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1.
Chest ; 2020 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-32450241

RESUMO

BACKGROUND: A number of circulating plasma biomarkers have been shown to predict survival in patients with idiopathic pulmonary fibrosis (IPF), but most were identified prior to the use of anti-fibrotic therapy (AF) in this population. Because pirfenidone and nintedanib have been shown to slow IPF progression and may prolong survival, the role of such biomarkers in AF treated patients is unclear. RESEARCH QUESTION: To determine whether plasma concentration of CA-125, CXCL13, MMP7, SP-D, YKL-40, VCAM-1 and OPN is associated with differential transplant-free survival (TFS) in AF exposed and non-exposed patients with IPF. STUDY DESIGN AND METHODS: A pooled, multi-center, propensity-matched analysis of IPF patients with and without AF exposure was performed. Optimal thresholds for biomarker dichotomization were identified in each group using iterative Cox regression. Longitudinal biomarker change was assessed in a subset of patients using linear mixed regression modeling. A clinical-molecular signature of IPF TFS was then derived and validated in an independent IPF cohort. RESULTS: Three hundred and twenty-five patients were assessed, of which 68 AF exposed and 172 non-exposed patients were included after propensity matching. CA-125, CXCL13, MMP7, YKL-40 and OPN predicted differential TFS in AF exposed patients but at higher thresholds than in AF non-exposed individuals. Plasma biomarker level generally increased over time in non-exposed patients but remained unchanged in AF exposed patients. A clinical-molecular signature predicted decreased TFS in AF exposed patients (HR 5.91; 95% CI 2.25-15.5; p<0.001) and maintained this association in an independent AF exposed cohort (HR 3.97; 95% CI 1.62-9.72; p=0.003). INTERPRETATION: A majority of plasma biomarkers assessed predicted differential TFS in AF exposed patients with IPF, but at higher thresholds than in non-exposed patients. A clinical-molecular signature of IPF TFS may provide a reliable predictor of outcome risk in AF treated patients but requires additional research for optimization and validation.

3.
Respir Med ; 146: 23-27, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30665514

RESUMO

INTRODUCTION: Idiopathic interstitial pneumonias (IIP) are diffuse lung diseases whose cause is unknown and often present with features of autoimmunity despite not meeting criteria for a connective tissue disease (CTD). Recent studies suggest that anti-RNA binding protein (anti-RBP) antibodies, which include anti-SSA, anti-SSB, anti-Sm, and anti-RNP, play a role in the loss of immune tolerance and severity of pulmonary hypertension (PH) in CTDs. We hypothesized that anti-RBP positive (RBP+) subjects would have worse measures of lung function, radiographic findings, PH, and survival than anti-RBP negative (RBP-) subjects. METHODS: Subjects with both IIP and serologies for review were identified retrospectively and stratified based on anti-RBP antibody seropositivity. Baseline cohort characteristics, pulmonary function tests (PFT), ambulatory oxygen requirement, radiographic characteristics, markers of PH, and transplant-free survival were compared between anti-RBP positive and negative groups. RESULTS: Five hundred twenty patients with IIP were identified, of which ten percent (n = 53) were anti-RBP positive. RBP+ as compared to RBP- subjects had significantly worse PFTs as indicated by FEV1 (59.6 vs. 64.9, p = 0.046) and FVC (71.6 vs. 78.8, p = 0.018). There was a higher prevalence of radiographic honeycombing (49.1% vs. 38.3%, p = 0.006) and emphysema (22.6% vs. 5.1%, p < 0.001) in the RBP+ group despite no difference in smoking history. The Pulmonary Artery-Aorta ratio was also larger in the RBP+ group (0.93 vs. 0.88, p = 0.040). There was no difference in transplant-free survival between groups (log rank = 0.912). CONCLUSION: Anti-RBP+ IIP patients may have worse lung function, increased chest radiographic abnormalities, and PH compared with those without these antibodies.


