RESUMEN
Glycans represent a promising but only marginally accessed source of cancer markers. We previously reported the development of a molecularly bottom-up approach to plasma and serum (P/S) glycomics based on glycan linkage analysis that captures features such as α2-6 sialylation, ß1-6 branching, and core fucosylation as single analytical signals. Based on the behavior of P/S glycans established to date, we hypothesized that the alteration of P/S glycans observed in cancer would be independent of the tissue in which the tumor originated yet exhibit stage dependence that varied little between cancers classified on the basis of tumor origin. Herein, the diagnostic utility of this bottom-up approach as applied to lung cancer patients (n = 127 stage I; n = 20 stage II; n = 81 stage III; and n = 90 stage IV) as well as prostate (n = 40 stage II), serous ovarian (n = 59 stage III), and pancreatic cancer patients (n = 15 rapid autopsy) compared to certifiably healthy individuals (n = 30), nominally healthy individuals (n = 166), and risk-matched controls (n = 300) is reported. Diagnostic performance in lung cancer was stage-dependent, with markers for terminal (total) fucosylation, α2-6 sialylation, ß1-4 branching, ß1-6 branching, and outer-arm fucosylation most able to differentiate cases from controls. These markers behaved in a similar stage-dependent manner in other types of cancer as well. Notable differences between certifiably healthy individuals and case-matched controls were observed. These markers were not significantly elevated in liver fibrosis. Using a Cox proportional hazards regression model, the marker for α2-6 sialylation was found to predict both progression and survival in lung cancer patients after adjusting for age, gender, smoking status, and stage. The potential mechanistic role of aberrant P/S glycans in cancer progression is discussed.
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Glicómica/métodos , Neoplasias/metabolismo , Polisacáridos/sangre , Secuencia de Carbohidratos , Estudios de Casos y Controles , Fucosa/metabolismo , Glicosilación , Humanos , Ácido N-Acetilneuramínico/metabolismo , Neoplasias/diagnóstico , Polisacáridos/metabolismo , PronósticoRESUMEN
BACKGROUND: Pulmonary hypertension (PH)-targeted therapy in the setting of pulmonary fibrosis (PF) is controversial; the main clinical concern is worsening of systemic hypoxaemia. We sought to determine the effects of gentle initiation and chronic administration of parenteral treprostinil on right heart function in patients with PF associated with an advanced PH phenotype. METHODS: Open-label, prospective analysis of patients with PF-PH referred for lung transplantation (LT). Advanced PH was defined as mean pulmonary artery pressure (mPAP) ≥35 mm Hg. We compared haemodynamics, Doppler echocardiography (DE), oxygenation, dyspnoea and quality of life indices, and 6 min walk distance (6MWD) before and 12 weeks after parenteral treprostinil. RESULTS: 15 patients were recruited in the study. After therapy, there were significant improvements in right heart haemodynamics (right atrial pressure (9.5 ± 3.4 vs 6.0 ± 3.7); mPAP (47 ± 8 vs 38.9 ± 13.4); CI (2.3 ± 0.5 vs 2.7 ± 0.6); pulmonary vascular resistance (698 ± 278 vs 496 ± 229); transpulmonary gradient (34.7 ± 8.7 vs 28.5 ± 10.3); mvO2 (65 ± 7.2 vs 70.9 ± 7.4); and stroke volume index (29.2 ± 6.7 vs 33 ± 7.3)) and DE parameters reflecting right heart function (right ventricular (RV) end diastolic area (36.4 ± 5.2 vs 30.9 ± 8.2 cm(2)), left ventricular eccentricity index (1.7 ± 0.6 vs 1.3 ± 0.5), tricuspid annular planar systolic excursion (1.6 ± 0.5 vs 1.9 ± 0.2 cm)). These changes occurred without significant alteration in systemic oxygenation, heart rate, or mean systemic arterial pressure. In addition, improvements were seen in 6MWD (171 ± 93 vs 230 ± 114), 36-Item Short Form Health Survey Mental Component Summary aggregate (38 ± 11 vs 44.2 ± 10.7), University of California, San Diego Shortness of Breath Questionnaire (87 ± 17.1 vs 73.1 ± 21), and brain natriuretic peptide (558 ± 859 vs 228 ± 340). CONCLUSIONS: PH-targeted therapy may improve right heart haemodynamics and echocardiographic function without affecting systemic oxygen saturation in an advanced PH phenotype associated with RV dysfunction in the setting of PF.
