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1.
Am J Respir Crit Care Med ; 191(7): 786-95, 2015 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-25594886

RESUMO

RATIONALE: Patient-reported outcome (PRO) measures have been developed to measure symptoms and other aspects of health-related quality of life. OBJECTIVES: The Sarcoidosis Assessment Tool (SAT), a sarcoidosis-specific PRO, was administered in a lung and skin sarcoidosis treatment trial. We explored SAT performance characteristics and correlation with standard clinical measurements to validate it as a useful clinical sarcoidosis-specific PRO. METHODS: The SAT analyses focused on baseline and Week 16 assessments. Besides the SAT, participants underwent clinical and physician assessments plus additional PROs that were used as anchor variables and were compared with the SAT. Reliability was evaluated by using Cronbach α coefficient. Spearman correlation coefficients were used to evaluate the association between SAT scores with clinical and other PRO measures. Changes between assessments in the clinical and PRO "anchor" variables were classified as improved, stable, or worsened. Mean differences between adjacent categories of the known groups and mean changes from the ability to detect change analyses were reviewed for appropriate clinically important difference estimates. MEASUREMENTS AND MAIN RESULTS: Results from 173 patients were analyzed. Each SAT module reflected appropriate anchor variables at baseline and in terms of change. The Cronbach α for each of these modules was at least 0.87. In addition, we successfully established a clinically important difference range for each SAT module. CONCLUSIONS: We demonstrated that the SAT is a reliable and consistent sarcoidosis-specific PRO. It has excellent internal consistency and reliability. A range of clinically important differences has been established for the SAT modules. Clinical trial registered with www.clinicaltrials.gov (NCT 00955279).


Assuntos
Pulmão/patologia , Avaliação de Resultados da Assistência ao Paciente , Sarcoidose/terapia , Pele/patologia , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Autoavaliação (Psicologia) , Inquéritos e Questionários , Resultado do Tratamento
2.
Eur Respir J ; 44(5): 1296-307, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25034562

RESUMO

Sarcoidosis is characterised by non-caseating granulomas that secrete pro-inflammatory cytokines, including interleukin (IL)-12, IL-23, and tumour necrosis factor (TNF)-α. Ustekinumab and golimumab are monoclonal antibodies that specifically inhibit IL-12/IL-23 and TNF-α, respectively. Patients with chronic pulmonary sarcoidosis (lung group) and/or skin sarcoidosis (skin group) received either 180 mg ustekinumab at week 0 followed by 90 mg every 8 weeks, 200 mg golimumab at week 0 followed by 100 mg every 4 weeks, or placebo. Patients underwent corticosteroid tapering between weeks 16 and 28. The primary end-point was week 16 change in percentage predicted forced vital capacity (ΔFVC % pred) in the lung group. Major secondary end-points were: week 28 for ΔFVC % pred, 6-min walking distance, St George's Respiratory Questionnaire (lung group), and Skin Physician Global Assessment response (skin group). At week 16, no significant differences were observed in ΔFVC % pred with ustekinumab (-0.15, p = 0.13) or golimumab (1.15, p = 0.54) compared with placebo (2.02). At week 28, there were no significant improvements in the major secondary end-points, although a nonsignificant numerically greater Skin Physician Global Assessment response was observed following golimumab treatment (53%) when compared with the placebo (30%). Serious adverse events were similar in all treatment groups. Although treatment was well tolerated, neither ustekinumab nor golimumab demonstrated efficacy in pulmonary sarcoidosis. However, trends towards improvement were observed with golimumab in some dermatological end-points.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Antirreumáticos/uso terapêutico , Sarcoidose/tratamento farmacológico , Sarcoidose/fisiopatologia , Adulto , Doença Crônica , Método Duplo-Cego , Feminino , Humanos , Interleucina-12/antagonistas & inibidores , Interleucina-23/antagonistas & inibidores , Masculino , Pessoa de Meia-Idade , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Ustekinumab
3.
Respir Res ; 13: 12, 2012 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-22300528

RESUMO

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is characterized by progressive worsening of airflow limitation associated with abnormally inflamed airways in older smokers. Despite correlative evidence for a role for tumor necrosis factor-alpha in the pathogenesis of COPD, the anti-tumor necrosis factor-alpha, infliximab did not show clinical efficacy in a double-blind, placebo-controlled, phase II clinical trial. This study sought to evaluate the systemic inflammatory profile associated with COPD and to assess the impact of tumor necrosis factor neutralization on systemic inflammation. METHODS: Serum samples (n = 234) from the phase II trial were collected at baseline and after 24 weeks of placebo or infliximab. Additionally, baseline serum samples were obtained from an independent COPD cohort (n = 160) and 2 healthy control cohorts (n = 50; n = 109). Serum concentrations of a broad panel of inflammation-associated analytes were measured using a 92-analyte multiplex assay. RESULTS: Twenty-five proteins were significantly elevated and 2 were decreased in COPD, including highly elevated CD40 ligand, brain-derived neurotrophic factor, epidermal growth factor, acute-phase proteins, and neutrophil-associated proteins. This profile was largely independent of smoking status, age, and clinical phenotype. The majority of these associations of serum analytes with COPD are novel findings. Increased serum creatine kinase-muscle/brain and myoglobin correlated modestly with decreased forced expiratory volume at 1 second, suggesting cardiac involvement. Infliximab did not affect this systemic inflammatory profile. CONCLUSIONS: A robust systemic inflammatory profile was associated with COPD. This profile was generally independent of disease severity. Because anti-tumor necrosis factor-alpha did not influence systemic inflammation, how to control the underlying pathology beyond symptom suppression remains unclear.


