RESUMO
Low-cost air quality monitors are increasingly being deployed in various indoor environments. However, data of high temporal resolution from those sensors are often summarized into a single mean value, with information about pollutant dynamics discarded. Further, low-cost sensors often suffer from limitations such as a lack of absolute accuracy and drift over time. There is a growing interest in utilizing data science and machine learning techniques to overcome those limitations and take full advantage of low-cost sensors. In this study, we developed an unsupervised machine learning model for automatically recognizing decay periods from concentration time series data and estimating pollutant loss rates. The model uses k-means and DBSCAN clustering to extract decays and then mass balance equations to estimate loss rates. Applications on data collected from various environments suggest that the CO2 loss rate was consistently lower than the PM2.5 loss rate in the same environment, while both varied spatially and temporally. Further, detailed protocols were established to select optimal model hyperparameters and filter out results with high uncertainty. Overall, this model provides a novel solution to monitoring pollutant removal rates with potentially wide applications such as evaluating filtration and ventilation and characterizing indoor emission sources.
Assuntos
Poluentes Atmosféricos , Poluição do Ar em Ambientes Fechados , Poluentes Ambientais , Poluentes Atmosféricos/análise , Material Particulado/análise , Monitoramento Ambiental/métodos , Análise por Conglomerados , Poluição do Ar em Ambientes Fechados/análiseRESUMO
Rationale: Tocilizumab, an anti-IL-6 receptor antibody, had no statistically significant effect on skin sclerosis but preserved lung function over 48 weeks in patients with early systemic sclerosis (SSc)-associated interstitial lung disease (ILD) in a phase 3 randomized controlled trial. Objectives: Assess long-term safety and efficacy of tocilizumab. Methods: Adults with diffuse cutaneous SSc for ⩽60 months and elevated acute-phase reactants, including those with ILD, received weekly placebo or tocilizumab 162 mg subcutaneously in the 48-week, double-blind period and then open-label tocilizumab from Weeks 48 to 96 (placebo-tocilizumab; continuous-tocilizumab). Measurements and Main Results: Eighty-two of 107 patients in the placebo-tocilizumab group and 85 of 105 patients in the continuous-tocilizumab group completed 96 weeks. Mean age and disease duration were 48 years and 23 months; high-resolution computed tomography revealed ILD in 61%. Mean (95% confidence interval [CI]) change in modified Rodnan skin score from baseline to week 96 was -8.4 (-10.0 to -6.8) for placebo-tocilizumab and -9.6 (-10.9 to -8.4) for continuous-tocilizumab. Mean (95% CI) change in FVC (percent predicted) from baseline to week 96 was -3.3 (-5.1 to -1.5) for placebo-tocilizumab and -0.5 (-2.4 to 1.3) for continuous-tocilizumab among completers and, in a post hoc analysis, -4.1 (-6.7 to -1.6) and -0.6 (-3.1 to 2.0), respectively, among completers with ILD (mean [95% CI] change from Weeks 48 to 96: 0.9 [-0.8 to 2.7] and -0.4 [-2.3 to 1.5], respectively). Rates per 100 patient-years of serious adverse events from Weeks 48 to 96 were 14.8 for placebo-tocilizumab and 15.8 for continuous-tocilizumab. Conclusions: Tocilizumab preserved lung function, slowing decline in FVC, in patients with SSc, including those with ILD. Long-term safety was consistent with the known safety profile of tocilizumab. Clinical trial registered with www.clinicaltrials.gov (NCT02453256).