Assuntos
Proteínas de Transporte/metabolismo , Pneumonias Intersticiais Idiopáticas/sangue , Pneumonias Intersticiais Idiopáticas/epidemiologia , Pneumonias Intersticiais Idiopáticas/fisiopatologia , Idoso , Anticorpos Antinucleares/imunologia , Autoimunidade/imunologia , Proteínas de Transporte/sangue , Doenças do Tecido Conjuntivo/epidemiologia , Feminino , Humanos , Hipertensão Pulmonar/fisiopatologia , Pneumonias Intersticiais Idiopáticas/diagnóstico por imagem , Pulmão/irrigação sanguínea , Pulmão/diagnóstico por imagem , Pulmão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Prevalência , Radiografia Torácica/métodos , Testes de Função Respiratória/métodos , Estudos Retrospectivos , Tomografia Computadorizada por Raios X
4.
Eur Respir J ; 51(6)2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29724923

RESUMO

We studied whether African-American race is associated with younger age and decreased survival time at diagnosis of interstitial lung disease (ILD).We performed a multicentre, propensity score-matched analysis of patients with an ILD diagnosis followed at five US hospitals between 2006 and 2016. African-Americans were matched with patients of other races based on a time-dependent propensity score calculated from multiple patient, physiological, diagnostic and hospital characteristics. Multivariable logistic regression models were used. All-cause mortality and hospitalisations were compared between race-stratified patient cohorts with ILD, and sensitivity analyses were performed.The study included 1640 patients with ILD, 13% of whom were African-American, followed over 5041 person-years. When compared with patients of other races, African-Americans with ILD were younger at diagnosis (56 years versus 67 years), but in the propensity-matched analyses had greater survival (hazard ratio 0.46, 95% CI 0.28-0.77; p=0.003) despite similar risk of respiratory hospitalisations (relative risk 1.04, 95% CI 0.83-1.31; p=0.709), and similar GAP-ILD (gender-age-physiology-ILD) scores at study entry. Sensitivity analyses in a separate cohort of 9503 patients with code-based ILD diagnosis demonstrated a similar association of baseline demographic characteristics with all-cause mortality.We conclude that African-Americans demonstrate a unique phenotype associated with younger age at ILD diagnosis and perhaps longer survival time.


Assuntos
Afro-Americanos , Hospitalização/estatística & dados numéricos , Doenças Pulmonares Intersticiais/mortalidade , Adulto , Idoso , Causas de Morte , Feminino , Humanos , Modelos Logísticos , Doenças Pulmonares Intersticiais/etnologia , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Pontuação de Propensão , Estudos Retrospectivos , Estados Unidos
5.
BMC Pulm Med ; 18(1): 30, 2018 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-29422061

RESUMO

BACKGROUND: Mortality is similarly high among individuals with usual interstitial pneumonia (UIP) due to idiopathic pulmonary fibrosis (IPF) and interstitial pneumonia with autoimmune features (IPAF). Circulating anti-nuclear antibodies (ANA) are commonly found in this patient population, suggesting possible aberrant immune activation. Because an environment of oxidative stress can result from immunologic activation, we hypothesized that ANA positive patients with UIP would have improved outcome when exposed to the antioxidant N-acetylcysteine (NAC) compared to ANA negative patients. METHODS: A single center, retrospective cohort analysis was performed. Patients with UIP due to IPF and IPAF were stratified according to ANA status to and NAC exposure. Transplant-free survival (TFS) was assessed using the Kaplan-Meier estimator and multivariable Cox regression adjusted for diagnosis, gender/age/physiology score, immunosuppressant exposure and anti-fibrotic exposure. RESULTS: Of 293 individuals with UIP due to IPF (74%) or IPAF (26%), NAC exposure was documented in 58 (19.8%). Among NAC exposed individuals, 33 (56.9%) were ANA seropositive and 25 (43.1%) were seronegative. NAC exposure was associated with improved TFS survival among ANA seropositive individuals in unadjusted analysis (plogrank = 0.02) and after multi-variable adjustment (HR 0.51, 95% CI 0.30-0.87; p = 0.01). There was no association between NAC exposure and TFS in ANA seronegative individuals (HR 1.26, 95% CI 0.69-2.32; p = 0.45). Formal interaction testing confirmed NAC*ANA interaction (p = 0.04) and sensitivity analysis demonstrated an increasing effect size associated with NAC therapy as ANA titer increased. Among patients with available genetic data, a marginally higher proportion of ANA positive patients (p = 0.08) carried the rs3750920 (TOLLIP) genotype previously shown to predict favorable outcome in NAC exposed patients. CONCLUSION: NAC exposure is associated with improved transplant-free survival ANA positive patients with UIP. These findings support the prospective collection of ANA data in in future NAC clinical trials performed in patients with UIP.


