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1.
Medicine (Baltimore) ; 98(33): e16622, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31415355

RESUMO

OBJECTIVE: This study aimed to investigate the correlation of serum Jun-amino-terminal kinase (JNK) pathway-associated phosphatase (JKAP) level with disease risk, severity, inflammation, and treatment response to tumor necrosis factor (TNF)-α inhibitor in Crohn disease (CD) patients. METHOD: Ninety-six active CD patients and 90 healthy controls (HCs) were consecutively enrolled. Serum JKAP level of participants was determined via enzyme-linked immunosorbent assay (ELISA). In CD patients, C-reactive protein (CRP), erythrocyte sedimentation rate, Crohn disease activity index (CDAI), and inflammatory cytokine levels (determined by ELISA) were recorded. All CD patients underwent infliximab (IFX) treatment for 12 weeks, then treatment response (defined as decrement of CDAI ≥70) was assessed at week 12 (W12). RESULTS: Serum JKAP level in CD patients was lower compared to HCs, and it disclosed a good predictive value for decreased CD risk; meanwhile, it was negatively correlated with CRP level, CDAI score, TNF-α, interleukin (IL)-6, and IL-17 levels in CD patients. Sixty-eight (70.8%) patients achieved treatment response to IFX at W12, and JKAP level was increased at W12 compared to baseline. Interestingly, baseline JKAP level in response patients was decreased compared to nonresponse patients, and it exhibited a good predictive value for decreased treatment response to IFX, multivariate logistic regression revealed that JKAP was an independent factor for predicting reduced IFX response. CONCLUSION: Circulating JKAP expression correlates with decreased disease risk, activity, and inflammation level, and it could be served as a novel biomarker for predicting reduced clinical response to TNF-α inhibitor in CD patients.


Assuntos
Doença de Crohn/tratamento farmacológico , Fármacos Gastrointestinais/uso terapêutico , Sistema de Sinalização das MAP Quinases/fisiologia , Monoéster Fosfórico Hidrolases/sangue , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Adulto , Biomarcadores/sangue , Sedimentação Sanguínea , Proteína C-Reativa/metabolismo , Doença de Crohn/sangue , Citocinas/sangue , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Inflamação , Infliximab/uso terapêutico , Masculino , Fatores de Risco , Resultado do Tratamento
2.
Bratisl Lek Listy ; 120(8): 586-592, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31379182

RESUMO

OBJECTIVE: In recent years, neutrophil-lymphocyte rate (NLR) and platelet-lymphocyte rate (PLR) are reported to be increasing in plenty of rheumatological diseases and the latter rates to be disease activity indicators. In our study, we aimed to search for the difference in NLR and PLR before and after the treatment, their relationship with the disease activity and their seasonal differences in patients using anti-TNF medication for rheumatoid arthritis (RA) and ankylosing spondylitis (AS) while. METHOD: Sixty-eight RA and 203 AS patients using anti-TNF medication for at least 6 months were included in the study. Patients with acute infection, diabetes, hypertension, cancer, renal failure and liver failure were excluded from the study. NLR, PLR, seasonal differences and the disease activities of the patients were evaluated retrospectively. RESULTS: We determined that NLR and PLR are strongly correlated with disease activity, erythrocyte sedimentation rate (ESR) and c-reactive protein (CRP). In addition, we determined that disease activity, thrombocytes and PLR are increased in spring and winter, especially in patients with RA. CONCLUSION: NLR and PLR are simple, cheap, and easily accessible parameters which can be used to evaluate disease activity and treatment response before and after anti-TNF treatment. Further studies are needed to enlighten the effect of seasonal differences on disease activity (Tab. 2, Fig. 2, Ref. 43).


Assuntos
Artrite Reumatoide/tratamento farmacológico , Estações do Ano , Espondilite Anquilosante/tratamento farmacológico , Artrite Reumatoide/patologia , Plaquetas/citologia , Contagem de Células , Humanos , Linfócitos/citologia , Neutrófilos/citologia , Estudos Retrospectivos , Espondilite Anquilosante/patologia , Fator de Necrose Tumoral alfa/antagonistas & inibidores
3.
Cochrane Database Syst Rev ; 8: CD012448, 2019 08 16.
Artigo em Inglês | MEDLINE | ID: mdl-31425625

