanos , Japão/epidemiologia , Cirrose Hepática/mortalidade , Cirrose Hepática/patologia , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Estudos Prospectivos , Fatores de Risco , Taxa de Sobrevida , Adulto JovemRESUMO
BACKGROUND: The new JAK3 inhibitor, CP690,550, has shown efficacy in the treatment of rheumatoid arthritis. The present study was undertaken to assess the effects of CP690,550 on cytokine production and cellular signaling in human CD4(+) T cells. RESULTS: CD4(+) T cells produced IL-2, IL-4, IL-17, IL-22 and IFN-γ in following stimulation with a CD3 antibody. At the optimal concentration, CP690,550 almost completely inhibited the production of IL-4, IL-17, IL-22 and IFN-γ from these activated CD4(+) T cells, but only had marginal effects on IL-2 production. Moreover CP690,550 inhibited anti-CD3-induced phosphorylation of STAT1, STAT3, STAT4, STAT5, and STAT6, but not the TCR-associated phosphorylation of ZAP-70. CONCLUSIONS: Therefore, CP690,550-mediated modification of the JAK/STAT pathway may be a new immunosuppressive strategy in the treatment of autoimmune diseases.
Assuntos
Artrite Reumatoide/imunologia , Linfócitos T CD4-Positivos/efeitos dos fármacos , Janus Quinase 3/antagonistas & inibidores , Pirimidinas/farmacologia , Pirróis/farmacologia , Fatores de Transcrição STAT/metabolismo , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/metabolismo , Artrite Reumatoide/tratamento farmacológico , Complexo CD3/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD4-Positivos/patologia , Células Cultivadas , Citocinas/metabolismo , Humanos , Terapia de Imunossupressão , Ativação Linfocitária/efeitos dos fármacos , Fosforilação , Piperidinas , Receptores de Antígenos de Linfócitos T/metabolismo , Fatores de Transcrição STAT/imunologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologiaRESUMO
BACKGROUND: Heparin-induced thrombocytopenia (HIT) is a thromboembolic complication that can occur with unfractionated heparin (UFH) or low molecular weight heparin (LMWH). Our objective was to determine and compare the incidence of IgG-class HIT antibodies in patients undergoing total hip arthroplasty (THA) or total knee arthroplasty (TKA) with different antithrombotic prophylaxis therapies and their contributions to the occurrence of venous thromboembolism (VTE). METHODS: A prospective observational study was performed for 374 Japanese patients undergoing THA or TKA to determine the incidence of VTE. IgG-class anti-PF4/heparin antibodies were measured using IgG-specific EIA before and after the operation. RESULTS: In the clinical outcome, the incidence of symptomatic deep vein thrombosis (DVT) was 15.0% (56/374, TKA; 35, THA; 21) and pulmonary emboli (PE) were not observed. The total seroconversion incidence of IgG-class PF4/heparin antibodies was 19.8% (74/374). The seroconversion incidence of IgG-class PF4/heparin antibodies was higher in patients receiving UFH (32.7%) compared to those receiving LMWH (9.5%) or fondaparinux (14.8%). Furthermore, the seroconversion incidence was significantly higher in patients undergoing TKA compared to those undergoing THA. Based on multivariate analysis, seroconversion of the IgG-class PF4/heparin antibodies was independent a risk factor for symptomatic DVT. CONCLUSION: Our findings show that the seroconversion of IgG-class anti-PF4/heparin antibodies differed with various anti-thrombotic prophylaxis therapeutics and was associated with the risk of DVT in a subset of patients undergoing total joint arthroplasty (TKA and THA).