Assuntos
Acetilcisteína/uso terapêutico , Depuradores de Radicais Livres/uso terapêutico , Fibrose Pulmonar Idiopática/tratamento farmacológico , Idoso , Anticorpos Antinucleares/imunologia , Estudos de Coortes , Feminino , Humanos , Fibrose Pulmonar Idiopática/imunologia , Fibrose Pulmonar Idiopática/mortalidade , Estimativa de Kaplan-Meier , Transplante de Pulmão/estatística & dados numéricos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Taxa de Sobrevida
6.
Chest ; 153(2): 349-360, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-28964798

RESUMO

BACKGROUND: The current interstitial lung disease (ILD) classification has overlapping clinical presentations and outcomes. Cluster analysis modeling is a valuable tool in identifying distinct clinical phenotypes in heterogeneous diseases. However, this approach has yet to be implemented in ILD. METHODS: Using cluster analysis, novel ILD phenotypes were identified among subjects from a longitudinal ILD cohort, and outcomes were stratified according to phenotypic clusters compared with subgroups according to current American Thoracic Society/European Respiratory Society ILD classification criteria. RESULTS: Among subjects with complete data for baseline variables (N = 770), four clusters were identified. Cluster 1 (ie, younger white obese female subjects) had the highest baseline FVC and diffusion capacity of the lung for carbon monoxide (Dlco). Cluster 2 (ie, younger African-American female subjects with elevated antinuclear antibody titers) had the lowest baseline FVC. Cluster 3 (ie, elderly white male smokers with coexistent emphysema) had intermediate FVC and Dlco. Cluster 4 (ie, elderly white male smokers with severe honeycombing) had the lowest baseline Dlco. Compared with classification according to ILD subgroup, stratification according to phenotypic clusters was associated with significant differences in monthly FVC decline (Cluster 4, -0.30% vs Cluster 2, 0.01%; P < .0001). Stratification by using clusters also independently predicted progression-free survival (P < .001) and transplant-free survival (P < .001). CONCLUSIONS: Among adults with diverse chronic ILDs, cluster analysis using baseline characteristics identified four distinct clinical phenotypes that might better predict meaningful clinical outcomes than current ILD diagnostic criteria.


Assuntos
Doenças Pulmonares Intersticiais/classificação , Idoso , Doença Crônica , Análise por Conglomerados , Feminino , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Fenótipo , Fibrose Pulmonar/patologia
7.
Clin Pulm Med ; 24(5): 191-196, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29276366

RESUMO

The accurate diagnosis of interstitial lung disease (ILD) is essential for optimal prognostication and management. While connective tissue disease (CTD) is among the most common causes of ILD, some patients have features suggestive of autoimmunity without meeting criteria for a specific CTD. To help define and study this disease entity more uniformly, a 2015 research statement proposed consensus-based criteria and coined the term "interstitial pneumonia with autoimmune features" (IPAF). In this review, we summarize and compare previously proposed criteria to characterize these patients, provide an overview of the IPAF criteria and highlight recent investigations aimed at characterizing IPAF cohorts. We then call attention to questions that have arisen with the application of the IPAF criteria and discuss future areas of study.