RESUMO

BACKGROUND: Kawasaki disease (KD) is an acute inflammatory vasculitis (inflammation of the blood vessels) that mainly affects children between six months and five years of age. The vasculitis primarily impacts medium-sized blood vessels, especially in the coronary arteries. In most children, intravenous immunoglobulin (IVIG) and aspirin therapy rapidly reduce inflammatory markers, fever, and other clinical symptoms. However, approximately 15% to 20% of children receiving the initial IVIG infusion show persistent or recurrent fever and are classified as IVIG-resistant. Tumor necrosis factor-alpha (TNF-α) is an inflammatory cytokine that plays an important role in host defence against infections and in immune responses. Several studies have established that blocking TNF-α is critical for obtaining anti-inflammatory effects in children with KD, thus, there is a need to identify benefits and risks of TNF-α blockers for the treatment of KD. OBJECTIVES: To evaluate the efficacy and safety of using TNF-α blockers (i.e. infliximab and etanercept) to treat children with Kawasaki disease. SEARCH METHODS: The Cochrane Vascular Information Specialist searched the Cochrane Vascular Specialised Register, CENTRAL, MEDLINE, Embase and CINAHL databases, the World Health Organization International Clinical Trials Registry Platform and ClinicalTrials.gov trials register to 19 September 2018. We also undertook reference checking of grey literature. SELECTION CRITERIA: We included randomised controlled trials (RCTs) that compared TNF-α blockers (i.e. infliximab and etanercept) to placebo or other drugs (including retreatment with IVIG) in children with KD, reported in abstract or full-text. DATA COLLECTION AND ANALYSIS: Two review authors independently applied the study selection criteria, assessed risk of bias and extracted data. When necessary, we contacted study authors for additional information. We used GRADE to assess the certainty of the evidence. MAIN RESULTS: We included five trials from 14 reports, with a total of 494 participants. All included trials were individual RCTs that examined the effect of TNF-α blockers for KD.Five trials (with 494 participants) reported the incidence of treatment resistance. TNF-α blockers reduced the incidence of treatment resistance (TNF-α blocker intervention group 30/237, control group 58/257; risk ratio (RR) 0.57, 95% confidence interval (CI) 0.38 to 0.86; low-certainty evidence).Four trials reported the incidence of coronary artery abnormalities (CAAs). Three trials (with 270 participants) contributed data to the meta-analysis, since we could not get the data needed for the analysis from the fourth trial. There was no clear difference between groups in the incidence of CAAs (TNF-α blocker intervention group 8/125, control group 9/145; RR 1.18, 95% CI 0.45 to 3.12; low-certainty evidence).Three trials with 250 participants reported the adverse effect 'infusion reactions' after treatment initiation. The TNF-α blocker intervention decreased infusion reactions (TNF-α blocker intervention group 0/126, control group 15/124; RR 0.06, 95% CI 0.01 to 0.45; low-certainty evidence).Two trials with 227 participants reported the adverse effect 'infections' after treatment initiation. There was no clear difference between groups (TNF-α blocker intervention group 7/114, control group 10/113; RR 0.68, 95% CI 0.33 to 1.37; low-certainty evidence).One trial (with 31 participants) reported the adverse effect 'cutaneous reactions' (rash and contact dermatitis). There was no clear difference between the groups for incidence of rash (TNF-α blocker intervention group 2/16, control group 0/15; RR 4.71, 95% CI 0.24 to 90.69; very low-certainty evidence) or for incidence of contact dermatitis (TNF-α blocker intervention group 1/16, control group 3/15; RR 0.31, 95% CI 0.04 to 2.68; very low-certainty evidence).No trials reported other adverse effects such as injection site reactions, neutropenia, infections, demyelinating disease, heart failure, malignancy, and induction of autoimmunity. AUTHORS' CONCLUSIONS: We found a limited number of RCTs examining the effect of TNF-α blockers for KD. In summary, low-certainty evidence indicates that TNF-α blockers have beneficial effects on treatment resistance and the adverse effect 'infusion reaction' after treatment initiation for KD when compared with no treatment or additional treatment with IVIG. Further research will add to the evidence base. Due to the small number of underpowered trials contributing to the analyses, the results presented should be treated with caution. Further large high quality trials with timing and type of TNF-α blockers used are needed to determine the effects of TNF-α blockers for KD.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Síndrome de Linfonodos Mucocutâneos/tratamento farmacológico , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Pré-Escolar , Humanos , Fatores Imunológicos , Lactente , Ensaios Clínicos Controlados Aleatórios como Assunto , Vasculite/tratamento farmacológico
4.
Expert Rev Clin Pharmacol ; 12(9): 885-891, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31305158

RESUMO

Introduction: Secondary loss of response to anti-tumor necrosis factor (TNF) therapy remains a challenge in the clinical management of inflammatory bowel disease (IBD) patients. A frequently observed reason for secondary loss of response to TNF blockers is inadequate drug exposure and sub-therapeutic serum drug concentrations. Areas covered: This review presents an overview of recent research on therapeutic drug monitoring (TDM)-based dosing with anti-TNF agents in IBD. The role of reactive and proactive TDM and different approaches on how to optimize anti-TNF treatment are discussed. Expert opinion: Due to variations within and between patients, the 'one size fits all' theory does not apply to all IBD patients receiving anti-TNF agents. Timing of TDM (i.e. reactive versus proactive) is a matter of debate. Both strategies might optimize anti-TNF treatment, although most trials did not show a clinical benefit compared to conventional dosing up to now. So-called dashboard systems might have an additive value in the optimization of anti-TNF treatment, since these tools enable clinicians to really personalize anti-TNF treatment.