Assuntos
Doenças Pulmonares Intersticiais , Escleroderma Sistêmico , Adulto , Anticorpos Monoclonais Humanizados , Método Duplo-Cego , Humanos , Doenças Pulmonares Intersticiais/complicações , Doenças Pulmonares Intersticiais/etiologia , Escleroderma Sistêmico/complicações , Escleroderma Sistêmico/tratamento farmacológico , Esclerose , Resultado do Tratamento , Capacidade VitalRESUMO
Evidence suggests that human exposure to airborne particles and associated contaminants, including respiratory pathogens, can persist beyond a single microenvironment. By accumulating such contaminants from air, clothing may function as a transport vector and source of "secondary exposure". To investigate this function, a novel microenvironmental exposure modeling framework (ABICAM) was developed. This framework was applied to a para-occupational exposure scenario involving the deposition of viable SARS-CoV-2 in respiratory particles (0.5-20 µm) from a primary source onto clothing in a nonhealthcare setting and subsequent resuspension and secondary exposure in a car and home. Variability was assessed through Monte Carlo simulations. The total volume of infectious particles on the occupant's clothing immediately after work was 4800 µm3 (5th-95th percentiles: 870-32â¯000 µm3). This value was 61% (5-95%: 17-300%) of the occupant's primary inhalation exposure in the workplace while unmasked. By arrival at the occupant's home after a car commute, relatively rapid viral inactivation on cotton clothing had reduced the infectious volume on clothing by 80% (5-95%: 26-99%). Secondary inhalation exposure (after work) was low in the absence of close proximity and physical contact with contaminated clothing. In comparison, the average primary inhalation exposure in the workplace was higher by about 2-3 orders of magnitude. It remains theoretically possible that resuspension and physical contact with contaminated clothing can occasionally transmit SARS-CoV-2 between humans.
Assuntos
COVID-19 , Vestuário , Humanos , Exposição por Inalação , Método de Monte Carlo , SARS-CoV-2RESUMO
Residents from low-income social housing are vulnerable to adverse health effects from indoor air pollution. Particle-bound concentrations of eight phthalates and 12 polycyclic aromatic hydrocarbons (PAHs) in indoor air were measured using quantitative filter forensics with portable air cleaners deployed for three one-week periods from 2015 to 2017. The sample included 143 apartments across seven multi-unit social housing buildings in Toronto, Canada, that went through energy retrofits in 2016. Eight phthalates and six PAHs were found in more than 50% of the apartments in either of the three sampling periods. Di(2-ethylhexyl) phthalate (DEHP) and phenanthrene were the dominant phthalate and PAH, with median concentrations of 146, 143, and 130 ng/m3 and 1.51, 0.58, and 0.76 ng/m3 in the late spring of 2015, and after retrofits in late spring 2017 and winter of 2017, respectively. SVOC concentrations were generally lower after energy retrofits, with significant differences for phenanthrene, fluoranthene, and pyrene. Lower concentrations post-retrofit may be related to less overheating and less need for opening windows. Concentrations of phthalates and PAHs in this study were similar to or higher than those reported in the literature. Results suggest that the use of portable air filters is a promising method to assess concentrations of indoor particle-bound SVOCs.
Assuntos
Filtros de Ar , Poluentes Atmosféricos , Poluição do Ar em Ambientes Fechados , Hidrocarbonetos Policíclicos Aromáticos , Poluentes Atmosféricos/análise , Poluição do Ar em Ambientes Fechados/análise , Monitoramento Ambiental , Habitação , Hidrocarbonetos Policíclicos Aromáticos/análiseRESUMO
Particle filtration can effectively reduce indoor concentrations of particulate matter (PM) but may incur high energy use. This study evaluates fixed and adaptive concentration thresholds to automate the operation of filtration systems. Simulated environments were derived from week-long continuous PM measurements from Dylos DC1700 (N = 104) and Alphasense OPC-N2 (N = 100) particle counters deployed in apartments in Toronto. A fixed threshold of 4.0 µg·m-3 resulted in a mean air cleaner runtime of 6.9%-21.0% depending on clean air delivery rate (CADR) and particle sensor, while providing mean concentration reductions of 67%-71% compared to operating the air cleaner constantly (runtime = 100%). In most environments, runtime could be further reduced by raising the fixed threshold while resulting in only a modest decrease in absolute and normalized mean exposure reduction. Using an adaptive threshold derived from a k-means clustering approach generally provided substantial exposure reduction while preventing high runtimes. These results were generally insensitive to cleaning power and the monitor used to measure particle concentrations. Reducing the energy usage of particle filter systems will make them a more viable and sustainable means of improving occupant health.