Assuntos
Autoanticorpos/biossíntese , Heparina/efeitos adversos , Heparina/imunologia , Imunoglobulina G/classificação , Fator Plaquetário 4/imunologia , Trombose Venosa/diagnóstico , Trombose Venosa/etiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Autoanticorpos/sangue , Autoanticorpos/classificação , Feminino , Humanos , Imunoglobulina G/biossíntese , Imunoglobulina G/sangue , Masculino , Pessoa de Meia-Idade , Fator Plaquetário 4/efeitos adversos , Estudos Prospectivos , Trombose Venosa/tratamento farmacológicoRESUMO
OBJECTIVES: Takayasu arteritis (TA) is a chronic vasculitis that affects large elastic arteries. Monitoring of disease activity is crucial because the disease may progress despite treatment with glucocorticoids. Elevated levels of B cell activating factor belonging to TNF family (BAFF) have been observed in patients with autoimmune diseases. In this study, we investigated whether dysregulation of BAFF occurs in TA. METHODS: Serum levels of BAFF were measured in sera from 9 patients with TA including 6 patients with follow up after induction therapy. RESULTS: Circulating BAFF levels in TA patients were higher than in those in healthy subjects. The high levels of BAFF in active TA patients were decreased when the patients entered remission. CONCLUSIONS: To our knowledge, this is the first study to show elevated levels of BAFF in active TA patients. These findings suggest that this cytokine contributes to vasculitis in TA and raise the possibility that monitoring of serum BAFF might aid clinicians in making adequate treatment adjustments in TA patients.
Assuntos
Fator Ativador de Células B/sangue , Biomarcadores/sangue , Índice de Gravidade de Doença , Arterite de Takayasu/sangue , Arterite de Takayasu/diagnóstico , Proteínas de Fase Aguda/metabolismo , Adulto , Idoso , Fator Ativador de Células B/imunologia , Linfócitos B/imunologia , Progressão da Doença , Ensaio de Imunoadsorção Enzimática , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Arterite de Takayasu/terapia , Adulto JovemRESUMO
BACKGROUND: Pneumococcal pneumonia is the most frequent form of pneumonia. We herein assessed the effectiveness of the 23-valent pneumococcal polysaccharide vaccine (PPSV23) in the prevention of pneumonia overall in rheumatoid arthritis (RA) patients at risk for infections. We hypothesized that PPSV23 vaccination is superior in preventing pneumococcal pneumonia compared with placebo in RA patients. METHODS: A prospective, multicenter, double-blinded, randomized, placebo-controlled (1:1) trial was conducted across departments of rheumatology in Japanese National Hospital Organization hospitals. RA patients (n = 900) who had been treated with biological or immunosuppressive agents were randomly assigned PPSV23 or placebo (sodium chloride). The primary endpoints were the incidences of all-cause pneumonia and pneumococcal pneumonia. The secondary endpoint was death from pneumococcal pneumonia, all-cause pneumonia, or other causes. Cox regression models were used to estimate the risk of pneumonia overall for the placebo group compared with the vaccine group. RESULTS: Seventeen (3.7%) of 464 patients in the vaccine group and 15 (3.4%) of 436 patients in the placebo group developed pneumonia. There was no difference in the rates of pneumonia between the two study groups. The overall rate of pneumonia was 21.8 per 1000 person-years for patients with RA. The presence of interstitial pneumonia (hazard ratio: 3.601, 95% confidence interval: 1.547-8.380) was associated with an increased risk of pneumonia in RA patients. CONCLUSION: PPSV23 does not prevent against pneumonia overall in RA patients at relative risk for infections. Our results also confirm that the presence of interstitial lung disease is associated with pneumonia in Japanese patients with RA. TRIAL REGISTRATION: UMIN-CTR UMIN000009566 . Registered 17 December 2012.