Assuntos
Monitoramento de Medicamentos/métodos , Fármacos Gastrointestinais/administração & dosagem , Doenças Inflamatórias Intestinais/tratamento farmacológico , Relação Dose-Resposta a Droga , Fármacos Gastrointestinais/farmacologia , Humanos , Medicina de Precisão/métodos , Fatores de Tempo , Fator de Necrose Tumoral alfa/antagonistas & inibidores
5.
Z Gastroenterol ; 57(7): 843-851, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31288280

RESUMO

OBJECTIVES: This study aimed to describe biologic treatment of German inflammatory bowel disease (IBD) patients, including biologics' dosage, health care resource use, and treatment-associated cost. METHODS: In this retrospective claims data analysis, all continuously insured adult IBD patients (Crohn's disease [CD] or ulcerative colitis [UC]) who started a new therapy with an anti-tumor necrosis factor alpha (anti-TNF-α) or vedolizumab (VDZ) were included. Observation started with the date of the first prescription of index biologic therapy and lasted 12 months. RESULTS: In the database, 1248 out of 57 296 IBD patients started a biologic treatment of interest (1020 anti-TNF-α, 228 VDZ), and 837 patients were bio-naïve (773 anti-TNF-α, 64 VDZ). The mean age of bio-naïve/bio-experienced anti-TNF-α patients was 39.2/38.1 years (54.9 %/56.7 % female) and 42.6/37.8 years for VDZ patients (56.3 %/54.9 % female). The proportion of patients receiving a maintenance dosage > 150 % compared to SmPC was 15.1 % for Adalimumab, 5.2-39.0 % for Golimumab, 14.7-34.5 % for Infliximab, and 19.7 % for VDZ patients. During the maintenance phase, up to 58.8 % of patients received at least 1 prescription of any CS, and 41.7 %/47.1 % (anti-TNF-α/VDZ) were treated in a hospital due to IBD. The mean IBD-related direct health care cost per patient year was €â€Š30 246 (anti-TNF-α)/ €â€Š28 227 (VDZ) for bio-naïve patients (p = 0.288) and €â€Š34 136 (anti-TNF-α)/ €â€Š32 112 (VDZ) for bio-experienced patients (p = 0.011). CONCLUSIONS: A substantial percentage of patients receive a high biologic dosage in the maintenance phase. Despite biologic therapy, 30-40 % receive a CS therapy and/or experience at least 1 IBD-associated hospitalization within a year, possibly indicating a remaining disease activity.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Produtos Biológicos/uso terapêutico , Colite Ulcerativa/tratamento farmacológico , Fármacos Gastrointestinais/uso terapêutico , Doenças Inflamatórias Intestinais/tratamento farmacológico , Doenças Inflamatórias Intestinais/economia , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Adulto , Colite Ulcerativa/economia , Feminino , Humanos , Infliximab , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos
6.
Expert Opin Drug Metab Toxicol ; 15(7): 527-539, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31177858

RESUMO

Introduction: Medical treatment of pediatric inflammatory bowel diseases (IBD) has been greatly changed by the introduction of a number of biologic agents that are able to target various players of the immune response. In particular, monoclonal antibodies against the pro-inflammatory cytokine TNF-alpha (TNF) such as infliximab, adalimumab, and golimumab are now in the clinics both in induction and maintenance therapy, and several efforts are currently ongoing to optimize the use of these drugs in children. Areas covered: This review focuses on therapeutic drug monitoring (TDM) of anti-TNF levels and antidrug antibodies (ADAs), in IBD children. A revision of the analytical assays used for assessing anti-TNF plasma levels is also provided. Expert opinion: Although there is a consensus across studies that higher anti-TNF trough levels are associated with a better clinical outcome, and that early anti-TNF serum measurements could be predictive of long-term response, it is still not clear what the best predictive time of sampling is and what the ideal target drug plasma concentration to achieve. Indeed, there are a number of published studies, particularly in pediatric cohorts, limited by the population size analyzed and more prospective large studies are needed to examine the value of these predictive markers.


Assuntos
Monitoramento de Medicamentos/métodos , Fármacos Gastrointestinais/uso terapêutico , Doenças Inflamatórias Intestinais/tratamento farmacológico , Adalimumab/farmacocinética , Adalimumab/uso terapêutico , Anticorpos Monoclonais/farmacocinética , Anticorpos Monoclonais/uso terapêutico , Criança , Fármacos Gastrointestinais/farmacocinética , Humanos , Infliximab/farmacocinética , Infliximab/uso terapêutico , Fator de Necrose Tumoral alfa/antagonistas & inibidores
7.
Expert Opin Drug Saf ; 18(8): 733-744, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31173698

RESUMO

Objectives: To examine agreement between the FDA Adverse Event Reporting System (FAERS) and observational studies in common infections for tumor necrosis factor inhibitors (TNFi's). Methods: Using MedDRA® preferred terms, all infection cases in FAERS with each TNFi were retrieved using EvidexTM. Observational studies reporting TNFi-related infections were identified from PubMed (OS-PM) and ClinicalTrials.gov (OS-CT). Infections with a reporting rate of ≥2% (based on percentage of total number of infections) from each data source were compiled. Fleiss's kappa and Cohen's kappa (κ) were calculated to determine agreement across all three sources and between each two sources. Results: A total of 163,789 FAERS infection cases, 53 OS-PM studies and 52 OS-CT studies were identified. The Fleiss' kappa that comparing all 3 data sources demonstrated lack of agreement. Significant moderate agreements were found between FAERS and OS-CT for etanercept and adalimumab, respectively (κ = 0.53, p = 0.02; κ = 0.56, p = 0.02), but no agreements (κ < 0) when comparing FAERS vs. OS-PM or OS-CT vs. OS-PM. Conclusion: For common TNFi-related infections, passive (FAERS) and active (observational studies) pharmacovigilance results are similar between FAERS vs. OS-CT for etanercept and adalimumab but dissimilar across the 3 sources. Our findings suggest incorporating both active and passive pharmacovigilance methods in post-marketing drug safety assessment.