Assuntos
Poluentes Atmosféricos , Poluição do Ar em Ambientes Fechados , Poluentes Atmosféricos/análise , Poluição do Ar em Ambientes Fechados/análise , Tamanho da Partícula , Material Particulado/análise , Ar Condicionado , Monitoramento Ambiental/métodosRESUMO
Essential oil products are increasingly used in indoor environments and have been found to negatively contribute to indoor air quality. Moreover, the chemicals and fragrances emitted by those products may affect the central nervous system and cognitive function. This study uses a double-blind between-subject design to investigate the cognitive impact of exposure to the emissions from essential oil used in an ultrasonic diffuser. In a simulated office environment where other environmental parameters were maintained constant, 34 female and 25 male university students were randomly allocated into four essential oil exposure scenarios. The first two scenarios contrast lemon oil to pure deionized water, while the latter two focus on different levels of particulate matter differentiated by HEPA filters with non-scented grapeseed oil as the source. Cognitive function was assessed using a computer-based battery consisting of five objective tests that involve reasoning, response inhabitation, memory, risk-taking, and decision-making. Results show that exposure to essential oil emissions caused shortened reaction time at the cost of significantly worse response inhabitation control and memory sensitivity, indicating potentially more impulsive decision-making. The cognitive responses caused by scented lemon oil and non-scented grapeseed oil were similar, as was the perception of odor pleasantness and intensity.
Assuntos
Poluentes Atmosféricos , Poluição do Ar em Ambientes Fechados , Óleos Voláteis , Poluentes Atmosféricos/análise , Poluição do Ar em Ambientes Fechados/análise , Cognição , Monitoramento Ambiental/métodos , Feminino , Humanos , Masculino , Material Particulado/análiseRESUMO
Since the publication of the last American Heart Association scientific statement on air pollution and cardiovascular disease in 2010, unequivocal evidence of the causal role of fine particulate matter air pollution (PM2.5, or particulate matter ≤2.5 µm in diameter) in cardiovascular disease has emerged. There is a compelling case to provide the public with practical personalized approaches to reduce the health effects of PM2.5. Such interventions would be applicable not only to individuals in heavily polluted countries, high-risk or susceptible individuals living in cleaner environments, and microenvironments with higher pollution exposures, but also to those traveling to locations with high levels of PM2.5. The overarching motivation for this document is to summarize the current evidence supporting personal-level strategies to prevent the adverse cardiovascular effects of PM2.5, guide the use of the most proven/viable approaches, obviate the use of ineffective measures, and avoid unwarranted interventions. The significance of this statement relates not only to the global importance of PM2.5, but also to its focus on the most tested interventions and viable approaches directed at particulate matter air pollution. The writing group sought to provide expert consensus opinions on personal-level measures recognizing the current uncertainty and limited evidence base for many interventions. In doing so, the writing group acknowledges that its intent is to assist other agencies charged with protecting public health, without minimizing the personal choice considerations of an individual who may decide to use these interventions in the face of ongoing air pollution exposure.