9.
Arch Pathol Lab Med ; 141(7): 960-969, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28467213

RESUMO

CONTEXT: - Patients with idiopathic interstitial pneumonia may display evidence of autoimmunity without meeting criteria for a defined connective tissue disease. A recent European Respiratory Society/American Thoracic Society statement proposed research criteria for interstitial pneumonia with autoimmune features (IPAF), which includes findings from the clinical, serologic, and morphologic domains. OBJECTIVES: - To investigate the importance of histopathologic criteria within the morphologic domain and to report our methodology for identifying these features. DESIGN: - Patients with idiopathic interstitial pneumonia at the University of Chicago who underwent surgical lung biopsy or lung transplantation were assessed for IPAF histopathologic features, using the initial pathology interpretation in the electronic records. A focused rereview of available slides by a pulmonary pathologist was then performed for patients who failed to meet IPAF criteria on initial pathology assessment. RESULTS: - Of 422 patients with idiopathic interstitial pneumonia, 176 (41.7%) underwent surgical lung biopsy or lung transplant. Forty-six of those 176 patients (26.1%) met IPAF criteria by initial pathology interpretation and a positive clinical or serologic feature. Of the remaining 130 patients, 73 (56.2%) met either the clinical or serologic domains without meeting the morphologic domain, whereas 36 (27.7%) had slides available for pathology rereview. This rereview demonstrated nonspecific interstitial pneumonia in 8 of 36 patients (22.2%) and lymphoplasmacytic infiltrates in 6 of 36 patients (16.7%), resulting in an additional 7 of 36 patients (19.4%) with idiopathic interstitial pneumonia that met the IPAF criteria. In IPAF, pulmonary vasculopathy was the most prevalent finding (45 of 84; 53.6%) and predicted increased mortality (hazard ratio, 2.5; P = .04). CONCLUSIONS: - Using a methodological approach to identifying IPAF pathology, we demonstrate a significant increase in the number of patients meeting IPAF criteria because of focused pathologic review and highlight the prognostic value of the IPAF pathologic findings.


Assuntos
Autoimunidade , Pneumonias Intersticiais Idiopáticas/diagnóstico , Patologia Clínica/métodos , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
10.
AJR Am J Roentgenol ; 208(6): 1229-1236, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28350485

RESUMO

OBJECTIVE: The objective of this study is to determine the CT findings and patterns of interstitial pneumonia with autoimmune features (IPAF) and to assess whether imaging can predict survival for patients with IPAF. MATERIALS AND METHODS: The study included 136 subjects who met the criteria for IPAF and had diagnostic-quality chest CT scans obtained from 2006 to 2015; a total of 74 of these subjects had pathologic samples available for review within 1 year of chest CT examination. CT findings and the presence of an usual interstitial pneumonitis (UIP) pattern of disease were assessed, as was the UIP pattern noted on pathologic analysis. Analysis of chest CT findings associated with survival was performed using standard univariate and multivariate Cox proportional hazards methods as well as the unadjusted log-rank test. Survival data were visually presented using the Kaplan-Meier survival curve estimator. RESULTS: Most subjects with IPAF (57.4%; 78/136) had a high-confidence diagnosis of a UIP pattern on CT. Substantially fewer subjects (28.7%; 39/136) had a pattern that was inconsistent with UIP noted on CT. The presence of a UIP pattern on CT was associated with smoking (p < 0.01), male sex (p < 0.01), and older age (p < 0.001). Approximately one-fourth of the subjects had a nonspecific interstitial pneumonitis pattern on CT. Of interest, nearly one-tenth of the subjects had a CT pattern that was most consistent with hypersensitivity pneumonitis rather than the customary CT patterns ascribed to lung disease resulting from connective tissue disease. Most subjects with a possible UIP pattern on CT (83.3%) had UIP diagnosed on the basis of pathologic findings. Focused multivariate analysis showed that honeycombing on CT (hazard ratio, 2.17; 95% CI, 1.05-4.47) and pulmonary artery enlargement on CT (hazard ratio, 2.08; 95% CI, 1.02-4.20) were independent predictors of survival. CONCLUSION: IPAF most often presents with a UIP pattern on CT and is associated with worse survival when concomitant honeycombing or pulmonary artery enlargement is present.


Assuntos
Doenças Autoimunes/diagnóstico por imagem , Doenças Autoimunes/mortalidade , Doenças Pulmonares Intersticiais/diagnóstico por imagem , Doenças Pulmonares Intersticiais/mortalidade , Análise de Sobrevida , Tomografia Computadorizada por Raios X/estatística & dados numéricos , Doenças Autoimunes/patologia , Chicago/epidemiologia , Comorbidade , Feminino , Humanos , Doenças Pulmonares Intersticiais/patologia , Masculino , Pessoa de Meia-Idade , Variações Dependentes do Observador , Prevalência , Prognóstico , Reprodutibilidade dos Testes , Estudos Retrospectivos , Medição de Risco , Sensibilidade e Especificidade , Estatística como Assunto
11.
Clin Cancer Res ; 23(1): 35-42, 2017 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-27486175