Assuntos
Fatores Imunológicos/efeitos adversos , Infecção/epidemiologia , Farmacovigilância , Vigilância de Produtos Comercializados/métodos , Adalimumab/administração & dosagem , Adalimumab/efeitos adversos , Sistemas de Notificação de Reações Adversas a Medicamentos/estatística & dados numéricos , Doenças Autoimunes/tratamento farmacológico , Etanercepte/administração & dosagem , Etanercepte/efeitos adversos , Humanos , Fatores Imunológicos/administração & dosagem , Infecção/induzido quimicamente , Vigilância de Produtos Comercializados/estatística & dados numéricos , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Estados Unidos , United States Food and Drug Administration
8.
Bratisl Lek Listy ; 120(6): 417-422, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31223021

RESUMO

OBJECTIVES: We aimed to investigate the effects of infliximab and HBO (hyperbaric oxygen) used alone or in combination on oxidative stress and the severity of pancreatitis in an experimental model of AP (acute pancreatitis). MATERIAL AND METHODS: A total of 60 rats were randomly divided into five groups. Group 1 underwent laparotomy; Group 2 underwent experimental AP; Group 3 was given an infliximab infusion and underwent AP; Group 4 was subjected to HBO therapy after AP; and Group 5 was given infliximab infusion before AP and subjected to HBO therapy. Serum amylase, superoxide dismutase (SOD), malondialdehyde (MDA), and glutathione peroxidase (GPX) levels in the pancreas tissues were measured. The pancreatic tissue samples were scored. RESULTS: There were statistically significant differences in the histopathological scores and amylase levels between non-treated AP and all the three treatment groups. Group 5 had the closest histopathological scores to the sham group. MDA levels were significantly different between non-treated AP and all the three treatment groups, but the SOD levels and GPX values were not. CONCLUSIONS: Combination of HBO therapy and Infliximab showed a synergistic effect on the reduction of histopathological severity and mortality in acute pancreatitis. All treatment modalities reduced the pathological findings by decreasing lipid peroxidation and partly increasing the antioxidant capacity in early period (Tab. 1, Fig. 3, Ref. 28).


Assuntos
Oxigenação Hiperbárica , Pancreatite , Fator de Necrose Tumoral alfa , Animais , Malondialdeído , Modelos Teóricos , Estresse Oxidativo , Pâncreas , Pancreatite/tratamento farmacológico , Pancreatite/fisiopatologia , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Superóxido Dismutase/metabolismo , Fator de Necrose Tumoral alfa/antagonistas & inibidores
9.
J Dairy Sci ; 102(8): 6738-6749, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31178178

RESUMO

Microbiome modulators such as probiotics are known to modulate oral diseases. Very few probiotics are commercially available for use in the oral cavity. In this context, we selected human-origin Lactobacillus salivarius AR809 as a promising oropharyngeal probiotic and characterized its functional and immunomodulatory properties. Results demonstrated that AR809 could efficiently adhere to pharyngeal epithelial FaDu cells, antagonize Staphylococcus aureus, adapt to the oral environment, and modulate host innate immunity by inducing potentially protective effects. Particularly, AR809 diminished proinflammatory activity by enhancing the production of IL10 and inhibiting the expression of tumor necrosis factor-α, IL1B, inducible nitric oxide synthase, and RELA. Finally, we observed that AR809 grew efficiently when cultured in milk, suggesting that the preparation of a fermented milk product containing AR809 could be a practical way to administer this probiotic to humans. In conclusion, AR809 has high potential to adhere to the pharyngeal mucosa and could be applied in novel milk-based probiotic fermented food products.


Assuntos
Aderência Bacteriana/fisiologia , Imunidade/fisiologia , Lactobacillus salivarius/isolamento & purificação , Lactobacillus salivarius/fisiologia , Boca/microbiologia , Faringe/microbiologia , Animais , Produtos Fermentados do Leite , Epitélio/microbiologia , Humanos , Inflamação/prevenção & controle , Probióticos , Fator de Necrose Tumoral alfa/antagonistas & inibidores
10.
Pol J Microbiol ; 68(1): 121-126, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31050260