Assuntos
Poluição do Ar/efeitos adversos , Poluição do Ar/prevenção & controle , American Heart Association , Doenças Cardiovasculares/prevenção & controle , Material Particulado/efeitos adversos , Saúde Pública/métodos , Poluentes Atmosféricos/efeitos adversos , Poluentes Atmosféricos/análise , Doenças Cardiovasculares/epidemiologia , Exposição Ambiental/efeitos adversos , Exposição Ambiental/prevenção & controle , Monitoramento Ambiental/métodos , Monitoramento Ambiental/normas , Humanos , Saúde Pública/normas , Estados Unidos/epidemiologiaRESUMO
Water-soluble trace gas (WSTG) loss from indoor air via air conditioning (AC) units has been observed in several studies, but these results have been difficult to generalize. In the present study, we designed a box model that can be used to investigate and estimate WSTG removal due to partitioning to AC coil condensate. We compared the model output to measurements of a suite of organic acids cycling in an indoor environment and tested the model by varying the input AC parameters. These tests showed that WSTG loss via AC cycling is influenced by Henry's law constant of the compound in question, which is controlled by air and water temperatures and the condensate pH. Air conditioning unit specifications also impact WSTG loss through variations in the sensible heat ratio, the effective recirculation rate of air through the unit, and the timing of coil and fan operation. These findings have significant implications for indoor modeling. To accurately model the fate of indoor WSTGs, researchers must either measure or otherwise account for these unique environmental and operational characteristics.
Assuntos
Poluição do Ar em Ambientes Fechados , Ar Condicionado , Poluição do Ar em Ambientes Fechados/análise , Gases , Compostos Orgânicos , ÁguaRESUMO
We applied filter forensics, the analysis of dust from the heating, ventilation, and air-conditioning (HVAC) filters, to measure particle size distribution in 21 residences in Toronto, Canada over a year. Four filters with different nominal efficiencies (Minimum Efficiency Reporting Value (MERV) 8-14 from ASHRAE Standard 52.2) were deployed in each residence each for three months, while the effective filtration volumes (the product of flow rate, runtime, and in-situ filter efficiency) were characterized over each filter lifetime. Using extraction and laser diffraction, we found that approximately 90% of the volumetric distributions were >10 µm and the volume median diameter (VMD) ranged from 23.4 to 75.1 µm. Using quantitative filter forensics (QFF), total suspended particle (TSP) concentrations ranged from 2.9 to 823.7 µg/m3 (median = 89.8 µg/m3 ) with a moderate correlation with the content of TSP on the filters (in terms of g) and with the TSP effective filtration volume (m3 ) indicating the importance of both filter forensics and HVAC metadata parameters to QFF concentration estimates. There was no strong correlation between PM10 or PM2.5 concentrations and hourly airborne particle number concentrations measured by low-cost sensors suggesting an evaluation of QFF is warranted, particularly for the exploration of smaller particles.
Assuntos
Filtros de Ar , Poluentes Atmosféricos , Poluição do Ar em Ambientes Fechados , Poluentes Atmosféricos/análise , Poluição do Ar em Ambientes Fechados/análise , Monitoramento Ambiental , Tamanho da Partícula , Material Particulado/análise , VentilaçãoRESUMO
Ultrasonic essential oil diffusers (EODs) are a popular type of indoor scenting source. We performed a chamber study in which we measured the emissions from EODs used with lemon, lavender, eucalyptus, and grapeseed oils. Over the course of 15 min, the most abundant VOCs released from lemon, lavender, eucalyptus, and grapeseed oils were 2.6 ± 0.7 mg of d-limonene, 3.5 ± 0.4 mg of eucalyptol, 1.0 ± 0.1 mg of linalyl acetate, and 0.2 ± 0.02 mg of linalyl acetate, respectively. Each oil had a unique particulate matter (PM) emission profile in terms of size, number density, and rate. The dominant size ranges of the PM were 10-100 nm for lemon oil, 50-100 nm for lavender oil, 10-50 nm for lemon oil, and above 200 nm for grapeseed oil. PM1 emission rates of approximately 2 mg/h, 0.1 mg/h, and 3 mg/h, were observed for lemon, lavender/eucalyptus, and grapeseed oils, respectively. A fivefold increase in PM1 emission was measured when the EOD with eucalyptus oil was filled with tap water as opposed to deionized water. Modeling suggests that reasonable use cases of EODs can contribute substantially to primary and secondary PM in indoor environments, but this potential varies depending on the oil and water types used.