Assuntos
Artrite Reumatoide/complicações , Vacinas Pneumocócicas/uso terapêutico , Pneumonia Pneumocócica/prevenção & controle , Streptococcus pneumoniae/efeitos dos fármacos , Idoso , Método Duplo-Cego , Feminino , Interações Hospedeiro-Patógeno/efeitos dos fármacos , Interações Hospedeiro-Patógeno/imunologia , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Avaliação de Resultados em Cuidados de Saúde/métodos , Avaliação de Resultados em Cuidados de Saúde/estatística & dados numéricos , Vacinas Pneumocócicas/imunologia , Pneumonia Pneumocócica/complicações , Pneumonia Pneumocócica/microbiologia , Modelos de Riscos Proporcionais , Estudos Prospectivos , Streptococcus pneumoniae/imunologia , Streptococcus pneumoniae/fisiologiaRESUMO
We conducted a randomized clinical trial to compare the effectiveness of the A-V Impulse System foot pump for reducing the incidence of deep-vein thrombosis (DVT) after total knee arthroplasty (TKA) in patients under edoxaban thromboprophylaxis. Patients undergoing primary TKA at our institution between September 2013 and March 2015 were enrolled after obtaining informed consent. The patients were randomized to use the foot pump (n = 58) and not to use the foot pump (n = 62). Both groups were given prophylactic edoxaban. Primary outcomes were any DVT as detected by bilateral ultrasonography up to postoperative day 10 (POD10) and pulmonary embolism (PE) up to POD28. The safety outcomes were bleeding and death of any cause up to POD28. Plasma D-dimer levels were measured before TKA and on POD10 after TKA. Immunoglobulin G (IgG)-class anti-PF4/heparin antibodies were measured using an IgG-specific enzyme-linked immunosorbent assay. The incidences of any DVT up to POD28 were 31.0% and 17.7% in patients with or without the foot pump, respectively. The incidences of major bleeding up to POD28 were 5.1% and 4.8% in patients with or without the foot pump, respectively. Foot pump use did not significantly reduce the incidence of DVTs in patients undergoing TKA under edoxaban thromboprophylaxis. Although seroconversion of anti-PF4/heparin antibodies was confirmed in one-fourth of patients, the seroconversion rates did not differ between patients with (20.7%) or without (25.8%) foot pump use. This study shows that the A-V Impulse system foot pump did not affect the incidence of DVT under edoxaban thromboprophylaxis in patients undergoing TKA. Seroconversion of anti-PF4/heparin antibodies was detected in a significant number of patients who underwent TKA under antithrombotic prophylaxis using edoxaban.
Assuntos
Artroplastia do Joelho/reabilitação , Modalidades de Fisioterapia , Complicações Pós-Operatórias/prevenção & controle , Trombose Venosa/prevenção & controle , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Anticoagulantes/administração & dosagem , Índice de Massa Corporal , Feminino , Humanos , Incidência , Japão , Masculino , Embolia Pulmonar/prevenção & controle , Piridinas/administração & dosagem , Fatores Sexuais , Tiazóis/administração & dosagemRESUMO
BACKGROUND: Heparin-induced thrombocytopenia is caused by antibodies (Abs) specific to platelet factor 4 (PF4)/heparin complexes. In this study, we evaluated the rates of seroconversion of anti-PF4/heparin Ab between patients with rheumatoid arthritis (RA) and with osteoarthritis (OA) who underwent total knee arthroplasty. METHODS: The subjects of this randomized controlled trial were 124 patients who underwent total knee arthroplasty (TKA) and received edoxaban with or without a foot pump as thromboprophylaxis. We measured anti-PF4/heparin Abs before and 10 days after surgery, as well as preoperative PF4, using commercially available ELISAs. We also used the database of J-PSVT, a hospital-based, prospective cohort study designed to document the effectiveness of thromboprophylactic agents during arthroplasty. RESULTS: The rates of seroconversion to anti-PF4/heparin Ab were lower in RA patients (4.0 %) than in OA patients (25.5 %). The anti-PF4/heparin IgG optical density (OD) values did not differ before and after surgery in RA patients. In contrast, there was a significant increase in anti-PF4/heparin IgG OD values in OA patients after TKA. In the J-PSVT data, the postoperative seroconversion rates of anti-PF4/heparin Ab were lower in RA patients (10.4 %) than in OA patients (21.8 %) who received fondaparinux. The titers of anti-CCP Ab were significantly lower in RA patients with postoperative ant-PF4/heparin Ab compared with those without postoperative ant-PF4/heparin Ab There was no significant difference in preoperative PF4 levels between RA patients and OA patients. The heparin-binding affinity of the circulating PF4 was similar between RA patients and OA patients; however, the IgG fractions isolated from the sera of RA patients contained PF4 more frequently (69.2 %) than those from OA patients (10.2 %). CONCLUSIONS: Our results showed a reduced likelihood of postoperative anti-PF/heparin Ab production in RA patients compared with OA patients. This suggests that the mechanisms underlying the anti-PF4 immune response in RA patients differ from the mechanisms of the anti-PF4/heparin immune response seen in OA patients after joint replacement. TRIAL REGISTRATION: ISRCTN 18090286. Registered 8 July 2016.