RESUMO

The aim of this study was to determine if there are quantitative differences in Candida fungi between pediatric patients with Crohn's disease (before and after exclusive enteral nutrition (EEN), and the biologic therapy with anti-tumor necrosis factor alpha - (IFX)), and healthy controls. DNA was isolated from fecal samples and PCR was used to determine the number of fungal cells. Both therapeutic interventions resulted in a statistically significant decrease in Pediatric Crohn's Disease Activity Index. The numbers of Candida decreased during both therapeutic intervention but the difference was statistically significant for the IFX intervention only (p = 0.045). Moreover, fungi population in both study groups declined during intervention when compared to the control group but the difference was significant before treatment only in the IFX group (p = 0.013). The total distribution of Candida with both IFX and EEN as well as in the control group differed significantly (p = 0.01) before treatment only. No correlation between the numbers of Candida and disease activity as well as the following biochemical parameters: serum iron concentration, protein or glucose level were found. It cannot be ruled out that, in combination with genetic and immunological disorders, fungi can contribute to the initiation of the disease process and perpetuation of active inflammation.The aim of this study was to determine if there are quantitative differences in Candida fungi between pediatric patients with Crohn's disease (before and after exclusive enteral nutrition (EEN), and the biologic therapy with anti-tumor necrosis factor alpha ­ (IFX)), and healthy controls. DNA was isolated from fecal samples and PCR was used to determine the number of fungal cells. Both therapeutic interventions resulted in a statistically significant decrease in Pediatric Crohn's Disease Activity Index. The numbers of Candida decreased during both therapeutic intervention but the difference was statistically significant for the IFX intervention only (p = 0.045). Moreover, fungi population in both study groups declined during intervention when compared to the control group but the difference was significant before treatment only in the IFX group (p = 0.013). The total distribution of Candida with both IFX and EEN as well as in the control group differed significantly (p = 0.01) before treatment only. No correlation between the numbers of Candida and disease activity as well as the following biochemical parameters: serum iron concentration, protein or glucose level were found. It cannot be ruled out that, in combination with genetic and immunological disorders, fungi can contribute to the initiation of the disease process and perpetuation of active inflammation.


Assuntos
Candida/crescimento & desenvolvimento , Candidíase/epidemiologia , Doença de Crohn/tratamento farmacológico , Nutrição Enteral/métodos , Infliximab/uso terapêutico , Intestino Grosso/microbiologia , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Adolescente , Glicemia/análise , Candida/genética , Candidíase/microbiologia , Candidíase/patologia , Criança , Pré-Escolar , DNA Fúngico/genética , Fezes/microbiologia , Feminino , Humanos , Intestino Grosso/patologia , Ferro/sangue , Masculino , Estudos Prospectivos , Fator de Necrose Tumoral alfa/imunologia
11.
Medicine (Baltimore) ; 98(20): e15517, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31096451

RESUMO

Access to care and management of Rheumatoid Arthritis (RA) patients may differ based on residential area. We described differences in the profile of patients initiating their first biologic disease modifying antirheumatic drug (bDMARD) based on their residential area type.Cross-sectional analysis of 793 adult RA patients in the longitudinal Ontario Best Practices Research Initiative (OBRI) registry initiating their first bDMARD <30 days prior to or anytime post-enrolment. Patient residential and clinic areas (rural vs. urban) were classified using 2 methods: postal codes and Statistics Canada population centres. Sociodemographics, disease characteristics, and RA medications (tumor necrosis factor inhibitor [TNFi] vs. non-TNFi, concurrent use of conventional synthetic DMARDs [csDMARDs], and intravenous [IV] vs. subcutaneous [SC] bDMARD) at initiation of first bDMARD were contrasted between residential area types.Other than marital status, first language, and race (higher proportion of married, English speaking, Caucasian patients in rural areas), no significant differences were observed in the demographic and disease characteristics of patients living in rural and urban areas. In multivariate analysis, there was no association between residential area type and type of bDMARD use, concurrent csDMARD(s) use or route of bDMARD. However, patients living farther from their treating clinic were significantly less likely to initiate IV bDMARD. Female rheumatologist and rural clinic location were independently associated with lower odds of IV bDMARD use.The use of SC vs. IV bDMARD was associated with being seen in a clinic located in a rural area, being treated by a female rheumatologist, and living farther from treating clinic. These results suggest possible prescription bias in bDMARD selection and/or patient preferences due to convenience.


Assuntos
Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Produtos Biológicos/uso terapêutico , Padrões de Prática Médica/estatística & dados numéricos , Características de Residência/estatística & dados numéricos , Adulto , Fatores Etários , Idoso , Antirreumáticos/administração & dosagem , Produtos Biológicos/administração & dosagem , Estudos Transversais , Vias de Administração de Medicamentos , Feminino , Acesso aos Serviços de Saúde , Humanos , Masculino , Pessoa de Meia-Idade , Ontário , População Rural/estatística & dados numéricos , Índice de Gravidade de Doença , Fatores Sexuais , Fatores Socioeconômicos , Fator de Necrose Tumoral alfa/antagonistas & inibidores , População Urbana/estatística & dados numéricos
12.
J Bras Pneumol ; 45(2): e20190023, 2019 Apr 25.
Artigo em Inglês, Português | MEDLINE | ID: mdl-31038654

RESUMO

Most people infected by Mycobacterium tuberculosis (Mtb) do not have any signs or disease symptoms, a condition known as latent tuberculosis infection (LTBI). The introduction of biological agents, mainly tumor necrosis factor (TNF) inhibitors, for the treatment of immune-mediated diseases such as Rheumatoid Arthritis (RA) and other rheumatic diseases, increased the risk of reactivation of LTBI, leading to development of active TB. Thus, this review will approach the aspects related to LTBI in patients with rheumatologic diseases, especially those using iTNF drugs. For this purpose it will be considered the definition and prevalence of LTBI, mechanisms associated with diseases and medications in use, criteria for screening, diagnosis and treatment. Considering that reactivation of LTBI accounts for a large proportion of the incidence of active TB, adequate diagnosis and treatment are crucial, especially in high-risk groups such as patients with rheumatologic diseases.