Assuntos
Poluentes Atmosféricos , Poluição do Ar em Ambientes Fechados , Óleos Voláteis , Compostos Orgânicos Voláteis , Poluentes Atmosféricos/análise , Poluição do Ar em Ambientes Fechados/análise , Material Particulado/análise , Ultrassom , Compostos Orgânicos Voláteis/análiseRESUMO
High-efficiency filtration in residential forced-air heating, ventilation, and air conditioning (HVAC) systems protects equipment and can reduce exposure to particulate matter. Laboratory tests provide a measure of the nominal efficiency, but they may not accurately reflect the in situ efficiency of the filters because of variations in system conditions and changes in filter performance over time. The primary focus of this paper is to evaluate the effective filtration efficiency, which is inclusive of any loading and system impacts, in 21 occupied residential homes through in-duct concentration measurements. We considered the role of filter media by testing both electret and non-electret media, as well as the role of loading by considering new and used filters. The results show that filters with higher nominal efficiency generally had higher effective filtration efficiency in the same home. In terms of performance change, there is no significant difference in efficiency between initial and 3-month non-electret filters, but the efficiency of electret filters generally decreased over time. However, both nominal efficiency and performance change were vastly overshadowed by the wide variety in loading and system conditions across homes, making it hard to predict filter efficiency in a given home without in situ measurements.
Assuntos
Ar Condicionado/métodos , Filtros de Ar , Poluição do Ar em Ambientes Fechados/análise , Ventilação/métodos , Poluição do Ar em Ambientes Fechados/estatística & dados numéricos , Monitoramento Ambiental , Filtração/instrumentação , Calefação/instrumentaçãoRESUMO
In this study, we explore different filter and contextual characteristics that influence effectiveness of high-efficiency filters in 21 residences in Toronto, Canada. The in situ effectiveness was assessed with decay tests at the beginning and the end of filter life with four different filters (MERV 8-14 from ASHRAE Standard 52.2) installed in operational HVAC systems, compared with either the system off or with no filter installed. There was considerable difference between median PM2.5 effectiveness of the non-electret filters when compared to electret filters (16% vs. 36%) of the same nominal efficiency (MERV 8). However, median PM2.5 effectiveness of electret filters only slightly improved (between 5% and 9% absolute increase) as MERV increased from 8 to 14. There was more variation in filter effectiveness between the same filter in different homes than there was between different filters in the same home. Variations in filter performance arose because home-specific particle loss rates (eg, ventilation rate) vary greatly in different buildings. The higher the loss rates due to non-filter factors, the lower the effectiveness of a filter. Given the relatively large variation in effectiveness for a given filter over time and in different homes, increasing system runtime may be a productive way to improve filter performance in many homes.
Assuntos
Ar Condicionado , Filtros de Ar , Poluição do Ar em Ambientes Fechados/análise , Ventilação , Poluição do Ar em Ambientes Fechados/estatística & dados numéricos , Canadá , Monitoramento Ambiental , Filtração , Habitação , Material ParticuladoRESUMO
Poor indoor air quality indicated by elevated indoor CO2 concentrations has been linked with impaired cognitive function, yet current findings of the cognitive impact of CO2 are inconsistent. This review summarizes the results from 37 experimental studies that conducted objective cognitive tests with manipulated CO2 concentrations, either through adding pure CO2 or adjusting ventilation rates (the latter also affects other indoor pollutants). Studies with varied designs suggested that both approaches can affect multiple cognitive functions. In a subset of studies that meet objective criteria for strength and consistency, pure CO2 at a concentration common in indoor environments was only found to affect high-level decision-making measured by the Strategic Management Simulation battery in non-specialized populations, while lower ventilation and accumulation of indoor pollutants, including CO2 , could reduce the speed of various functions but leave accuracy unaffected. Major confounding factors include variations in cognitive assessment methods, study designs, individual and populational differences in subjects, and uncertainties in exposure doses. Accordingly, future research is suggested to adopt direct air delivery for precise control of CO2 inhalation, include brain imaging techniques to better understand the underlying mechanisms that link CO2 and cognitive function, and explore the potential interaction between CO2 and other environmental stimuli.