Assuntos
Artrite Reumatoide/imunologia , Inibidores do Fator Xa/efeitos adversos , Fator Plaquetário 4/imunologia , Piridinas/efeitos adversos , Tiazóis/efeitos adversos , Trombocitopenia/induzido quimicamente , Idoso , Artrite Reumatoide/cirurgia , Artroplastia do Joelho/efeitos adversos , Autoanticorpos/imunologia , Autoantígenos/imunologia , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Immunoblotting , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Masculino , Pessoa de Meia-Idade , Osteoartrite/cirurgia , Fator Plaquetário 4/sangue , Soroconversão , Tromboembolia/etiologia , Tromboembolia/prevenção & controleRESUMO
BACKGROUND: The aim of this study was to evaluate the clinical manifestations and prevalence of familial Mediterranean fever (FMF) in Japanese patients with unexplained fever and rheumatic manifestations. METHODS: We enrolled 601 patients with unexplained fever or suspected FMF throughout Japan between 2009 and 2015. Patients were divided into three groups according to Tel Hashomer criteria: sure FMF, probable FMF, and non-FMF patients, including definitive rheumatic diseases. Mutation detection in exons 1, 2, 3, and 10 of the FMF gene MEFV was performed by direct sequencing. RESULTS: A total of 192 patients (31.9 %) were diagnosed with FMF according to FMF diagnostic criteria. These could be divided into sure FMF (56.3 %, n = 108) and probable FMF (43.7 %, n = 84) patients. Fever, abdominal symptoms, and thoracic symptoms were significantly more common in FMF than non-FMF patients. Among FMF patients, 26 (13.5 %) had concomitant rheumatic diseases. Most FMF patients (94.3 %, 181/192) carried at least one MEFV mutation. Allele frequencies of M694I (13.5 % vs 0 %) and E148Q (39.1 % vs 24.8 %) mutations were significantly higher in FMF compared with healthy subjects. Allele frequencies of common MEFV mutations in FMF patients were M694I (13.5 %), P369S (8.6 %), R408Q (8.1 %), G304R (2.9 %), R202Q (4.4 %), E148Q (39.1 %), L110P (11.7 %), and E84K (3.1 %). Patients with a sure FMF phenotype had a higher frequency of MEFV exon 10 mutation (M694I) and a lower frequency of MEFV exon 3 mutations (P369S, R408Q) compared with those with a probable FMF phenotype. CONCLUSION: The high prevalence of FMF in Japanese patients with unexplained fever was confirmed in the present study. FMF should be suspected in cases of unexplained fever or non-specific rheumatic manifestations, and mutational analysis of MEFV could be useful to predict the clinical phenotypes of FMF in Japan.