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Antihipertensivos/uso terapéutico , Epoprostenol/análogos & derivados , Hipertensión Pulmonar/tratamiento farmacológico , Fibrosis Pulmonar/complicaciones , Disfunción Ventricular Derecha/tratamiento farmacológico , Anciano , Disnea/tratamiento farmacológico , Disnea/etiología , Disnea/fisiopatología , Ecocardiografía Doppler , Epoprostenol/uso terapéutico , Prueba de Esfuerzo/métodos , Femenino , Hemodinámica/efectos de los fármacos , Humanos , Hipertensión Pulmonar/diagnóstico por imagen , Hipertensión Pulmonar/etiología , Hipertensión Pulmonar/fisiopatología , Masculino , Persona de Mediana Edad , Consumo de Oxígeno/efectos de los fármacos , Fenotipo , Proyectos Piloto , Estudios Prospectivos , Calidad de Vida , Resultado del Tratamiento , Disfunción Ventricular Derecha/diagnóstico por imagen , Disfunción Ventricular Derecha/etiología , Disfunción Ventricular Derecha/fisiopatologíaRESUMEN
OBJECTIVES: SSc is associated with an increased prevalence of atherosclerosis (ATS). This study assessed the prevalence of subclinical ATS as measured by carotid US and explored serum proteins to identify potential biomarkers of SSc-ATS. METHODS: Forty-six SSc female patients and 46 age- and ethnicity-matched controls underwent carotid US to assess the presence of plaque and carotid intima media thickness (CIMT). Abstracted data included demographics, ATS risk factors and serum measurements [cholesterol, proinflammatory high-density lipoprotein (piHDL), CRP, lipoproteins]. Serum cytokines/proteins analyses included circulating type I IFN activity by quantifying IFN-inducible genes, soluble junctional adhesion molecule A (sJAM-A) and 100 serum proteins by using a microplate-based multiplex platform. Proteins significant at P < 0.05 on bivariate analyses for the presence of plaque were used to develop a composite measure. RESULTS: Patients with SSc had more plaque (45.6% vs 19.5%, P = 0.01) but similar CIMT compared with controls. Multiplex analysis detected significant associations between serum proteins of inflammation, vasculopathy and fibrosis with ATS in SSc, including IL-2, IL-6, CRP, keratinocyte growth factor, intercellular adhesion molecule 1, endoglin, plasminogen activator inhibitor 1 and insulin-like growth factor binding protein 3 associated with carotid plaque. Myeloid progenitor inhibitory factor 1, serum amyloid A, thrombomodulin, N-terminal pro-brain natriuretic peptide (BNP), and Clara cell secretory protein 16 kD correlated with CIMT. The median composite score for the plaque group was 6 and for the no plaque group it was 2 (P < 0.0001). CONCLUSION: Patients with SSc have a higher prevalence of carotid plaque than matched controls, and patients with SSc-plaque vs patients without plaque have elevated serum proteins implicated in both vasculopathy and fibrosis. Further studies are needed to evaluate the role of these proteins in SSc compared with healthy controls.
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Enfermedades de las Arterias Carótidas/complicaciones , Placa Aterosclerótica/complicaciones , Esclerodermia Sistémica/complicaciones , Adulto , Antígenos CD/sangre , Enfermedades Asintomáticas , Biomarcadores , Proteína C-Reactiva/metabolismo , Arterias Carótidas/diagnóstico por imagen , Enfermedades de las Arterias Carótidas/sangre , Enfermedades de las Arterias Carótidas/diagnóstico por imagen , Grosor Intima-Media Carotídeo , Estudios de Casos y Controles , Quimiocinas CC/sangre , Estudios Transversales , Endoglina , Femenino , Factor 7 de Crecimiento de Fibroblastos/sangre , Humanos , Proteína 3 de Unión a Factor de Crecimiento Similar a la Insulina/sangre , Molécula 1 de Adhesión Intercelular/sangre , Interleucina-2/sangre , Interleucina-6/sangre , Persona de Mediana Edad , Péptido Natriurético Encefálico/sangre , Fragmentos de Péptidos/sangre , Placa Aterosclerótica/sangre , Placa Aterosclerótica/diagnóstico por imagen , Inhibidor 1 de Activador Plasminogénico/sangre , Receptores de Superficie Celular/sangre , Factores de Riesgo , Esclerodermia Sistémica/sangre , Esclerodermia Sistémica/diagnóstico por imagen , Proteína Amiloide A Sérica , Trombomodulina/sangre , Uteroglobina/sangreRESUMEN
OBJECTIVE: To evaluate the impact of comorbidities on achieving remission by examining changes in the clinical disease activity index (CDAI) in RA patients in the community-based Consortium of Rheumatology Researchers of North America (CORRONA) registry. METHODS: A subcohort of 1548 RA subjects with varying disease duration met the following inclusion criteria: started a DMARD/biologic agent, continued therapy ≥ 3 months, CDAI ≥ 2.8 at study entry and followed longitudinally from baseline to follow-up (mean time 7.46 months). Patients reported comorbidities according to a standardized list of 33 conditions. Entry characteristics were compared across age categories using one-way analysis of variance. Linear and logistic regression models were constructed to assess characteristics [e.g. age, disease duration, number of previous DMARDs/biologics, baseline modified health assessment questionnaire (MHAQ), baseline CDAI and number of comorbidities] associated with primary outcomes: change in CDAI (baseline to follow-up) and CDAI remission (yes/no). RESULTS: Although disease activity measures at entry were similar across age categories, older patients had more comorbidities, less improvement in CDAI/MHAQ and were less likely to attain remission at follow-up. However, after adjusting covariates an increasing number of patient-reported comorbidities and higher baseline CDAI (but not age) were consistently and independently associated with a lower likelihood of clinical improvement or remission (P < 0.001). CONCLUSION: In this observational cohort of community RA patients an increasing number of patients reported comorbidities, independently correlated with less CDAI improvement over time. These results reaffirm that comorbidities may be an important factor in consideration of treat-to-target recommendations and aid in understanding achievable RA therapeutic goals.
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Antirreumáticos/uso terapéutico , Artritis Reumatoide/tratamiento farmacológico , Artritis Reumatoide/epidemiología , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Productos Biológicos/uso terapéutico , Comorbilidad , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Inducción de Remisión , Índice de Severidad de la Enfermedad , Resultado del Tratamiento , Estados Unidos/epidemiología , Adulto JovenRESUMEN
OBJECTIVES: UCLA-SCTC-GIT 2.0 is an instrument designed to evaluate gastrointestinal (GI) symptoms in systemic sclerosis (SSc). The objective of our study was to assess the associations between the upper GI (UGI) symptom scales (reflux and distention/bloating [D/B] scales) versus objective/laboratory studies. METHODS: Fifty-five patients with SSc were enrolled at 2 centres. Each patient completed the GIT 2.0 and had objective and laboratory tests. Correlations were assessed using the Spearman's test. We also assessed the average scores in patients with positive vs. negative tests and compared them using the t-test and Wilcoxon test. RESULTS: The mean (SD) age was 53.6 (11.8), 90% were women and 49% had limited SSc. The mean reflux and D/B scores were 0.82 and 1.25, respectively (moderate severity). The reflux scale had moderate correlations with upper GI objective evaluations (correlation coefficient ≥0.40) and was able to differentiate between patients with endoscopy proven esophagitis and manometric abnormalities (p=0.01 for both). D/B scores were numerically higher in patients with abnormal objective tests. The GIT 2.0 reflux and D/B scales had a high sensitivity ranging from 80% to 94% but very low specificity (range; 0-20%) based on objective gold standard GI measures. CONCLUSIONS: The GIT 2.0 reflux and D/B scales have a high sensitivity (range 80-94%) for UGI involvement. The GIT 2.0 instrument complements the objective tests for assessment of the UGI.