Assuntos
Tuberculose Latente/etiologia , Doenças Reumáticas/complicações , Doenças Reumáticas/tratamento farmacológico , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Antirreumáticos/efeitos adversos , Humanos , Testes de Liberação de Interferon-gama , Tuberculose Latente/diagnóstico , Tuberculose Latente/tratamento farmacológico , Fatores de Risco , Teste Tuberculínico
13.
Paediatr Drugs ; 21(2): 81-93, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31087279

RESUMO

Childhood-onset Takayasu arteritis (c-TA) is the third most common systemic vasculitic disorder in children. Vascular stenosis is the main complication, and aneurysms are reported in 19-65% of cases, often in combination with stenotic lesions. Management of patients with c-TA is largely based on studies involving predominantly patients with adult-onset TA (a-TA). More widely used criteria for patients with c-TA have been devised by the joint European League Against Rheumatism, Pediatric Rheumatology International Trials Organization, and Pediatric Rheumatology European Society. Of the available imaging modalities, those that do not use radiation (color Doppler ultrasound and magnetic resonance angiogram) are preferred over 18F-labeled fluoro-2-deoxyglucose (18F-FDG) positron-emission tomography, computed tomography (CT), and CT angiogram in children. Remission rates have been reported to be lower in c-TA than in a-TA, and published mortality rates in c-TA range from 16 to 40%, which is much higher than reported in patients with a-TA. The usual drug therapy options include steroids plus steroid-sparing second-line immunosuppressants, such as mycophenolate, azathioprine, methotrexate, cyclophosphamide, and cyclosporine, along with antiplatelet agents. Interleukin-6 inhibitors such as tocilizumab, as well as the tumor necrosis factor inhibitors, are other aggressive therapeutic options. As yet, no randomized controlled trials have been conducted in c-TA.


Assuntos
Arterite de Takayasu/tratamento farmacológico , Adolescente , Adulto , Idade de Início , Anticorpos Monoclonais Humanizados/uso terapêutico , Azatioprina/uso terapêutico , Criança , Pré-Escolar , Diagnóstico Diferencial , Feminino , Humanos , Imunossupressores/uso terapêutico , Lactente , Arterite de Takayasu/diagnóstico por imagem , Fator de Necrose Tumoral alfa/antagonistas & inibidores
14.
Rev Assoc Med Bras (1992) ; 65(4): 554-567, 2019 05 02.
Artigo em Inglês | MEDLINE | ID: mdl-31066809

RESUMO

The Guidelines Project, an initiative of the Brazilian Medical Association, aims to combine information from the medical field in order to standardize producers to assist the reasoning and decision-making of doctors. The information provided through this project must be assessed and criticized by the physician responsible for the conduct that will be adopted, depending on the conditions and the clinical status of each patient.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Doença de Crohn/tratamento farmacológico , Adalimumab/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Brasil , Certolizumab Pegol/uso terapêutico , Tomada de Decisão Clínica , Quimioterapia Combinada , Humanos , Infliximab/uso terapêutico , Indução de Remissão , Fatores de Tempo , Resultado do Tratamento , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Ustekinumab/uso terapêutico
15.
Clin Drug Investig ; 39(7): 625-630, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31098835

RESUMO

BACKGROUND AND OBJECTIVES: Anti-tumor necrosis factor alpha (anti-TNFα) therapy is key to the treatment of inflammatory bowel diseases (IBDs), including ulcerative colitis (UC) and Crohn's disease (CD). The objective of this study was to investigate prescribing patterns and non-persistence of anti-TNFα therapy for the treatment of IBD in a real-world scenario. METHODS: Data from the Korean National Health Insurance claims database obtained between 2010 and 2014 were evaluated to identify patients with IBD who had received anti-TNFα therapy (infliximab or adalimumab). Patient characteristics and prescribing patterns were investigated. The non-persistence rate and associated reasons were determined in patients who initiated therapy between 2010 and 2012. RESULTS: A total of 131,158 patients with UC and 57,286 with CD were identified. Of these 1747 UC (1.3%) and 3731 (6.5%) CD patients had received anti-TNFα therapy and were included in the analysis. Infliximab was prescribed more frequently than adalimumab (84.6% vs 15.4% in UC and 80.7% vs 19.4% in CD); 81.0% of UC and 72.0% of CD patients received anti-TNFα alone or in combination with 5-aminosalicylic acid. The non-persistence rate of anti-TNFα therapy was 72.6% and 80.4% in the UC and CD groups, respectively, with discontinuation of medication being the most common reason in both the UC and CD groups (63.9% and 73.3%, respectively). CONCLUSION: The use of anti-TNFα therapy was seen to be low, with a high rate of non-persistence. Further research efforts are required to improve the response rate and, therefore, improve persistence in patients with IBD.