Assuntos
Anti-Inflamatórios/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Proteínas de Fase Aguda/análise , Adulto , Idoso , Fator Neurotrófico Derivado do Encéfalo/sangue , Proteína C-Reativa/análise , Antígenos CD40/sangue , Creatina Quinase/sangue , Fator de Crescimento Epidérmico/sangue , Feminino , Humanos , Inflamação/sangue , Inflamação/tratamento farmacológico , Infliximab , Masculino , Pessoa de Meia-Idade , Doença Pulmonar Obstrutiva Crônica/sangue , Índice de Gravidade de Doença
4.
Thorax ; 66(12): 1036-42, 2011 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-21602542

RESUMO

BACKGROUND: Lung function is a major criterion used to assess asthma control. Fluctuation analyses can account for lung function history over time, and may provide an additional dimension to characterise control. The relationships between mean and fluctuations in lung function with asthma control, exacerbation and quality of life were studied in two independent data sets. METHODS: Data from 132 adults with mild to moderate asthma and 159 adults with severe asthma were analysed separately. Fluctuations in twice-daily peak expiratory flow (PEF) over 6 months were measured by α, representing the strength of correlation with past lung function and potentially asthma stability. α and mean percentage predicted PEF (%predPEF) were plotted with and compared between patients grouped by asthma control defined by recent GINA (Global Initiative for Asthma) guidelines, the Asthma Control Questionnaire score, exacerbations and Asthma Quality of Life Questionnaire score. Associations of α and %predPEF with these outcomes were examined using multiple regression analyses. RESULTS: Both α and %predPEF differed with and were significantly associated with GINA-defined asthma control in both the mild to moderate and severe asthma groups. Only α was related to whether or not exacerbations occurred in mild to moderate asthma, while %predPEF was more significantly related than α in severe asthma. In those with severe asthma, only %predPEF was significantly related to Asthma Control Questionnaire and Asthma Quality of Life Questionnaire scores. CONCLUSION: Lung function history quantified by fluctuation analysis provides additional information to mean lung function, and may help characterise the current state of asthma control. It may also potentially aid in phenotyping clinical asthma.


Assuntos
Albuterol/análogos & derivados , Albuterol/uso terapêutico , Antiasmáticos/uso terapêutico , Asma/tratamento farmacológico , Asma/fisiopatologia , Pico do Fluxo Expiratório , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Administração por Inalação , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Albuterol/administração & dosagem , Análise de Variância , Antiasmáticos/administração & dosagem , Feminino , Humanos , Injeções Subcutâneas , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Placebos , Guias de Prática Clínica como Assunto , Qualidade de Vida , Análise de Regressão , Xinafoato de Salmeterol , Índice de Gravidade de Doença , Estatísticas não Paramétricas , Inquéritos e Questionários , Fatores de Tempo , Resultado do Tratamento
5.
J Allergy Clin Immunol ; 127(6): 1494-502.e3, 2011 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-21333347

RESUMO

BACKGROUND: Determination of future risk of exacerbations is a key issue in the management of asthma. We previously developed a method to calculate conditional probabilities (π) of future decreases in lung function by using the daily fluctuations in peak expiratory flow (PEF). OBJECTIVE: We aimed to extend calculation of π values to individual patients, validated by using electronically recorded data from 2 past clinical trials. METHODS: Twice-daily PEF data were analyzed from 78 patients with severe (study A) and 61 patients with poorly controlled (study B) asthma. For each patient, the π value was calculated from 5000 PEF data points simulated based on the correlation and distribution properties of observed PEF. Given an initial PEF, the π value was defined as the probability of a decrease in PEF to less than 80% of predicted value on 2 consecutive days within a month. These probabilities were then compared with actual occurrences of such events and clinically defined exacerbations within the following month. RESULTS: π Values were related to actual occurrences of decreases in PEF (adjusted R(2) > 0.800 for both studies). Every increase of 10% in π value was associated with an odds ratio of having a future exacerbation of 1.24 (95% CI, 1.07-1.43) for study A and 1.13 (95% CI, 1.02-1.26) for study B, with better sensitivity and specificity than clinic-measured FEV(1). CONCLUSION: These results from 2 independent datasets with differing asthmatic populations and differing exacerbation criteria provide support that clinically relevant quantification of individual future risk of exacerbations is possible.