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Enfermedades Gastrointestinales/diagnóstico , Enfermedades Gastrointestinales/etiología , Esclerodermia Difusa/complicaciones , Esclerodermia Limitada/complicaciones , Esclerodermia Sistémica/complicaciones , Adulto , Anciano , Esófago de Barrett/diagnóstico , Esófago de Barrett/etiología , Pruebas Respiratorias , Esofagitis/diagnóstico , Esofagitis/etiología , Femenino , Reflujo Gastroesofágico/diagnóstico , Reflujo Gastroesofágico/etiología , Motilidad Gastrointestinal , Humanos , Masculino , Manometría , Persona de Mediana Edad , Sensibilidad y Especificidad , Úlcera Gástrica/diagnóstico , Úlcera Gástrica/etiologíaRESUMEN
BACKGROUND: Patients with normal (mean pulmonary arterial pressure (mPAP) ≤20 mm Hg) and borderline mean pulmonary pressures (21-24 mm Hg) are "at risk" of developing pulmonary hypertension (PH). The objectives of this analysis were to examine the baseline characteristics in systemic sclerosis (SSc) with normal and borderline mPAP and to explore long-term outcomes in SSc patients with borderline mPAP versus normal haemodynamics. METHODS: PHAROS is a multicentre prospective longitudinal cohort of patients with SSc "at risk" or recently diagnosed with resting PH on right heart catheterisation (RHC). Baseline clinical characteristics, pulmonary function tests, high-resolution CT, 2-dimensional echocardiogram and RHC results were analysed in normal and borderline mPAP groups. RESULTS: 206 patients underwent RHC (results showed 35 normal, 28 borderline mPAP, 143 resting PH). There were no differences in the baseline demographics. Patients in the borderline mPAP group were more likely to have restrictive lung disease (67% vs 30%), fibrosis on high-resolution CT and a higher estimated right ventricular systolic pressure on echocardiogram (46.3 vs 36.2 mm Hg; p<0.05) than patients with normal haemodynamics. RHC revealed higher pulmonary vascular resistance and more elevated mPAP on exercise (≥30; 88% vs 56%) in the borderline mPAP group (p<0.05 for both). Patients were followed for a mean of 25.7 months and 24 patients had a repeat RHC during this period. During follow-up, 55% of the borderline mPAP group and 32% of the normal group developed resting PH (p=NS). CONCLUSIONS: Patients with borderline mPAP have a greater prevalence of abnormal lung physiology, pulmonary fibrosis and the presence of exercise mPAP ≥30 mm Hg.
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Presión Sanguínea/fisiología , Hipertensión Pulmonar/fisiopatología , Arteria Pulmonar/fisiopatología , Esclerodermia Sistémica/fisiopatología , Cateterismo Cardíaco , Femenino , Estudios de Seguimiento , Hemodinámica , Humanos , Hipertensión Pulmonar/complicaciones , Hipertensión Pulmonar/diagnóstico , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Fibrosis Pulmonar/complicaciones , Fibrosis Pulmonar/fisiopatología , Pruebas de Función Respiratoria , Esclerodermia Sistémica/complicaciones , Esclerodermia Sistémica/diagnósticoRESUMEN
OBJECTIVE: The National Institutes of Health Patient-Reported Outcomes Measurement Information System (PROMIS) roadmap initiative is a cooperative group program of research designed to develop, evaluate, and standardize item banks to measure patient-reported outcomes relevant across medical conditions. The objective of the current study was to assess feasibility and evaluation of the construct validity of PROMIS item banks versus legacy measures in an observational study in systemic sclerosis (SSc). We hypothesized that the PROMIS item banks can be administered in a clinical setting if there is adequate staff support without disrupting the flow of clinic. METHODS: Patients with SSc in a single academic center completed computerized adaptive test (CAT) administered PROMIS item banks during the clinic visit and legacy measures (using paper and pencil). The construct validity of PROMIS items was evaluated by examining correlations with corresponding legacy measures using multitrait-multimethod analysis. RESULTS: Participants consisted of 143 SSc patients with an average age of 51.5 years; 71% were female and 68% were white. The average number of items completed for each CAT-administered item bank ranged from 5 to 8 (69 CAT items per patient), and the average time to complete each CAT-administered item bank ranged from 48 seconds to 1.9 minutes per patient (average time = 11.9 minutes/per patient for 11 banks). All correlations between PROMIS domains and respective legacy measures were large and in the hypothesized direction (ranged from 0.61 to 0.82). CONCLUSION: Our study supports the construct validity of the CAT-administered PROMIS item banks and shows that they can be administered successfully in a clinic with support staff. Future studies should assess the feasibility of PROMIS item banks in a busy clinical practice.