Assuntos
Febre Familiar do Mediterrâneo/epidemiologia , Doenças Raras/epidemiologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Análise Mutacional de DNA , Febre Familiar do Mediterrâneo/genética , Feminino , Frequência do Gene , Humanos , Lactente , Recém-Nascido , Japão/epidemiologia , Masculino , Pessoa de Meia-Idade , Mutação , Reação em Cadeia da Polimerase , Prevalência , Adulto JovemRESUMO
Few data are available regarding vertebral fracture risk in patients treated with corticosteroids including patients with interstitial lung disease (ILD). The aim of the present study was to identify risk factors for symptomatic vertebral fracture analyzed in patients with newly diagnosed autoimmune diseases.This was an observational cohort study conducted in the National Hospital Organization-EBM study group from 2006 to 2008. The study subjects were autoimmune disease patients who were newly treated with glucocorticoids (GCs). The primary endpoint was the first occurrence of vertebral fracture diagnosed by x-rays. Cox proportional-hazards regression was used to determine independent risk factors for vertebral fracture with covariates including sex, age, comorbidity, laboratory data, use of immunosuppressants, and dose of GCs. Survival was analyzed according to the Kaplan-Meier method and assessed by the log-rank test.Among 604 patients of mean age 59.5 years and mean GC dose 50.4âmg/d (first 1 months), 19 patient (3.1%) had at least 1 symptomatic vertebral fracture during 1.9 years of follow-up period. Cox regression model demonstrated that the relative risk for symptomatic vertebral fracture was independently higher in patient with ILD (hazard ratio [HR]â=â2.86, 95% confidence interval [CI]â=â1.10-7.42, Pâ=â0.031) and in every 10-year increment of the age of disease onset (HRâ=â1.57, 95% CIâ=â1.09-2.26, Pâ=â0.015). Kaplan-Meier analyses demonstrated that the incidence of vertebral fractures in patients with ILD was significantly higher in comparison with those without ILD.Our results indicate a higher risk of vertebral facture in patients with ILD and elderly patients during the initial GC treatment against autoimmune diseases. There is a need for further, even longer-term, prospective studies subjected patients with autoimmune disease, including ILD, under GC treatment.
Assuntos
Doenças Autoimunes/complicações , Doenças Autoimunes/tratamento farmacológico , Glucocorticoides/efeitos adversos , Doenças Pulmonares Intersticiais/complicações , Fraturas da Coluna Vertebral/induzido quimicamente , Adulto , Fatores Etários , Idoso , Comorbidade , Relação Dose-Resposta a Droga , Feminino , Glucocorticoides/uso terapêutico , Humanos , Imunossupressores/uso terapêutico , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Fatores de Risco , Fatores SexuaisRESUMO
OBJECTIVE: To compare the incidence of venous thromboembolism (VTE) following total knee arthroplasty (TKA) between patients with rheumatoid arthritis (RA) and those with osteoarthritis (OA). METHODS: The subjects were composed of 1084 Japanese patients with OA and 204 with RA. Primary effectiveness outcomes were any deep vein thrombosis (DVT) as detected by bilateral ultrasonography up to postoperative Day 10 (POD10) and pulmonary embolism (PE) up to POD28. The main safety outcomes were bleeding and death from any cause up to POD28. Plasma D-dimer levels were measured before and at POD10 after TKA. RESULTS: The study cohort was composed of 1288 patients from 34 hospitals. There was no death up to POD28. PE occurred in 2 patients with OA and in no patients with RA. The incidence of primary effectiveness outcome was 24.3% and 24.0% in patients with OA and RA, respectively. The incidence of major bleeding up to POD28 was 1.3% and 0.5% in patients with OA and RA, respectively. No differences in the incidence of VTE (symptomatic/asymptomatic DVT plus PE) or bleeding were noted between patients with RA and OA. D-dimer levels on POD10 were significantly higher in patients with OA compared with those with RA. Also, D-dimer levels on POD10 were significantly lower in patients receiving fondaparinux than in patients without pharmacological prophylaxis. CONCLUSION: Despite some differences in demographic data, patients with RA and OA have equivalent risks of VTE and bleeding following TKA.