Assuntos
Asma/etiologia , Asma/fisiopatologia , Pico do Fluxo Expiratório , Adolescente , Adulto , Idoso , Asma/terapia , Progressão da Doença , Modificador do Efeito Epidemiológico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Probabilidade , Recidiva , Estudos Retrospectivos , Fatores de Risco , Adulto Jovem
6.
Am J Respir Crit Care Med ; 179(7): 549-58, 2009 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-19136369

RESUMO

RATIONALE: The treatment effect of golimumab, a human monoclonal antibody against tumor necrosis factor (TNF)-alpha, in severe persistent asthma is unknown. OBJECTIVES: To assess the safety and efficacy of golimumab in a large population of patients with uncontrolled, severe persistent asthma. METHODS: From 2004 to 2006, 309 patients with severe and uncontrolled asthma, despite high-dose inhaled corticosteroids and long-acting beta(2) agonists, were randomized 1:1:1:1 to monthly subcutaneous injections of placebo or golimumab (50, 100, or 200 mg) through Week 52. Coprimary endpoints were the change from baseline through Week 24 in prebronchodilator percent-predicted FEV(1) and the number of severe asthma exacerbations through Week 24. MEASUREMENTS AND MAIN RESULTS: No significant differences were observed for the change in percent-predicted FEV1 (least squares mean: placebo, 2.44 [95% confidence interval (CI) -0.574 to 5.461]; combined 100-mg and 200-mg, 2.91 [0.696-5.116]) or severe exacerbations (mean +/- SD: placebo, 0.5 +/- 1.07 vs. combined 100-mg and 200-mg 0.5 +/- 0.97) through week 24. Through Week 24, 2.6% of patients treated with placebo vs. 19.5% of those treated with golimumab discontinued the study agent, and 1.3% and 7.8% discontinued study participation, respectively. An unfavorable risk-benefit profile led to early discontinuation of study-agent administration after the Week-24 database lock. Through Week 76, 20.5% of patients treated with placebo and 30.3% of patients treated with golimumab experienced serious adverse events, with serious infections occurring more frequently in golimumab-treated patients. One death and all eight malignancies occurred in the active groups. CONCLUSIONS: Overall, treatment with golimumab did not demonstrate a favorable risk-benefit profile in this study population of patients with severe persistent asthma. Clinical trial registered with www.clinicaltrials.gov (NCT00207740).


Assuntos
Anticorpos Monoclonais/administração & dosagem , Asma/tratamento farmacológico , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Adulto , Idoso , Anticorpos Monoclonais/efeitos adversos , Asma/fisiopatologia , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Volume Expiratório Forçado , Humanos , Infecções/etiologia , Injeções Subcutâneas , Masculino , Pessoa de Meia-Idade
7.
Am J Respir Crit Care Med ; 175(9): 926-34, 2007 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-17290043

RESUMO

RATIONALE: Chronic obstructive pulmonary disease (COPD) is a progressive, smoking-related, inflammatory lung disease in which tumor necrosis factor-alpha is overexpressed and has been suggested to play a pathogenic role. OBJECTIVES: To determine if infliximab, an anti-TNF-alpha antibody, results in clinical benefit and has an acceptable safety profile in patients with moderate to severe COPD. METHODS: In a multicenter, randomized, double-blind, placebo-controlled, parallel-group, dose-finding study, subjects with moderate to severe COPD received infliximab (3 mg/kg [n = 78] or 5 mg/kg [n = 79]) or placebo (n = 77) at Weeks 0, 2, 6, 12, 18, and 24. Efficacy, health status, and safety were assessed through Week 44. MEASUREMENTS AND MAIN RESULTS: Infliximab was generally well tolerated, but showed no treatment benefit as measured by the primary endpoint, Chronic Respiratory Questionnaire total score. Similarly, there was no change in secondary measures, including prebronchodilator FEV(1), 6-min walk distance, SF-36 physical score, transition dyspnea index, or moderate-to-severe COPD exacerbations. Post hoc analysis revealed that subjects who were younger or cachectic showed improvement in the 6-min walk distance. Malignancies were diagnosed during the study in 9 of 157 infliximab-treated subjects versus 1 of 77 placebo-treated subjects. No opportunistic infections were observed, and there were no differences in the occurrence of antibiotic-requiring infections, although the incidence of pneumonia was higher in infliximab-treated subjects. No infection-related mortality was observed. Higher proportions of infliximab-treated subjects discontinued the study agent due to adverse events (20-27%) than did placebo-treated subjects (9%). CONCLUSIONS: Subjects with moderate to severe COPD did not benefit from treatment with infliximab. Although not statistically significant, more cases of cancer and pneumonia were observed in the infliximab-treated subjects. The impact of infliximab on malignancy risk in patients with COPD needs to be further elucidated.


Assuntos
Anti-Inflamatórios/administração & dosagem , Anticorpos Monoclonais/administração & dosagem , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Idoso , Relação Dose-Resposta a Droga , Método Duplo-Cego , Esquema de Medicação , Tolerância ao Exercício , Feminino , Nível de Saúde , Humanos , Infliximab , Masculino , Pessoa de Meia-Idade , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Testes de Função Respiratória , Índice de Gravidade de Doença , Resultado do Tratamento
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