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Evaluación de Resultado en la Atención de Salud/métodos , Calidad de Vida , Esclerodermia Sistémica/psicología , Encuestas y Cuestionarios , Anciano , Instituciones de Atención Ambulatoria , Estudios de Factibilidad , Femenino , Estado de Salud , Humanos , Masculino , Salud Mental , Persona de Mediana Edad , National Institutes of Health (U.S.) , Psicometría , Reproducibilidad de los Resultados , Esclerodermia Sistémica/fisiopatología , Factores de Tiempo , Estados UnidosRESUMEN
OBJECTIVE: Systemic sclerosis (SSc) is characterized by calcification, vasculopathy, and endothelial wall damage, all of which can increase the risk of developing atherosclerosis and cardiovascular disease. The aim of this study was to perform a systematic review and meta-analysis to determine whether the risk of atherosclerosis is increased in SSc patients compared to healthy individuals. METHODS: A systematic search was performed to identify studies published in PubMed and the Cochrane database up to May 2010, and recently published abstracts were also reviewed. Two reviewers independently screened articles to identify studies comparing the rate of atherosclerosis in SSc patients to that in healthy controls. The studies utilized one of the following methods: angiography, Doppler ultrasound to assess plaque and carotid intima-media thickness (IMT), computed tomography, magnetic resonance imaging, flow-mediated vasodilation (assessed as the FMD%), the ankle-brachial index, or autopsy. For carotid IMT and FMD% values, we computed a pooled estimate of the summary mean difference and explored predictors of carotid IMT using random-effects meta-regression. RESULTS: Of the 3,156 articles initially identified, 31 were selected for systematic review. The meta-analysis included 14 studies assessing carotid IMT and 7 assessing brachial artery FMD%. Compared to healthy controls, SSc patients had a higher prevalence of coronary atherosclerosis, peripheral vascular disease, and cerebrovascular calcification. Meta-analysis showed that SSc patients had increased carotid IMT (summary mean difference 0.11 mm, 95% confidence interval [95% CI] 0.05 mm, 0.17 mm; P = 0.0006) and lower FMD% (summary mean difference -3.07%, 95% CI -5.44%, -0.69%; P = 0.01) compared to controls. There was marked heterogeneity between the studies, which was mainly attributable to variations in disease duration and differences in the mean/median age between SSc patients and controls. CONCLUSION: Patients with SSc have an increased risk of atherosclerosis compared to healthy subjects. Further studies should elucidate the mechanism of this increased risk.
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Aterosclerosis/complicaciones , Esclerodermia Sistémica/complicaciones , Aterosclerosis/diagnóstico por imagen , Aterosclerosis/patología , Arteria Braquial/diagnóstico por imagen , Arteria Braquial/patología , Arterias Carótidas/diagnóstico por imagen , Arterias Carótidas/patología , Humanos , Riesgo , Esclerodermia Sistémica/diagnóstico por imagen , Esclerodermia Sistémica/patología , Túnica Íntima/diagnóstico por imagen , Túnica Íntima/patología , Túnica Media/diagnóstico por imagen , Túnica Media/patología , UltrasonografíaRESUMEN
OBJECTIVE: Transforming growth factor ß (TGFß) and platelet-derived growth factor (PDGF) may play a critical role in systemic sclerosis (SSc)-related interstitial lung disease (ILD), and imatinib is a potent inhibitor of TGFß and PDGF production. In this 1-year, phase I/IIa open-label pilot study of imatinib in patients with SSc-related active ILD, our primary aim was to assess the safety of imatinib; we also explored its efficacy. METHODS: We recruited 20 SSc patients with a forced vital capacity (FVC) of <85% predicted, dyspnea on exertion, and presence of a ground-glass appearance on high-resolution computed tomography. Patients received oral therapy with imatinib (up to 600 mg/day) for a period of 1 year. Adverse events were recorded, pulmonary function was tested, and the modified Rodnan skin thickness score (MRSS) was assessed every 3 months. The course of changes in lung function, the Health Assessment Questionnaire (HAQ) disability index (DI), and the MRSS were modeled over the period of study to explore treatment efficacy. RESULTS: The majority of patients were female (65%), Caucasian (75%), and had diffuse cutaneous SSc (70%). At baseline, the mean ± SD FVC % predicted was 65.2 ± 14.0 and the mean ± SD MRSS was 18.7 ± 10.1. The mean ± SD dosage of imatinib was 445 ± 125 mg/day. Of the 20 SSc patients, 12 completed the study, 7 discontinued because of adverse events (AEs), and 1 patient was lost to followup. Common AEs (≥20%) included fatigue, facial/lower extremity edema, nausea and vomiting, diarrhea, generalized rash, and new-onset proteinuria. Treatment with imatinib showed a trend toward improvement in the FVC % predicted (1.74%; P not significant) and the MRSS (3.9 units; P < 0.001). CONCLUSION: Use of high-dose daily therapy with imatinib (600 mg/day) in SSc patients with ILD was associated with a large number of AEs. Our experience with AEs suggests that dosages of imatinib lower than 600 mg/day may be appropriate and that further dose ranging analysis is needed in order to understand the therapeutic index of imatinib in SSc.