Assuntos
Artrite Reumatoide/cirurgia , Artroplastia do Joelho/efeitos adversos , Articulação do Joelho/cirurgia , Osteoartrite do Joelho/cirurgia , Tromboembolia Venosa/etiologia , Distribuição por Idade , Idoso , Idoso de 80 Anos ou mais , Artrite Reumatoide/complicações , Artrite Reumatoide/diagnóstico , Artroplastia do Joelho/métodos , Estudos de Coortes , Bases de Dados Factuais , Feminino , Fibrinolíticos , Humanos , Incidência , Japão , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Osteoartrite do Joelho/complicações , Osteoartrite do Joelho/diagnóstico por imagem , Cuidados Pós-Operatórios , Complicações Pós-Operatórias/diagnóstico , Complicações Pós-Operatórias/epidemiologia , Estudos Prospectivos , Radiografia , Medição de Risco , Distribuição por Sexo , Resultado do Tratamento , Tromboembolia Venosa/tratamento farmacológico , Tromboembolia Venosa/epidemiologiaRESUMO
INTRODUCTION: Patients with rheumatoid arthritis (RA) treated with abatacept (ABT) are at increased risk for vaccine-preventable infections. The aim of the present study is to evaluate the humoral response to 23-valent pneumococcal polysaccharide (PPSV23) vaccination in RA patients receiving ABT. METHODS: The immunogenicity study was nested within a randomized, double-blind placebo-controlled study, designed to evaluate the efficacy of the PPSV23. PPSV23 was given to 111 RA patients, who were classified into three groups: RA control (n = 35), methotrexate (MTX) alone (n = 55), and ABT (n = 21). Before and 4-6 weeks after vaccination, we measured the patients' concentrations of antibodies against pneumococcal serotypes 6B and 23F using an enzyme-linked immunosorbent assay and determined their antibody functionality using a multiplexed opsonophagocytic killing assay, reported as the opsonization index (OI). RESULTS: The pneumococcal serotype-specific IgG concentrations and OIs were both significantly increased in all treatment groups in response to PPSV23 vaccination. In the ABT group, the IgG responses for the 6B serotype were lower compared with those in the MTX alone or control groups, whereas the OI responses were similar to those in the other two groups. In a subgroup analysis, the pneumococcal serotype-specific IgG responses were significantly lower in both serotypes (6B and 23F) in the ABT/MTX group; however, the OI responses in the ABT group were not different from the control group. There was no association between the pneumococcal serotype-specific IgG and OI responses for the 6B serotype in patients receiving ABT in contrast to the control or MTX alone patients. No severe adverse effects were observed in any of the treatment groups. CONCLUSIONS: OI responses indicate antibody functionality rather than simply their amount, so the similarity of these measurements between all three groups suggests that RA patients receiving ABT still benefit from receiving the PPSV23 vaccination, even though they produce less IgG in response to it. The results suggest an influence of ABT on the humoral response to PPSV23 vaccination under MTX treatment; however, preserved opsonin responses are expected in RA patients treated with ABT plus MTX. TRIAL REGISTRATION: University Hospital Medical Information Network Clinical Trials Registry: UMIN000009566. Registered 12 December 2012.