Assuntos
Poluição do Ar em Ambientes Fechados/estatística & dados numéricos , Dióxido de Carbono/análise , Cognição , Monitoramento Ambiental , Poluição do Ar em Ambientes Fechados/análise , Humanos , VentilaçãoRESUMO
Resuspension of microbes in floor dust and subsequent inhalation by human occupants is an important source of human microbial exposure. Microbes in carpet dust grow at elevated levels of relative humidity, but rates of this growth are not well established, especially under changing conditions. The goal of this study was to model fungal growth in carpet dust based on indoor diurnal variations in relative humidity utilizing the time-of-wetness framework. A chamber study was conducted on carpet and dust collected from 19 homes in Ohio, USA and exposed to varying moisture conditions of 50%, 85%, and 100% relative humidity. Fungal growth followed the two activation regime model, while bacterial growth could not be evaluated using the framework. Collection site was a stronger driver of species composition (P = 0.001, R2 = 0.461) than moisture conditions (P = 0.001, R2 = 0.021). Maximum moisture condition was associated with species composition within some individual sites (P = 0.001-0.02, R2 = 0.1-0.33). Aspergillus, Penicillium, and Wallemia were common fungal genera found among samples at elevated moisture conditions. These findings can inform future studies of associations between dampness/mold in homes and health outcomes and allow for prediction of microbial growth in the indoor environment.
Assuntos
Microbiologia do Ar , Poluição do Ar em Ambientes Fechados/análise , Fungos/crescimento & desenvolvimento , Poeira/análise , Monitoramento Ambiental , Pisos e Cobertura de Pisos , Habitação , Umidade , PenicilliumRESUMO
The presence of biofilms on the cooling coils of commercial air conditioning (AC) units can significantly reduce the heat transfer efficiency of the coils and may lead to the aerosolization of microbes into occupied spaces of a building. We investigated how climate and AC operation influence the ecology of microbial communities on AC coils. Forty large-scale commercial ACs were considered with representation from warm-humid and hot-dry climates. Both bacterial and fungal ecologies, including richness and taxa, on the cooling coil surfaces were significantly impacted by outdoor climate, through differences in dew point that result in increased moisture (condensate) on coils, and by the minimum efficiency reporting value (MERV 8 vs MERV 14) of building air filters. Based on targeted qPCR and sequence analysis, low efficiency upstream filters (MERV 8) were associated with a greater abundance of pathogenic bacteria and medically relevant fungi. As the implementation of air conditioning continues to grow worldwide, better understanding of the factors impacting microbial growth and ecology on cooling coils should enable more rational approaches for biofilm control and ultimately result in reduced energy consumption and healthier buildings.
Assuntos
Ar Condicionado , Microbiologia do Ar , Poluição do Ar em Ambientes Fechados/análise , Monitoramento Ambiental , Fungos/crescimento & desenvolvimento , Clima , Ecologia , MicrobiotaRESUMO
Analysis of the dust from heating, ventilation, and air conditioning (HVAC) filters is a promising long-term sampling method to characterize airborne particle-bound contaminants. This filter forensics (FF) approach provides valuable insights about differences between buildings, but does not allow for an estimation of indoor concentrations. In this investigation, FF is extended to quantitative filter forensics (QFF) by using measurements of the volume of air that passes through the filter and the filter efficiency, to assess the integrated average airborne concentrations of total fungal and bacterial DNA, 36 fungal species, endotoxins, phthalates, and organophosphate esters (OPEs) based on dust extracted from HVAC filters. Filters were collected from 59 homes located in central Texas, USA, after 1 month of deployment in each summer and winter. Results showed considerable differences in the concentrations of airborne particle-bound contaminants in studied homes. The airborne concentrations for most of the analytes are comparable with those reported in the literature. In this sample of homes, the HVAC characterization measurements varied much less between homes than the variation in the filter dust concentration of each analyte, suggesting that even in the absence of HVAC data, FF can provide insight about concentration differences for homes with similar HVAC systems.