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Enfermedades Pulmonares Intersticiales/tratamiento farmacológico , Piperazinas/uso terapéutico , Inhibidores de Proteínas Quinasas/uso terapéutico , Pirimidinas/uso terapéutico , Esclerodermia Sistémica/complicaciones , Adulto , Benzamidas , Femenino , Humanos , Mesilato de Imatinib , Enfermedades Pulmonares Intersticiales/etiología , Masculino , Persona de Mediana Edad , Proyectos Piloto , Piperazinas/efectos adversos , Estudios Prospectivos , Inhibidores de Proteínas Quinasas/efectos adversos , Pirimidinas/efectos adversos , Resultado del TratamientoRESUMEN
Background: Viral infections are pervasive and leading causes of myocarditis. Immune-suppression after chemotherapy increases opportunistic infections, but the incidence of virus-induced myocarditis is unknown. Objective: An unbiased, blinded screening for RNA viruses was performed after chemotherapy with correlation to cardiac function. Methods: High-throughput sequencing of RNA isolated from blood samples was analyzed following chemotherapy for hematological malignancies (N = 28) and compared with left ventricular ejection fraction (LVEF). Results: On initial rigorous analysis, low levels of influenza orthomyxovirus and avian paramyxovirus sequences were detectable, but without significant correlation to LVEF (r = 0.208). A secondary broad data mining analysis for virus sequences, without filtering human sequences, detected significant correlations for paramyxovirus with LVEF after chemotherapy (r = 0.592, P < 0.0096). Correlations were similar for LVEF pre- and post- chemotherapy for orthomyxovirus (R = 0.483, P < 0.0421). Retrovirus detection also correlated with LVEF post (r = 0.453, p < 0.0591), but not pre-chemotherapy, but is suspect due to potential host contamination. Detectable phage and anellovirus had no correlation. Combined sequence reads (all viruses) demonstrated significant correlation (r = 0.621, P < 0.0078). Reduced LVEF was not associated with chemotherapy (P = NS). Conclusions: This is the first report of RNA virus screening in circulating blood and association with changes in cardiac function among patients post chemotherapy, using unbiased, blinded, high-throughput sequencing. Influenza orthomyxovirus, avian paramyxovirus and retrovirus sequences were detectable in patients with reduced LVEF. Further analysis for RNA virus infections in patients with cardiomyopathy after chemotherapy is warranted.
RESUMEN
T cells, particularly those producing IL-4, are implicated in inflammation-mediated fibrosis. In our phase I/IIa open-label pilot study in 15 patients with scleroderma-interstitial lung disease (SSc-ILD), high-dose imatinib treatment showed modest improvement in lung function and skin score, but with several adverse events. Here, we investigated T cell phenotype and cytokine production in bronchoalveolar lavage (BAL) from patients enrolled in this trial. We found that IL-4(+) T cells showed a stronger correlation with ground glass opacity (GGO) than fibrosis scores on lung high-resolution computer tomography scans. Frequencies of IL-4(+) T cells also discriminated patients with high (≥20) versus low (<20) GGO scores. Functional annotation clustering of proteins that correlated with T cells identified two major clusters that belonged to immune/inflammatory and wounding response. Repeat analyses after 1 year of treatment in 10 BAL samples, one each from the right middle and lower lobes of lung from 5 patients, showed that post-imatinib, IL-4(+) T cells were profoundly reduced but CD4(+) T cells increased, except in one patient who showed worsening of SSc-ILD. Post-imatinib increase in CD4(+) T cells correlated with soluble ICAM-3 and PECAM-1 levels in BAL, which associated with the lack of worsening in SSc-ILD. Thus, imatinib might confer its therapeutic effect in fibrosis via re-directing T cell responses from type 2 to other, non-type 2 cytokine producing CD4(+) T cells.
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Líquido del Lavado Bronquioalveolar/inmunología , Linfocitos T CD4-Positivos/efectos de los fármacos , Interleucina-4/inmunología , Piperazinas/uso terapéutico , Inhibidores de Proteínas Quinasas/uso terapéutico , Pirimidinas/uso terapéutico , Esclerodermia Sistémica/tratamiento farmacológico , Adulto , Antígenos CD/análisis , Antígenos CD/inmunología , Benzamidas , Linfocitos T CD4-Positivos/inmunología , Moléculas de Adhesión Celular/análisis , Moléculas de Adhesión Celular/inmunología , Ensayos Clínicos Fase II como Asunto , Femenino , Humanos , Mesilato de Imatinib , Pulmón/diagnóstico por imagen , Pulmón/inmunología , Masculino , Persona de Mediana Edad , Proyectos Piloto , Molécula-1 de Adhesión Celular Endotelial de Plaqueta/análisis , Molécula-1 de Adhesión Celular Endotelial de Plaqueta/inmunología , Radiografía , Esclerodermia Sistémica/diagnóstico por imagen , Esclerodermia Sistémica/inmunologíaRESUMEN
OBJECTIVE: Short Form-36 (SF-36) is a validated outcome measure to assess health-related quality of life (HRQOL) in patients with gout. We assessed responsiveness to change of SF-36 in patients with gout. METHODS: SF-36 was administered at baseline and at yearly intervals. We assessed the minimal clinically important differences (MCIDs) at the first and second year. We also assessed the responsiveness to change (effect size) and interpreted it based on Cohen's criteria. We modelled the improvement (defined as ≥MCID) in SF-36 scales and summary scores. Covariates included age, presence of tophi, comorbidities, baseline joint involvement, baseline serum urate, change in serum urate and the number of flares from baseline to 12 months. RESULTS: Of 99 subjects, 96 were male, mean age was 57.1 years, disease duration was 8.2 years and 40.4% had tophi. Ninety-two patients were treated with urate-lowering therapy (ULT) and daily colchicine, and seven were only on colchicine. Baseline mean serum urate level was 8.9 mg/dl and mean number of flares was 4.7 over last year. ULTs were associated with reduction in serum uric acid and number of flares (P < 0.001 for both) over 12 months. Therapy was associated with 22-70% of the patients achieving MCID in SF-36 scores at 12 months. Effect size estimates ranged from negligible to large (SF-36 mental component summary 0.08-bodily pain 1.09). Reduction in flares independently predicted improvements in three SF-36 physical scales (P = 0.001-0.06). Improvement in SF-36 scores was maintained at 2 years. CONCLUSION: In our real-life observational cohort, chronic urate lowering therapy and colchicine was associated with clinically meaningful improvements in HRQOL at 1 year and then maintained at 2 years. SF-36, especially physical domains and physical component summary, are responsive to change in gout.