RESUMO

PURPOSE: Therapeutic regimens for adult T-cell leukemia/lymphoma (ATL) are limited with unsatisfactory results, thereby warranting development of novel therapies. This study investigated antitumor activity and toxicity of alemtuzumab with regard to response, duration of response, progression-free survival, and overall survival in patients with human T-cell lymphotropic virus-1 (HTLV-1)-associated ATL. EXPERIMENTAL DESIGN: Twenty-nine patients with chronic, acute, and lymphomatous types of ATL were enrolled in a single-institution, nonrandomized, open-label phase II trial wherein patients received intravenous alemtuzumab 30 mg three times weekly for a maximum of 12 weeks. RESULTS: Twenty-nine patients were evaluable for response and toxicity. The overall objective response was 15 of 29 patients [95% confidence interval (CI), 32.5%-70.6%]. The 15 patients who responded manifested a median time to response of 1.1 months. Median response duration was 1.4 months for the whole group and 14.5 months among responders. Median progression-free survival was 2.0 months. Median overall survival was 5.9 months. The most common adverse events were 2 with vasovagal episodes (7%) and 3 with hypotensive episodes (10%), leukopenia (41%) grade 3 and (17%) grade 4, lymphocytopenia (59%) grade 3, neutropenia (31%) grade 3, anemia (24%), and thrombocytopenia (10%). All patients developed cytomegalovirus antigenemia (CMV). Three were symptomatic and all responded to antiviral therapy. Grade 3 or 4 infections were reported in 4 (14%) of patients. CONCLUSIONS: Alemtuzumab induced responses in patients with acute HTLV-1-associated ATL with acceptable toxicity, but with short duration of responses. These studies support inclusion of alemtuzumab in novel multidrug therapies for ATL. Clin Cancer Res; 23(1); 35-42. ©2016 AACR.


Assuntos
Alemtuzumab/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Infecções por HTLV-I/complicações , Vírus Linfotrópico T Tipo 1 Humano , Leucemia-Linfoma de Células T do Adulto/tratamento farmacológico , Leucemia-Linfoma de Células T do Adulto/etiologia , Adulto , Idoso , Alemtuzumab/administração & dosagem , Alemtuzumab/efeitos adversos , Antineoplásicos Imunológicos/administração & dosagem , Antineoplásicos Imunológicos/efeitos adversos , Feminino , Infecções por HTLV-I/virologia , Humanos , Imunofenotipagem , Estimativa de Kaplan-Meier , Leucemia-Linfoma de Células T do Adulto/diagnóstico , Leucemia-Linfoma de Células T do Adulto/mortalidade , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Retratamento , Resultado do Tratamento , Adulto Jovem
12.
Respir Med ; 121: 117-122, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27888985

RESUMO

BACKGROUND: Azathioprine is a commonly prescribed therapy for connective tissue disease-associated interstitial lung disease (CTD-ILD). Combination therapy that included azathioprine was recently shown to increase the risk of death and hospitalization in patients with idiopathic pulmonary fibrosis. Whether azathioprine increases the risk of adverse outcomes in patients with fibrotic CTD-ILD, including those with CTD-associated usual interstitial pneumonia (UIP), remains unknown. METHODS: A retrospective cohort analysis was performed to determine the combined incidence rate of death, transplant and respiratory hospitalization associated with azathioprine exposure. A fibrotic CTD-ILD cohort treated with mycophenolate mofetil served as a comparator group. Incidence rates were compared with an incidence rate ratio (IRR) generated by negative binomial regression. Longitudinal pulmonary function response was then assessed using mixed effects linear regression models. RESULTS: Fifty-four patients were treated with azathioprine and forty-three with mycophenolate. Medication discontinuation due to non-respiratory side effects occurred in 27% and 5% of the azathioprine and mycophenolate cohorts, respectively. The combined incidence rate of adverse outcomes was 0.015 and 0.013 for azathioprine and mycophenolate, respectively (IRR 1.23; 95% CI 0.49-3.12; p = 0.66). Similar incidence rates were observed among those with CTD-UIP (IRR 0.83; 95% CI 0.21-3.31; p = 0.79). Both groups demonstrated pulmonary function stability over time, with the azathioprine group demonstrating a marginal improvement. CONCLUSIONS: A significant minority of patients could not tolerate azathioprine due to non-respiratory side effects. Of those who did tolerate azathioprine, a similar incidence of adverse outcomes was observed as those treated with mycophenolate. Both therapies were associated with stability in pulmonary function.