Assuntos
Doenças Inflamatórias Intestinais/tratamento farmacológico , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Adolescente , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
16.
Cochrane Database Syst Rev ; 5: CD010455, 2019 05 24.
Artigo em Inglês | MEDLINE | ID: mdl-31125448

RESUMO

BACKGROUND: Anti-tumour necrosis factor (TNF) agents are effective in treating people with rheumatoid arthritis (RA), but are associated with (dose-dependent) adverse effects and high costs. To prevent overtreatment, several trials have assessed the effectiveness of down-titration compared with continuation of the standard dose. This is an update of a Cochrane Review published in 2014. OBJECTIVES: To evaluate the benefits and harms of down-titration (dose reduction, discontinuation, or disease activity-guided dose tapering) of anti-TNF agents on disease activity, functioning, costs, safety, and radiographic damage compared with usual care in people with RA and low disease activity. SEARCH METHODS: We searched MEDLINE, Embase, Web of Science and CENTRAL (29 March 2018) and four trial registries (11 April 2018) together with reference checking, citation searching, and contact with study authors to identify additional studies. We screened conference proceedings (American College of Rheumatology and European League Against Rheumatism 2005-2017). SELECTION CRITERIA: Randomised controlled trials (RCTs) and controlled clinical trials (CCTs) comparing down-titration (dose reduction, discontinuation, disease activity-guided dose tapering) of anti-TNF agents (adalimumab, certolizumab pegol, etanercept, golimumab, infliximab) to usual care/no down-titration in people with RA and low disease activity. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methodology. MAIN RESULTS: One previously included trial was excluded retrospectively in this update because it was not an RCT/CCT. We included eight additional trials, for a total of 14 studies (13 RCTs and one CCT, 3315 participants in total) reporting anti-TNF down-titration. Six studies (1148 participants) reported anti-TNF dose reduction compared with anti-TNF continuation. Eight studies (2111 participants) reported anti-TNF discontinuation compared with anti-TNF continuation (three studies assessed both anti-TNF discontinuation and dose reduction), and three studies assessed disease activity-guided anti-TNF dose tapering (365 participants). These studies included data on all anti-TNF agents, but primarily adalimumab and etanercept. Thirteen studies were available in full text, one was available as abstract. We assessed the included studies generally at low to moderate risk of bias; our main concerns were bias due to open-label treatment and unblinded outcome assessment. Clinical heterogeneity between the trials was high. The included studies were performed at clinical centres around the world and included people with early as well as established RA, the majority of whom were female with mean ages between 47 and 60. Study durations ranged from 6 months to 3.5 years.We found that anti-TNF dose reduction leads to little or no difference in mean disease activity score (DAS28) after 26 to 52 weeks (high-certainty evidence, mean difference (MD) 0.06, 95% confidence interval (CI) -0.11 to 0.24, absolute risk difference (ARD) 1%) compared with continuation. Also, anti-TNF dose reduction does not result in an important deterioration in function after 26 to 52 weeks (Health Assessment Questionnaire Disability Index (HAQ-DI)) (high-certainty evidence, MD 0.09, 95% CI 0.00 to 0.19, ARD 3%). Next to this, anti-TNF dose reduction may slightly reduce the proportion of participants switched to another biologic (low-certainty evidence), but probably slightly increases the proportion of participants with minimal radiographic progression after 52 weeks (moderate-certainty evidence, risk ratio (RR) 1.22, 95% CI 0.76 to 1.95, ARD 2% higher). Anti-TNF dose reduction may cause little or no difference in serious adverse events, withdrawals due to adverse events and proportion of participants with persistent remission (low-certainty evidence).Results show that anti-TNF discontinuation probably slightly increases the mean disease activity score (DAS28) after 28 to 52 weeks (moderate-certainty evidence, MD 0.96, 95% CI 0.67 to 1.25, ARD 14%), and that the RR of persistent remission lies between 0.16 and 0.77 (low-certainty evidence). Anti-TNF discontinuation increases the proportion participants with minimal radiographic progression after 52 weeks (high-certainty evidence, RR 1.69, 95% CI 1.10 to 2.59, ARD 7%) and may lead to a slight deterioration in function (HAQ-DI) (low-certainty evidence). It is uncertain whether anti-TNF discontinuation influences the number of serious adverse events (due to very low-certainty evidence) and the number of withdrawals due to adverse events after 28 to 52 weeks probably increases slightly (moderate-certainty evidence, RR 1.46, 95% CI 0.75 to 2.84, ARD 1% higher).Anti-TNF disease activity-guided dose tapering may result in little or no difference in mean disease activity score (DAS28) after 72 to 78 weeks (low-certainty evidence). Furthermore, anti-TNF disease activity-guided dose tapering results in little or no difference in the proportion of participants with persistent remission after 18 months (high-certainty evidence, RR 0.89, 95% CI 0.75 to 1.06, ARD -9%) and may result in little or no difference in switching to another biologic (low-certainty evidence). Anti-TNF disease activity-guided dose tapering may slightly increase proportion of participants with minimal radiographic progression (low-certainty evidence) and probably leads to a slight deterioration of function after 18 months (moderate-certainty evidence, MD 0.2 higher, 0.02 lower to 0.42 higher, ARD 7% higher), It is uncertain whether anti-TNF disease activity-guided dose tapering influences the number of serious adverse events due to very low-certainty evidence. AUTHORS' CONCLUSIONS: We found that fixed-dose reduction of anti-TNF, after at least three to 12 months of low disease activity, is comparable to continuation of the standard dose regarding disease activity and function, and may be comparable with regards to the proportion of participants with persistent remission. Discontinuation (also without disease activity-guided adaptation) of anti-TNF is probably inferior to continuation of treatment with respect to disease activity, the proportion of participants with persistent remission, function, and minimal radiographic damage. Disease activity-guided dose tapering of anti-TNF is comparable to continuation of treatment with respect to the proportion of participants with persistent remission and may be comparable regarding disease activity.Caveats of this review are that available data are mainly limited to etanercept and adalimumab, the heterogeneity between studies, and the use of superiority instead of non-inferiority designs.Future research should focus on the anti-TNF agents infliximab and golimumab; assessment of disease activity, function, and radiographic outcomes after longer follow-up; and assessment of long-term safety, cost-effectiveness, and predictors for successful down-titration. Also, use of a validated flare criterion, non-inferiority designs, and disease activity-guided tapering instead of fixed-dose reduction or discontinuation would allow researchers to better interpret study findings and generalise to clinical practice.