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Colchicina/uso terapéutico , Evaluación de la Discapacidad , Supresores de la Gota/uso terapéutico , Gota/tratamiento farmacológico , Calidad de Vida , Anciano , Enfermedad Crónica , Estudios de Cohortes , Relación Dosis-Respuesta a Droga , Femenino , Gota/fisiopatología , Encuestas Epidemiológicas , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Resultado del Tratamiento , Ácido Úrico/sangreRESUMEN
OBJECTIVE: Rheumatologic disorders are associated with sleep disturbances. This study examines sleep disturbance correlates in patients with SSc. METHODS: Participants are 180 SSc patients in an observational study. At baseline, patients completed the Medical Outcomes Study Sleep measure (MOS-Sleep scale). In addition, patients were administered other patient-reported outcome (PRO) measures including the 36-item short form (SF-36), HAQ disability index (HAQ-DI), Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue), Center for Epidemiologic Studies Depression (CESD) scale and a University of California at Los Angeles Scleroderma Clinical Trial Consortium Gastrointestinal Tract Questionnaire (UCLA SCTC GIT 2.0). Descriptive statistics were assessed for six scales of MOS-Sleep and the 9-item sleep problem index (SLP-9; a composite index). We computed Spearman's rank-order correlations between the MOS-Sleep scales and the HAQ-DI, FACIT-Fatigue, CESD, SSc-SCTC GIT 2.0 and SF-36 scales. In addition, we developed a regression model to assess predictors of SLP-9 scores. Covariates included demographics, physician variables of disease severity and patient-reported variables of worsening symptoms and the PRO measures. RESULTS: SSc patients reported a mean (s.d.) of 7.1 (1.73) h of sleep a night. Patients reported worse scores on four of six scales (except for snoring and sleep quantity) compared with the US general population (P < 0.001). SLP-9 was correlated with worsening pain and dyspnoea over the past 1 month, reflux scale of the UCLA SCTC GIT 2.0, CESD and FACIT-Fatigue (ρ 0.26-0.56). In the stepwise multivariate regression model, the CESD, worsening dyspnoea and reflux scale were significantly associated with SLP-9 index. CONCLUSION: Sleep disturbances are common in SSc and are associated with worsening dyspnoea, depressed mood and severity of reflux symptoms.
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Calidad de Vida , Esclerodermia Sistémica/diagnóstico , Esclerodermia Sistémica/epidemiología , Trastornos del Sueño-Vigilia/diagnóstico , Trastornos del Sueño-Vigilia/epidemiología , Centros Médicos Académicos , Distribución por Edad , Anciano , Comorbilidad , Femenino , Humanos , Estudios Longitudinales , Los Angeles , Masculino , Persona de Mediana Edad , Prevalencia , Análisis de Regresión , Índice de Severidad de la Enfermedad , Distribución por Sexo , Perfil de Impacto de EnfermedadRESUMEN
OBJECTIVE: Although the incidence of dcSSc is higher in African-American and Hispanic populations compared with European Caucasian patients, it is not clear whether there are differences in subsequent disease course. Also, the potential impact of gender on the disease course of dcSSc is not well defined. Our objective was to assess the course of modified Rodnan skin score (MRSS), HAQ-disability index (HAQ-DI) and forced vital capacity per cent (FVC%) predicted between men vs women and three ethnic groups with dcSSc participating in three randomized clinical trials (RCTs). METHOD: Data from RCTs (n = 495) were pooled and analysed. Baseline characteristics were compared in men vs women and among ethnic groups. A linear mixed effects model was used to assess the predictors of MRSS, HAQ-DI and FVC%. The primary independent variables were time-in-study and its interaction with gender and ethnicity. The models were adjusted for other covariates that were significant at baseline between gender and ethnicity analyses. RESULTS: Men had lower HAQI-DI scores compared with women (P < 0.05). Among the three ethnic groups, Caucasians were older, African-Americans had lower FVC% predicted and Hispanics had greater tender joint counts (P < 0.05). The course of MRSS, HAQ-DI and FVC% predicted during the study period was not significantly different between gender and three ethnicities. Time-in-study was an independent predictor of improvement in MRSS and HAQ-DI. CONCLUSION: Our analysis explores the influence of gender and ethnicity on disease course in RCTs. These findings are relevant to issues of future trial design.
Asunto(s)
Esclerodermia Difusa/etnología , Índice de Severidad de la Enfermedad , Adulto , Negro o Afroamericano/etnología , Evaluación de la Discapacidad , Progresión de la Enfermedad , Femenino , Hispánicos o Latinos/etnología , Humanos , Masculino , Persona de Mediana Edad , Ensayos Clínicos Controlados Aleatorios como Asunto , Esclerodermia Difusa/patología , Factores Sexuales , Estadística como Asunto , Población Blanca/etnologíaRESUMEN
OBJECTIVES: SSc-associated gastrointestinal tract involvement (SSc-GIT) is an important predictor of depressive symptoms. University of California at Los Angeles Scleroderma Clinical trial Consortium Gastrointestinal Tract 2.0 (UCLA SCTC GIT 2.0) is a 34-item valid instrument that captures GIT symptom severity and impact on quality of life. It has seven GI-specific scales and a total GIT score. The objectives were to assess: (i) whether there is an association between depressed mood with GI symptom scales as assessed by the UCLA SCTC GIT 2.0 instrument; and (ii) to explore which GI-specific symptom scales are associated with depressed mood in patients with SSc. METHODS: One hundred and fifty-two patients with SSc completed the UCLA SCTC GIT 2.0 and the Center for Epidemiologic Studies Short Depression scale (CES-D10). Patients were divided into depressed (CES-D ≥ 10) or non-depressed group (CES-D < 10) and compared using t-test or chi-square test. Multiple linear regression was used to determine associations between GI scales and depressed mood (CES-D). RESULTS: Study participants were 84% female, 78% Caucasian and 40% had depressed mood (CES-D10 ≥ 10). Patients with depressed mood had statistically worse GI scale scores (except fecal soilage) and worse total GIT score (P < 0.05). In the multivariable model reflux and constipation scales were independently associated with worse CES-D scores (P = 0.01-0.06) CONCLUSION: SSc-GIT involvement is associated with depressed mood. Reflux and constipation scales of UCLA-SCTC GIT 2.0 were independently associated with CES-D. Future studies should assess if treatment of GIT symptoms will improve depressed mood in patients with SSc-GIT.