Assuntos
Azatioprina/uso terapêutico , Doenças do Tecido Conjuntivo/complicações , Imunossupressores/uso terapêutico , Doenças Pulmonares Intersticiais/tratamento farmacológico , Adulto , Idoso , Azatioprina/efeitos adversos , Doenças do Tecido Conjuntivo/fisiopatologia , Estudos Cross-Over , Feminino , Hospitalização/estatística & dados numéricos , Humanos , Imunossupressores/efeitos adversos , Doenças Pulmonares Intersticiais/etiologia , Doenças Pulmonares Intersticiais/fisiopatologia , Masculino , Pessoa de Meia-Idade , Ácido Micofenólico/efeitos adversos , Ácido Micofenólico/uso terapêutico , Capacidade de Difusão Pulmonar/efeitos dos fármacos , Sistema de Registros , Estudos Retrospectivos , Capacidade Vital/efeitos dos fármacos
13.
Eur Respir J ; 47(6): 1767-75, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-27103387

RESUMO

Patients with interstitial lung disease (ILD) may have features of connective tissue disease (CTD), but lack findings diagnostic of a specific CTD. A recent European Respiratory Society/American Thoracic Society research statement proposed criteria for patients with interstitial pneumonia with autoimmune features (IPAF).We applied IPAF criteria to patients with idiopathic interstitial pneumonia and undifferentiated CTD-ILD (UCTD). We then characterised the clinical, serological and morphological features of the IPAF cohort, compared outcomes to other ILD cohorts and validated individual IPAF domains using survival as an endpoint.Of 422 patients, 144 met IPAF criteria. Mean age was 63.2 years with a slight female predominance. IPAF cohort survival was marginally better than patients with idiopathic pulmonary fibrosis, but worse than CTD-ILD. A non-usual interstitial pneumonia pattern was associated with improved survival, as was presence of the clinical domain. A modified IPAF cohort of those meeting the clinical domain and a radiographic or histological feature within the morphological domain displayed survival similar to those with CTD-ILD.IPAF is common among patients with idiopathic interstitial pneumonia and UCTD. Specific IPAF features can identify subgroups with differential survival. Further research is needed to replicate these findings and determine whether patients meeting IPAF criteria benefit from immunosuppressive therapy.


Assuntos
Doenças Autoimunes/diagnóstico , Doenças Autoimunes/imunologia , Pneumonias Intersticiais Idiopáticas/diagnóstico , Pneumonias Intersticiais Idiopáticas/imunologia , Idoso , Biópsia , Estudos de Coortes , Doenças do Tecido Conjuntivo/diagnóstico , Doenças do Tecido Conjuntivo/imunologia , Feminino , Humanos , Imunossupressores/uso terapêutico , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Tempo , Resultado do Tratamento
14.
Proc Natl Acad Sci U S A ; 112(42): 13045-50, 2015 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-26438866