Assuntos
Anticorpos Antibacterianos/sangue , Artrite Reumatoide/imunologia , Imunidade Humoral/imunologia , Vacinas Pneumocócicas/imunologia , Abatacepte/uso terapêutico , Idoso , Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Método Duplo-Cego , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Masculino , Metotrexato/uso terapêutico , Pessoa de Meia-Idade , Pneumonia Pneumocócica/prevenção & controleRESUMO
Vaccination against Streptococcus pneumoniae is recommended for rheumatoid arthritis (RA) patients receiving immunosuppressive treatments. The objective of this study was to evaluate the humoral response to 23-valent pneumococcal polysaccharide vaccination (PPSV23) in RA patients receiving methotrexate (MTX) alone or in combination with a tumor necrosis factor inhibitor, golimumab (GOM).PPSV23 was given to 114 RA patients, who were classified into three groups: RA control (nâ=â35), MTX alone (nâ=â55), and GOMâ+âMTX (nâ=â24). Before and 4 to 6 weeks after vaccination, concentrations of antibodies against pneumococcal serotypes 6B and 23F were measured using an enzyme-linked immunosorbent assay and antibody functionality was determined using a multiplexed opsonophagocytic killing assay, reported as the opsonization index (OI).The IgG concentrations and OIs were both significantly increased in all treatment groups in response to PPSV23 vaccination. In the GOMâ+âMTX group, the IgG responses were lower than those in the MTX alone or control groups, whereas the OI responses were similar to those in the other 2 groups. Furthermore, discrepancies between the IgG and OI responses were found in GOMâ+âMTX group. No severe adverse effect was observed in any treatment groups.OI responses indicate that antibody functionality rather than antibody quantity is important. The similarity of these measurements between all 3 groups suggests that RA patients receiving MTXâ+âGOM still benefit from receiving the PPSV23 vaccination, even though they produce less IgG in response to it. These results can help clinicians to better schedule and evaluate pneumococcal vaccination for RA patients.
Assuntos
Anticorpos Monoclonais , Formação de Anticorpos/efeitos dos fármacos , Artrite Reumatoide , Metotrexato , Vacinas Pneumocócicas , Pneumonia Pneumocócica/prevenção & controle , Idoso , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/imunologia , Antirreumáticos/administração & dosagem , Antirreumáticos/imunologia , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/imunologia , Método Duplo-Cego , Monitoramento de Medicamentos/métodos , Feminino , Humanos , Imunoglobulina G/sangue , Imunossupressores/administração & dosagem , Imunossupressores/imunologia , Masculino , Metotrexato/administração & dosagem , Metotrexato/imunologia , Pessoa de Meia-Idade , Vacinas Pneumocócicas/administração & dosagem , Vacinas Pneumocócicas/imunologia , Sorogrupo , Streptococcus pneumoniae/imunologia , Resultado do TratamentoRESUMO
BACKGROUND: Previous genome-wide association studies have evaluated the impact of common genetic variants and identified several non-HLA risk loci associated with autoimmune liver diseases. More recent genome-wide association studies and replication analyses reported an association between variants of the CARD10 polymorphism rs6000782 and risk of type 1 autoimmune hepatitis (AIH). In this case-control study, we genotyped 326 Japanese AIH patients and 214 control subjects. RESULTS: Genomic DNA from 540 individuals of Japanese origin, including 326 patients with type-1 AIH and 214 healthy controls, was analyzed for two single nucleotide polymorphisms (SNPs) in the CARD10 gene. We selected CARD10 rs6000782 SNPs and genotyped these using PCR-RFLP method and direct sequencing. The Chi square test revealed that the rs6000782 variant alle (c) was not associated with the susceptibility for AIH in a Japanese population [p = 0.376, odds ratio (OR) 1.271, 95 % confidence interval (CI) 0.747-2.161] in an allele model. Our data also showed that CARD10 rs6000782 variants were not associated with AIH or with the clinical parameters of AIH. CONCLUSIONS: In this study we examined an association between rs6000782 SNPs in the CARD10 gene and type-1 AIH. Results showed no significant association of rs62000782 with type-1 AIH in a Japanese population. This study demonstrated no association between CARD10 rs6000782 variants and AIH in a Japanese population.