Asunto(s)
Estreñimiento/complicaciones , Depresión/complicaciones , Reflujo Gastroesofágico/complicaciones , Esclerodermia Sistémica/complicaciones , Esclerodermia Sistémica/psicología , Adulto , Estreñimiento/fisiopatología , Depresión/fisiopatología , Femenino , Reflujo Gastroesofágico/fisiopatología , Humanos , Los Angeles , Masculino , Persona de Mediana Edad , Calidad de Vida , Esclerodermia Sistémica/fisiopatología , Índice de Severidad de la Enfermedad , Encuestas y CuestionariosRESUMEN
OBJECTIVES: The UCLA Scleroderma Clinical Trial Consortium Gastrointestinal Tract Instrument (UCLA-SCTCGIT) 2.0 was developed to assess systemic sclerosis (SSc) associated gastrointestinal tract (GIT) symptoms severity and its impact on patients' well-being. Our objective was to translate the UCLA-GIT 2.0 from English to French and to evaluate the reliability and validity of the French version. METHODS: UCLA-GIT 2.0 was adapted into French using a formal forward-backward translation method and administered to 76 French speaking patients with SSc. The patients also completed the SF-36. We evaluated the internal consistency reliability and construct validity by exploring associations between the UCLA SCTC GIT 2.0 and SF-36 scales. Patients were also classified into two groups based on unintended weight loss within the past 6 months (≥5% vs. <5% of total body weight). RESULTS: Participants were mostly white (90%), female (81%) and had limited SSc (50%). Mean score of the UCLA-GIT 2.0 scales were: 0.35 for faecal soilage, 0.44 for diarrhoea, 0.45 for emotional well-being, 0.48 for both constipation and social functioning, 0.52 for reflux, and 0.95 for distension/bloating. The instrument had acceptable reliability (defined as Cronbach alpha≥0.69) except for the diarrhoea scale (alpha=0.56). The majority of hypothesized correlations were of moderate magnitude (coefficient≥0.30) and were in the appropriate direction. Patients with ≥5% unintended weight loss had worse UCLA-GIT scores in all scales (p<0.05 for distention/bloating scale). CONCLUSIONS: The French version of the UCLA-GIT 2.0 has acceptable psychometric properties and can be used in French speaking SSc patients.
Asunto(s)
Esclerodermia Sistémica/diagnóstico , Esclerodermia Sistémica/fisiopatología , Encuestas y Cuestionarios , Anciano , Diarrea/etiología , Incontinencia Fecal/etiología , Femenino , Francia , Tracto Gastrointestinal/fisiopatología , Humanos , Masculino , Persona de Mediana Edad , Psicometría , Calidad de Vida , Reproducibilidad de los Resultados , Esclerodermia Sistémica/complicaciones , Esclerodermia Sistémica/psicología , Índice de Severidad de la Enfermedad , Perfil de Impacto de Enfermedad , Encuestas y Cuestionarios/normas , TraduccionesRESUMEN
OBJECTIVES: Treatment for gastrointestinal tract (GIT) disease in systemic sclerosis (SSc) is challenging as no immunosuppressive or anti-fibrotic therapy is available with clearly proven efficacy. Probiotics are viable, non-pathogenic microorganisms that are hypothesized to improve the composition of the intestinal microbiota from a potentially harmful composition to a composition that is beneficial to the host. Our hypothesis is that GIT symptoms in SSc patients with moderate bloating would improve with probiotic implementation. METHODS: Ten patients with a moderate-to-severe distention/bloating score (1.25-3.00) on the University of California Los Angeles Scleroderma Clinical Trials Consortium Gastrointestinal Tract 2.0 (UCLA SCTC GIT 2.0), but otherwise stable organ disease not requiring any medication adjustment were recruited from the University of Utah Scleroderma Center. We compared the GIT 2.0 scores at baseline and after 2 months of use of Align (bifidobacterium infantis; 109 CFU per capsule) or Culturelle (lactobacillus GG; 109 CFU per capsule) using paired t-test and calculated effect size (ES). RESULTS: Significant improvement in total GIT 2.0 score (ES = 0.82), reflux (ES = 0.33), bloating/distention (ES = 1.76), and emotional scales (ES = 0.18) were reported after two months of daily probiotic use. CONCLUSIONS: This pilot study suggests probiotics significantly improve the reflux, distention/ bloating, and total GIT scales in SSc patients. As hypothesized, the largest effect was seen in distention/bloating scale. Probiotics may be useful for treatment of SSc-associated distention/ bloating.