RESUMO

Despite significant advances in the treatment of Hodgkin's lymphoma (HL), a significant proportion of patients will not respond or will subsequently relapse. We identified CD25, the IL-2 receptor alpha subunit, as a favorable target for systemic radioimmunotherapy of HL. The scientific basis for the clinical trial was that, although most normal cells with exception of Treg cells do not express CD25, it is expressed by a minority of Reed-Sternberg cells and by most polyclonal T cells rosetting around Reed-Sternberg cells. Forty-six patients with refractory and relapsed HL were evaluated with up to seven i.v. infusions of the radiolabeled anti-CD25 antibody (90)Y-daclizumab. (90)Y provides strong ß emissions that kill tumor cells at a distance by a crossfire effect. In 46 evaluable HL patients treated with (90)Y-daclizumab there were 14 complete responses and nine partial responses; 14 patients had stable disease, and nine progressed. Responses were observed both in patients whose Reed-Sternberg cells expressed CD25 and in those whose neoplastic cells were CD25(-) provided that associated rosetting T cells expressed CD25. As assessed using phosphorylated H2AX (γ-H2AX) as a bioindicator of the effects of radiation exposure, predominantly nonmalignant cells in the tumor microenvironment manifested DNA damage, as reflected by increased expression of γ-H2AX. Toxicities were transient bone-marrow suppression and myelodysplastic syndrome in six patients who had not been evaluated with bone-marrow karyotype analyses before therapy. In conclusion, repeated (90)Y-daclizumab infusions directed predominantly toward nonmalignant T cells rosetting around Reed-Sternberg cells provided meaningful therapy for select HL patients.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Doença de Hodgkin/tratamento farmacológico , Imunoglobulina G/uso terapêutico , Subunidade alfa de Receptor de Interleucina-2/imunologia , Radioisótopos de Ítrio/química , Adulto , Idoso , Anticorpos Monoclonais Humanizados/química , Anticorpos Monoclonais Humanizados/imunologia , Daclizumabe , Feminino , Doença de Hodgkin/imunologia , Humanos , Imunoglobulina G/química , Imunoglobulina G/imunologia , Masculino , Pessoa de Meia-Idade , Fosforilação , Recidiva , Adulto Jovem
15.
Am J Respir Crit Care Med ; 192(12): 1475-82, 2015 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-26331942

RESUMO

RATIONALE: Idiopathic pulmonary fibrosis (IPF) is a devastating lung disease of unknown etiology. The genes TOLLIP and MUC5B play important roles in lung host defense, which is an immune process influenced by oxidative signaling. Whether polymorphisms in TOLLIP and MUC5B modify the effect of immunosuppressive and antioxidant therapy in individuals with IPF is unknown. OBJECTIVES: To determine whether single-nucleotide polymorphisms (SNPs) within TOLLIP and MUC5B modify the effect of interventions in subjects participating in the Evaluating the Effectiveness of Prednisone, Azathioprine, and N-Acetylcysteine in Patients with Idiopathic Pulmonary Fibrosis (PANTHER-IPF) clinical trial. METHODS: SNPs within TOLLIP (rs5743890/rs5743894/rs5743854/rs3750920) and MUC5B (rs35705950) were genotyped. Interaction modeling was conducted with multivariable Cox regression followed by genotype-stratified survival analysis using a composite endpoint of death, transplantation, hospitalization, or a decline of ≥ 10% in FVC. MEASUREMENTS AND MAIN RESULTS: Significant interaction was observed between N-acetylcysteine (NAC) therapy and rs3750920 within TOLLIP (P interaction = 0.001). After stratifying by rs3750920 genotype, NAC therapy was associated with a significant reduction in composite endpoint risk (hazard ratio, 0.14; 95% confidence interval, 0.02-0.83; P = 0.03) in those with a TT genotype, but a nonsignificant increase in composite endpoint risk (hazard ratio, 3.23; 95% confidence interval, 0.79-13.16; P = 0.10) was seen in those with a CC genotype. These findings were then replicated in an independent IPF cohort. CONCLUSIONS: NAC may be an efficacious therapy for individuals with IPF with an rs3750920 (TOLLIP) TT genotype, but it was associated with a trend toward harm in those with a CC genotype. A genotype-stratified prospective clinical trial should be conducted before any recommendation regarding the use of off-label NAC to treat IPF.


Assuntos
Acetilcisteína/uso terapêutico , Fibrose Pulmonar Idiopática/tratamento farmacológico , Fibrose Pulmonar Idiopática/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Mucina-5B/genética , Idoso , Estudos de Coortes , Feminino , Predisposição Genética para Doença/genética , Humanos , Fibrose Pulmonar Idiopática/imunologia , Peptídeos e Proteínas de Sinalização Intracelular/imunologia , Masculino , Mucina-5B/imunologia , Polimorfismo de Nucleotídeo Único/genética , Polimorfismo de Nucleotídeo Único/imunologia , Risco
16.
Chest ; 148(3): 692-700, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25811599