Assuntos
Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Receptores do Fator de Necrose Tumoral/uso terapêutico , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Anticorpos Monoclonais Humanizados , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Ensaios Clínicos Controlados Aleatórios como Assunto , Recidiva , Indução de Remissão
17.
Eur J Med Chem ; 175: 114-128, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31077997

RESUMO

In order to discover novel anti-inflammatory agents, total thirty-seven new resveratrol-based flavonol derivatives were designed and synthesized. All compounds have been screened for their anti-inflammatory activity by evaluating their inhibition effect of LPS-induced NO production in RAW 264.7 macrophages. Their toxicity was also assessed in vitro. Structure-activity relationships (SARs) have been concluded, and finally 2-(2,4-dimethoxy-6-(4-methoxystyryl)phenyl)-3-hydroxy-4H-chromen-4-one was found to be the most active scaffold with low toxicity. This compound could significantly decrease productions of NO, IL-6 and TNF-α with IC50 values of 1.35, 1.12 and 1.92 µM, respectively in RAW 264.7 macrophages. Preliminary mechanism studies indicated that it could inhibit the expression of TLR4 protein, resulting in activation of the NF-ĸB cell signaling pathway. The in vivo anti-inflammatory activity of this compound could reduce pulmonary inflammation by mouse model of LPS-induced acute lung injury (ALI). We believe these findings would further support studies of rational design of more efficient acute lung injury regulatory inhibitors.


Assuntos
Anti-Inflamatórios/síntese química , Anti-Inflamatórios/farmacologia , Flavonoides/síntese química , Flavonoides/farmacologia , Interleucina-6/antagonistas & inibidores , Óxido Nítrico/antagonistas & inibidores , Resveratrol/química , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Animais , Anti-Inflamatórios/toxicidade , Flavonoides/química , Flavonoides/toxicidade , Técnicas In Vitro , Concentração Inibidora 50 , Lipopolissacarídeos/toxicidade , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Camundongos , Simulação de Acoplamento Molecular , NF-kappa B/metabolismo , Células RAW 264.7 , Relação Estrutura-Atividade , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
19.
Einstein (Sao Paulo) ; 17(2): eAO4539, 2019 Apr 01.
Artigo em Inglês, Português | MEDLINE | ID: mdl-30942280

RESUMO

OBJECTIVE: To investigate the prevalence of electrocardiographic changes in patients with spondyloarthritis and to correlate these changes with use of anti-tumor necrosis factor-alpha (TNF-α) drugs and HLA-B27 positivity. METHODS: Retrospective study including 100 patients diagnosed with spondyloarthritis according to Assessment of SpondyloArthritis International Society (ASAS) criteria and 50 controls. Epidemiological and clinical features, results of inflammatory activity tests, HLA-B27 positivity, and medication use data were extracted from medical records. Disease activity was assessed using the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI). All participants were submitted to electrocardiogram performed using a 12-lead device; rhythm, heart rate, conduction disorders and QT interval corrected using the Bazett formula were analyzed. RESULTS: Of 100 patients with spondyloarthritis, 51 were on anti-TNF-α drugs and 49 were not. HLA-B27 was detected in 53.1% of patients in the sample. Patients with spondyloarthritis had lower heart rate (p=0.06), longer QT interval (p<0.0001) and higher prevalence of right bundle branch block (p=0.014) compared to controls. Duration of disease was weakly correlated with heart rate (Rho=0.26; 95%CI: 0.06-0.44; p=0.008). The prevalence of right bundle branch block was positively correlated with HLA-B27 positivity. Use of Anti-TNF-α drugs did not interfere with electrocardiographic parameters. CONCLUSION: Patients with spondyloarthritis had lower heart rate, longer QT interval and a higher prevalence of right bundle branch block compared to controls. HLA-B27 positivity was associated with the prevalence of right bundle branch block. Anti-TNF-α drugs had no impact on electrocardiographic findings.


Assuntos
Eletrocardiografia , Espondilartrite/tratamento farmacológico , Espondilartrite/fisiopatologia , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Adolescente , Adulto , Idoso , Brasil/epidemiologia , Bloqueio de Ramo/epidemiologia , Bloqueio de Ramo/fisiopatologia , Estudos de Casos e Controles , Feminino , Antígeno HLA-B27/análise , Frequência Cardíaca/fisiologia , Humanos , Masculino , Pessoa de Meia-Idade , Prevalência , Valores de Referência , Estudos Retrospectivos , Espondilartrite/epidemiologia , Espondilartrite/imunologia , Estatísticas não Paramétricas , Fatores de Tempo , Adulto Jovem
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