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OBJECTIVES: Develop and validate a thorough exposure questionnaire to comprehensively explore crystalline silica (SiO2) exposure in the general population (gender-specific, occupational and non-occupational) and in patients with autoimmune diseases (rheumatoid arthritis (RA), systemic sclerosis (SSc)). METHODS: Lifetime exposures to SiO2 in occupational and non-occupational settings were assessed using a thorough exposure questionnaire. The questionnaire was applied to a general population panel (n = 2911) sampled from the French rolling census, and to unselected patients with SSc (n = 100) and RA (n = 97). Global (GES), occupational (OES) and non-occupational (NOES) exposure scores were assessed in SSc and RA patients, and compared with up to four controls from the general population, matched by age group, sex and tobacco consumption. RESULTS: Patients had higher GES than their matched controls (SSc: P = 0.001; RA: P < 0.0001) due to higher OES (P < 0.0001 for SSc and RA). Men had higher GES than women (SSc: P < 0.0001; RA: P = 0.002) due to higher OES (P < 0.0001 for SSc and RA). The NOES did not differ between men and women. In SSc patients: Men had higher GES than controls (P < 0.0001). Men and women with SSc had higher OES than controls (P < 0.0001). In RA patients: GES and OES were higher in both men (P = 0.00521; P < 0.0001) and women (P < 0.0001; P < 0.0001) than in their respective controls. Women had higher NOES than controls (P = 0.045). CONCLUSION: The lifetime SiO2 exposure gap between RA and SSc patients and controls was substantially due to occupational exposure. In both diseases, men had higher exposure scores than women.
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Artritis Reumatoide , Esclerodermia Sistémica , Masculino , Humanos , Femenino , Estudios Transversales , Factores de Riesgo , Dióxido de Silicio/efectos adversos , Artritis Reumatoide/epidemiología , Esclerodermia Sistémica/epidemiología , Esclerodermia Sistémica/inducido químicamenteRESUMEN
PURPOSE: The SARS-CoV-2 infection can lead to a severe acute respiratory distress syndrome (ARDS) with prolonged mechanical ventilation and high mortality rate. Interestingly, COVID-19-associated ARDS share biological and clinical features with sepsis-associated immunosuppression since lymphopenia and acquired infections associated with late mortality are frequently encountered. Mechanisms responsible for COVID-19-associated lymphopenia need to be explored since they could be responsible for delayed virus clearance and increased mortality rate among intensive care unit (ICU) patients. METHODS: A series of 26 clinically annotated COVID-19 patients were analyzed by thorough phenotypic and functional investigations at days 0, 4, and 7 after ICU admission. RESULTS: We revealed that, in the absence of any difference in demographic parameters nor medical history between the two groups, ARDS patients presented with an increased number of myeloid-derived suppressor cells (MDSC) and a decreased number of CD8pos effector memory cell compared to patients hospitalized for COVID-19 moderate pneumonia. Interestingly, COVID-19-related MDSC expansion was directly correlated to lymphopenia and enhanced arginase activity. Lastly, T cell proliferative capacity in vitro was significantly reduced among COVID-19 patients and could be restored through arginine supplementation. CONCLUSIONS: The present study reports a critical role for MDSC in COVID-19-associated ARDS. Our findings open the possibility of arginine supplementation as an adjuvant therapy for these ICU patients, aiming to reduce immunosuppression and help virus clearance, thereby decreasing the duration of mechanical ventilation, nosocomial infection acquisition, and mortality.