RESUMO

BACKGROUND: A significant minority of patients with idiopathic pulmonary fibrosis (IPF) display features of autoimmunity without meeting the criteria for overt connective tissue disease. A link between IPF and other immune-mediated processes, such as hypothyroidism (HT), has not been reported. In this investigation, we aimed to determine whether HT is associated with IPF and if outcomes differ between patients with IPF with and without HT. METHODS: A retrospective case-control analysis was conducted. Of 311 patients referred to the University of Chicago Interstitial Lung Disease Center with an initial diagnosis of IPF, 196 met the inclusion criteria and were included in the final analysis. Each case was matched 1:1 by age, sex, and race to a control subject with COPD. RESULTS: HT was identified in 16.8% of cases and 7.1% of control subjects (OR, 2.7; 95% CI, 1.31-5.54; P = .01). Among patients with IPF, HT was associated with reduced survival time (P < .001) and was found to be an independent predictor of mortality in multivariable Cox regression analysis (hazard ratio, 2.12; 95% CI, 1.31-3.43; P = .002). A secondary analysis of two IPF clinical trial datasets supports these findings. CONCLUSIONS: HT is common among patients with IPF, with a higher prevalence than in those with COPD and the general population. The presence of HT also predicts mortality in IPF, a finding that may improve future prognostication models. More research is needed to determine the biologic link between IPF and HT and how the presence of thyroid disease may influence disease progression.


Assuntos
Doenças Autoimunes/etiologia , Hipotireoidismo/etiologia , Fibrose Pulmonar Idiopática/complicações , Idoso , Doenças Autoimunes/epidemiologia , Estudos de Casos e Controles , Feminino , Humanos , Hipotireoidismo/epidemiologia , Fibrose Pulmonar Idiopática/diagnóstico por imagem , Fibrose Pulmonar Idiopática/mortalidade , Illinois/epidemiologia , Masculino , Radiografia , Estudos Retrospectivos , Fatores de Risco , Análise de Sobrevida
18.
Proc Natl Acad Sci U S A ; 103(2): 401-6, 2006 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-16387851

RESUMO

Twelve patients with T cell large granular lymphocyte leukemia and associated hematocytopenia were treated in a phase I dose-escalation trial with the murine monoclonal antibody Mikbeta1. Mikbeta1 identifies CD122, the beta-subunit shared by the IL-2 and IL-15 receptors. At the doses administered in this study the antibody inhibited the actions of IL-15 on both natural killer and T cells and that of IL-2 when the intermediate-affinity IL-2 receptor was expressed. Mikbeta1 treatment was not associated with significant toxicity or with the development of an immune response to the infused monoclonal antibody. At these doses of Mikbeta1, >95% saturation of the IL-2/IL-15beta receptor (CD122) on the surfaces of the leukemic cells was achieved. Furthermore, in seven patients this led to the down-modulation of the receptor from the surfaces of the leukemic cells. Nevertheless, no patients manifested a reduction in peripheral leukemic cell count or an amelioration of their hematocytopenia. This latter observation may reflect the fact that the monoclonal T cell large granular lymphocyte leukemia leukemic cells of the patients did not produce IL-2 or IL-15 or require their actions for cell survival. In light of the lack of toxicity and lack of immunogenicity of the antibody observed in the present study and the role for IL-15 in the pathogenesis of autoimmune diseases, clinical trials should be performed using the humanized version of Mikbeta1 in groups of patients with human T cell lymphotropic virus I-associated myelopathy/tropical spastic paraparesis, rheumatoid arthritis, multiple sclerosis and refractory celiac disease.


Assuntos
Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/uso terapêutico , Interleucina-15/antagonistas & inibidores , Interleucina-15/imunologia , Leucemia de Células T/imunologia , Leucemia de Células T/terapia , Adulto , Idoso , Animais , Anticorpos Monoclonais/efeitos adversos , Comunicação Autócrina/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Feminino , Humanos , Imunoterapia , Interleucina-2/imunologia , Leucemia de Células T/metabolismo , Leucemia de Células T/patologia , Masculino , Camundongos , Pessoa de Meia-Idade , Comunicação Parácrina/efeitos dos fármacos , Receptores de Interleucina-2/metabolismo , Células Tumorais Cultivadas
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