Assuntos
Proteínas Adaptadoras de Sinalização CARD/genética , Predisposição Genética para Doença/genética , Hepatite Autoimune/genética , Polimorfismo de Nucleotídeo Único , Idoso , Povo Asiático/genética , Sequência de Bases , Estudos de Casos e Controles , Distribuição de Qui-Quadrado , Feminino , Frequência do Gene , Predisposição Genética para Doença/etnologia , Genótipo , Hepatite Autoimune/classificação , Hepatite Autoimune/etnologia , Humanos , Japão , Desequilíbrio de Ligação , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Polimorfismo de Fragmento de Restrição , Fatores de Risco , Análise de Sequência de DNARESUMO
Recent studies have demonstrated that micro (mi)RNA molecules can be detected in the circulation and can serve as potential biomarkers of various diseases. This study used microarray analysis to identify aberrantly expressed circulating miRNAs in patients with type 1 autoimmune hepatitis (AIH) compared with healthy controls. Patients with well-documented and untreated AIH were selected from the National Hospital Organization (NHO)-AIH-liver-network database. They underwent blood sampling and liver biopsy with inflammation grading and fibrosis staging before receiving treatment. To further confirm the microarray data, circulating expression levels of miR-21 and miR-122 were quantified by real-time quantitative polymerase chain reaction in 46 AIH patients, 40 patients with chronic hepatitis C (CHC), and 13 healthy controls. Consistent with the microarray data, serum levels of miR-21 were significantly elevated in AIH patients compared with CHC patients and healthy controls. miR-21 and miR-122 serum levels correlated with alanine aminotransferase levels. Circulating levels of miR-21 and miR-122 were significantly reduced in AIH patients with liver cirrhosis, and were inversely correlated with increased stages of fibrosis. By contrast, levels of circulating miR-21 showed a significant correlation with the histological grades of inflammation in AIH. We postulate that aberrantly expressed serum miRNAs are potential biomarkers of AIH and could be implicated in AIH pathogenesis. Alternations of miR-21 and miR-122 serum levels could reflect their putative roles in the mediation of inflammatory processes in AIH.
Assuntos
Hepatite Autoimune/sangue , MicroRNAs/sangue , Corticosteroides/uso terapêutico , Adulto , Idoso , Biomarcadores/sangue , Estudos de Casos e Controles , Feminino , Hepatite C Crônica/sangue , Hepatite Autoimune/tratamento farmacológico , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
BACKGROUND/AIMS: Serum amyloid A (SAA) is an acute phase reactant with significant immunological activities, including effects on cytokine synthesis and neutrophil chemotaxis. Neutrophils can also release cytokines with proinflammatory properties. IL-1ß is a key proinflammatory cytokine, the secretion of which is controlled by inflammasome. We investigated the proinflammatory effects of SAA in vitro in relation to the NLRP3 inflammasome in neutrophils. METHODOLOGY/PRINCIPAL FINDINGS: Human neutrophils isolated form healthy subjects were stimulated with serum amyloid A (SAA). The cellular supernatants were analyzed by western blot using anti-IL-1ß or anti-caspase-1 antibodies. IL-1ß or Nod-like receptor family, pyrin domain containing 3 (NLRP3) mRNA expressions were analyzed by real-time PCR or reverse transcription-PCR (RT-PCR) method. SAA stimulation induced pro-IL-1ß mRNA expression in neutrophils. Furthermore, SAA engaged the caspase-1-activating inflammasome, resulting in the production of active IL-1ß. SAA-induced pro-IL-1ß expression was marginally suppressed by the Syk specific inhibitor, R406, and SAA-induced pro-IL-1ß processing in neutrophils was prevented by R406. Furthermore, SAA-induced NLRP3 mRNA expression was completely blocked by R406. Analysis of intracellular signaling revealed that SAA stimulation activated the tyrosine kinase Syk and mitogen-activated protein kinase (MAPK). CONCLUSIONS/SIGNIFICANCE: These results demonstrate that the innate neutrophil immune response against SAA involves a two-step activation process: an initial signal promoting expression of pro-IL-1ß and a second signal involving Syk-dependent activation of the NLRP3 inflammasome and caspase-1, allowing processing of pro-IL-1ß and secretion of mature IL-1ß.