Asunto(s)
Bifidobacterium , Flatulencia , Lactobacillus , Metagenoma/efectos de los fármacos , Probióticos/uso terapéutico , Esclerodermia Sistémica/complicaciones , Adulto , Anciano , Antiespumantes/uso terapéutico , Bifidobacterium/efectos de los fármacos , Bifidobacterium/metabolismo , Suplementos Dietéticos , Femenino , Flatulencia/microbiología , Flatulencia/patología , Flatulencia/fisiopatología , Enfermedades Gastrointestinales/microbiología , Enfermedades Gastrointestinales/patología , Enfermedades Gastrointestinales/fisiopatología , Tracto Gastrointestinal/microbiología , Tracto Gastrointestinal/patología , Tracto Gastrointestinal/fisiopatología , Humanos , Lactobacillus/efectos de los fármacos , Lactobacillus/metabolismo , Masculino , Persona de Mediana Edad , Proyectos Piloto , Esclerodermia Sistémica/fisiopatología , Índice de Severidad de la Enfermedad , Resultado del TratamientoRESUMEN
BACKGROUND: Systemic sclerosis (SSc) is associated with a marked economic burden, high treatment costs and decreased productivity. Although treatment strategies for SSc can have a substantial effect on patients' outcomes, it is not known whether patients with SSc consistently receive such care. Evaluation of process-of-care quality requires specification of quality indicators (QIs), clinically detailed statements of the eligible patients and the care they should receive to achieve a minimal level of quality of care. Our objective was to develop QIs for patients with SSc. METHODS: We performed a comprehensive literature review of diagnosis and treatment of SSc and proposed QIs that were evaluated by a national Expert Panel (n=9) who were asked to review the supporting literature and individually rank the validity of each QI. These rankings formed the basis of discussion at a face-to-face meeting following the RAND/UCLA method to integrate expert opinion with literature review to identify a set of final QIs. We then presented these QIs to members of the Scleroderma Clinical Trials Consortium (SCTC). RESULTS: Thirty-two QIs for SSc care were judged valid by the Expert Panel. The QI set includes 9 QIs for newly diagnosed with SSc, 12 follow-up QIs for management of SSc, and 11 treatment QIs. The SCTC experts agreed with the validity of each of the 32 QI and agreed that for all but one QI the specified tests, procedures and treatments recommended in the QI were generally available. CONCLUSIONS: We have developed 32 QIs for SSc using a rigorous methodology that can be employed to evaluate and improve care for patients with SSc, as well as inform policy decisions supporting appropriate care for SSc patients.
Asunto(s)
Comités Consultivos/organización & administración , Conferencias de Consenso como Asunto , Evaluación de Procesos y Resultados en Atención de Salud/organización & administración , Formulación de Políticas , Indicadores de Calidad de la Atención de Salud/normas , Esclerodermia Sistémica/terapia , Humanos , Mejoramiento de la Calidad , Esclerodermia Sistémica/diagnósticoRESUMEN
OBJECTIVE: Exercise-induced pulmonary hypertension (PH) may represent an early but clinically relevant phase in the spectrum of pulmonary vascular disease. There are limited data on the prevalence of exercise-induced PH determined by right heart catheterization in scleroderma spectrum disorders. We undertook this study to describe the hemodynamic response to exercise in a homogeneous population of patients with scleroderma spectrum disorders at risk of developing pulmonary vascular disease. METHODS: Patients with normal resting hemodynamics underwent supine lower extremity exercise testing. A classification and regression tree (CART) analysis was used to assess combinations of variables collected during resting right heart catheterization that best predicted abnormal exercise physiology, applicable to each individual subject. RESULTS: Fifty-seven patients who had normal resting hemodynamics underwent subsequent exercise right heart catheterization. Four distinct hemodynamic groups were identified during exercise: a normal group, an exercise-induced pulmonary venous hypertension (ePVH) group, an exercise out of proportion PH (eoPH) group, and an exercise-induced PH (ePH) group. The eoPH and ePVH groups had higher pulmonary capillary wedge pressure (PCWP) than the ePH group (P < 0.05). The normal and ePH groups had exercise PCWP ≤18 mm Hg, which was lower than that in the ePVH and eoPH groups (P < 0.05). During submaximal exercise, the transpulmonary gradient and pulmonary vascular resistance (PVR) were elevated in the ePH and eoPH groups as compared with the normal and ePVH groups (P < 0.05). CART analysis suggested that resting mean pulmonary artery pressure (mPAP) ≥14 mm Hg and PVR ≥160 dynes/seconds/cm(-5) were associated with eoPH and ePH (positive predictive value 89% for mPAP 14-20 mm Hg and 100% for mPAP >20 mm Hg). CONCLUSION: We characterized the exercise hemodynamic response in at-risk patients with scleroderma spectrum disorders who did not have resting PH. Four distinct hemodynamic groups were identified during exercise. These groups may have potentially different prognoses and treatment options.
Asunto(s)
Ejercicio Físico , Hipertensión Pulmonar/clasificación , Hipertensión Pulmonar/fisiopatología , Esclerodermia Sistémica/complicaciones , Esclerodermia Sistémica/fisiopatología , Adulto , Anciano , Algoritmos , Cateterismo Cardíaco , Estudios de Cohortes , Árboles de Decisión , Femenino , Hemodinámica/fisiología , Humanos , Hipertensión Pulmonar/epidemiología , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Factores de Riesgo , Capacidad Vital/fisiologíaRESUMEN
BACKGROUND: Arthritis is the leading cause of disability in the United States. We assess the generic health-related quality-of-life (HRQOL) among a nationally representative sample of U.S. adults with and without self-reported arthritis. METHODS: The NHMS, a cross-sectional survey of 3,844 adults (35-89 years) administered EuroQol-5D (EQ-5D), Health Utilities Index Mark 2 (HUI2) and 3 (HUI3), SF-36v2™, Quality of Well-being Scale self-administered form (QWB-SA), and the Health and Activities Limitations index (HALex) to each respondent via a telephone interview. Weighted multiple linear regression was used to generate age-gender-arthritis-stratified unadjusted HRQOL means and means adjusted for sociodemographic, socioeconomic covariates and comorbidities by arthritis-age category. RESULTS: The estimated population prevalence of self-reported arthritis was 31%. People with arthritis were more likely to be woman, older, of lower socioeconomic status, and had more self-reported comorbidities than were those not reporting arthritis. Adults with arthritis had lower HRQOL on six different indexes compared with adults without arthritis, with overall differences ranging from 0.03 (QWB-SA, age-group 65-74) to 0.17 (HUI3, age-group 35-44; all P-value < .05). CONCLUSION: Arthritis in adults is associated with poorer HRQOL. We provide age-related reference values for six generic HRQOL measures in people with arthritis.