Assuntos
Filtros de Ar/microbiologia , Poluição do Ar em Ambientes Fechados/análise , Poeira/análise , Monitoramento Ambiental/métodos , Ar Condicionado/instrumentação , Microbiologia do Ar , DNA Bacteriano/análise , Endotoxinas/análise , Fungos/isolamento & purificação , Calefação/instrumentação , Habitação , Humanos , Organofosfatos/análise , Ácidos Ftálicos/análise , Estações do Ano , Texas , Ventilação/instrumentaçãoRESUMO
OBJECTIVES: Skin fibrosis mediated by activated dermal fibroblasts is a hallmark of systemic sclerosis (SSc), especially in the subset of patients with diffuse disease. Transforming growth factor-beta (TGFß) and interleukin-6 (IL-6) are key candidate mediators in SSc. Our aim was to elucidate the specific effect of IL-6 pathway blockade on the biology of SSc fibroblasts in vivo by using samples from a unique clinical experiment-the faSScinate study-in which patients with SSc were treated for 24 weeks with tocilizumab (TCZ), an IL-6 receptor-α inhibitor. METHODS: We analysed the molecular, functional and genomic characteristics of explant fibroblasts cultured from matched skin biopsy samples collected at baseline and at week 24 from 12 patients receiving placebo (n=6) or TCZ (n=6) and compared these with matched healthy control fibroblast strains. RESULTS: The hallmark functional and molecular-activated phenotype was defined in SSc samples and was stable over 24 weeks in placebo-treated cases. RNA sequencing analysis robustly defined key dysregulated pathways likely to drive SSc fibroblast activation in vivo. Treatment with TCZ for 24 weeks profoundly altered the biological characteristics of explant dermal fibroblasts by normalising functional properties and reversing gene expression profiles dominated by TGFß-regulated genes and molecular pathways. CONCLUSIONS: We demonstrated the exceptional value of using explant dermal fibroblast cultures from a well-designed trial in SSc to provide a molecular framework linking IL-6 to key profibrotic pathways. The profound impact of IL-6R blockade on the activated fibroblast phenotype highlights the potential of IL-6 as a therapeutic target in SSc and other fibrotic diseases. TRIAL REGISTRATION NUMBER: NCT01532869; Post-results.
Assuntos
Anticorpos Monoclonais Humanizados/farmacologia , Fibroblastos/efeitos dos fármacos , Interleucina-6/imunologia , Escleroderma Sistêmico/tratamento farmacológico , Pele/patologia , Fator de Crescimento Transformador beta/fisiologia , Adulto , Anticorpos Monoclonais Humanizados/uso terapêutico , Biópsia , Células Cultivadas , Método Duplo-Cego , Feminino , Fibroblastos/imunologia , Fibroblastos/patologia , Fibrose , Regulação da Expressão Gênica/imunologia , Humanos , Imunossupressores/farmacologia , Imunossupressores/uso terapêutico , Masculino , Pessoa de Meia-Idade , Terapia de Alvo Molecular/métodos , Receptores de Interleucina-6/antagonistas & inibidores , Escleroderma Sistêmico/genética , Escleroderma Sistêmico/imunologia , Escleroderma Sistêmico/patologia , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Pele/imunologiaRESUMO
OBJECTIVES: Assess the efficacy and safety of tocilizumab in patients with systemic sclerosis (SSc) in a phase II study. METHODS: Patients with SSc were treated for 48 weeks in an open-label extension phase of the faSScinate study with weekly 162 mg subcutaneous tocilizumab. Exploratory end points included modified Rodnan Skin Score (mRSS) and per cent predicted forced vital capacity (%pFVC) through week 96. RESULTS: Overall, 24/44 (55%) placebo-tocilizumab and 27/43 (63%) continuous-tocilizumab patients completed week 96. Observed mean (SD (95% CI)) change from baseline in mRSS was -3.1 (6.3 (-5.4 to -0.9)) for placebo and -5.6 (9.1 (-8.9 to-2.4)) for tocilizumab at week 48 and -9.4 (5.6 (-8.9 to -2.4)) for placebo-tocilizumab and -9.1 (8.7 (-12.5 to -5.6)) for continuous-tocilizumab at week 96. Of patients who completed week 96, any decline in %pFVC was observed for 10/24 (42% (95% CI 22% to 63%)) placebo-tocilizumab and 12/26 (46% (95% CI 27% to 67%)) continuous-tocilizumab patients in the open-label period; no patients had >10% absolute decline in %pFVC. Serious infection rates/100 patient-years (95% CI) were 10.9 (3.0 to 27.9) with placebo and 34.8 (18.0 to 60.8) with tocilizumab during the double-blind period by week 48 and 19.6 (7.2 to 42.7) with placebo-tocilizumab and 0.0 (0.0 to 12.2) with continuous-tocilizumab during the open-label period. CONCLUSIONS: Skin score improvement and FVC stabilisation in the double-blind period were observed in placebo-treated patients who transitioned to tocilizumab and were maintained in the open-label period. Safety data indicated increased serious infections in patients with SSc but no new safety signals with tocilizumab. TRIAL REGISTRATION NUMBER: NCT01532869; Results.
Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Antirreumáticos/administração & dosagem , Escleroderma Sistêmico/tratamento farmacológico , Pele/patologia , Adulto , Idoso , Anticorpos Monoclonais Humanizados/efeitos adversos , Antirreumáticos/efeitos adversos , Método Duplo-Cego , Feminino , Humanos , Injeções Subcutâneas , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de Doença , Pele/efeitos dos fármacos , Resultado do Tratamento , Capacidade Vital/efeitos dos fármacosRESUMO
Objectives: Patient acceptable symptom state (PASS) as an absolute state of well-being has shown promise as an outcome measure in many rheumatologic conditions. We aimed to assess whether PASS may be effective in active diffuse cutaneous SSc differentiating active from placebo. Methods: Data from the phase 2 Safety and Efficacy of Subcutaneous Tocilizumab in Adults with Systemic Sclerosis (faSScinate) trial were used, which compared tocilizumab (TCZ) vs placebo over 48 weeks followed by an open-label TCZ period to 96 weeks. Three different types of PASS questions were evaluated at weeks 8, 24, 48 and 96, including if a current state would be acceptable over time as a yes vs no response and Likert scales about how acceptable a current state is if remaining over time. Additional outcomes assessed included modified Rodnan skin score, HAQ disability index (HAQ-DI), physician and patient global assessments on a visual analogue scale, CRP and ESR. Results: The placebo group consisted of 44 patients and the TCZ group had 43 patients. At baseline, 33% achieved a PASS for all three PASS questions, with the proportion increasing to 69, 71 and 78%, respectively, at 96 weeks. Changes in PASS scores showed a moderately negative correlation with HAQ-DI and patient and physician global assessments visual analogue scales, which indicates expected improvements as PASS improved. The PASS question, 'Considering all of the ways your scleroderma has affected you, how acceptable would you rate your level of symptoms?' showed significant correlations with patient-reported outcomes and differentiating placebo vs TCZ at 48 weeks (P = 0.023). Conclusion: PASS may be used as a patient-centred outcome in SSc, especially as a 7-point Likert scale. Further validation is required to determine the utility as an outcome measure in trials and clinical practice.