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Arginina/metabolismo , COVID-19/complicaciones , Linfopenia/etiología , Células Supresoras de Origen Mieloide/fisiología , Síndrome de Dificultad Respiratoria/inmunología , SARS-CoV-2 , Anciano , Infección Hospitalaria/etiología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Síndrome de Dificultad Respiratoria/etiología , Síndrome de Dificultad Respiratoria/metabolismo , Índice de Severidad de la EnfermedadRESUMEN
OBJECTIVES: To evaluate the diagnostic value of hand ultrasound (US) in systemic sclerosis (SSc) and to explore its relevance within a combined diagnostic approach. METHODS: 224 patients with suspected SSc were consecutively included. They all had US evaluation assessing the presence of fibrotic tenosynovitis (fibrotic TS) and ulnar artery occlusion (UAO). The final diagnosis of SSc was based on the clinical evaluation of a board of experts independently of any pre-established classification criteria. RESULTS: 166 patients were finally diagnosed as SSc according to the experts as reference standard. 62 SSc and 8 non-SSc patients had UAO (uni or bilateral) (p=0.001). 23 SSc patients and 1 non-SSc patient had US fibrotic TS (p=0.007). A US SSc-pattern (presence of UAO and/or fibrotic TS) was reported in 73 SSc patients and 9 non-SSc patients (p<0.001). UAO had an area under ROC curve (AUC) for the diagnosis of SSc of 0.618 (95%CI 0.539- 0.697); with Se=0.373 (0.304-0.449) and Sp=0.862 (0.751-0.928). Fibrotic TS had an AUC of 0.561 (0.480-0.643); with Se=0.139 (0.094-0.199) and Sp=0.983 (0.909-0.997). The US-SSc pattern had a AUC of 0.641 (0.563- 0.695), with Se=0.440 (0.367-0.516) and Sp=0.845 (0.731-0.916). A scoring system including these US parameters and items from ACR/EULAR classification criteria had an AUC of 0.979 (0.962-0.996)) and allows the substitution of capillaroscopy by US parameters with similar performances. CONCLUSIONS: The use of hand US parameters may help to refine the diagnostic strategy of SSc and their inclusion in a combined diagnostic approach could be discussed.
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Esclerodermia Localizada , Esclerodermia Sistémica , Humanos , Angioscopía Microscópica , Arteria Cubital , UltrasonografíaRESUMEN
A defect in the apoptotic cell clearance (efferocytosis) by phagocytic cells may participate in autoimmunity and chronic inflammation. The mechanisms leading to the emergence of autoimmunity in systemic sclerosis (SSc) are still to be determined. In this study, the efferocytosis capacities of blood monocyte-derived macrophages (MDM) from patients with SSc were evaluated. Blood monocytes obtained from patients with SSc and healthy donors (HD) were differentiated in vitro into macrophages. The capacities of MDM to engulf CFSE+ apoptotic Jurkat human T lymphocytes were compared between SSc MDM and HD using flow cytometry. The expression of classical engulfing receptors in SSc MDM and HD MDM was also evaluated and their involvement in the modulation of efferocytosis was confirmed using a siRNA approach. The mean phagocytic index (PI) reflecting efferocytosis capacities of SSc MDM (PI = 19.3 ± 3.0; n = 21) was significantly decreased in comparison with the PI of HD MDM (PI = 35.9 ± 3.0; n = 31; P < 0.001). In comparison with HD, SSc MDM exhibited a downregulated expression of scavenger receptor (SR)-B1, SR-A1 and integrin ß5 (ITGß5). In HD MDM, the extinction of these receptors was followed by a reduction of efferocytosis only for the repression of ITGß5, suggesting a possible selective role of this integrin in the impaired efferocytosis observed in SSc. As efferocytosis may be at the crossroads of inflammation, autoimmunity and fibrosis, in showing impaired efferocytosis capacities of blood MDM in SSc, our study offers new pathogenesis considerations for the involvement of macrophages in the autoimmune processes driving this disorder.
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Macrófagos/inmunología , Fagocitosis/inmunología , Esclerodermia Sistémica/inmunología , Estudios de Casos y Controles , Humanos , Cadenas beta de Integrinas/metabolismo , Macrófagos/metabolismo , Monocitos/inmunología , Monocitos/metabolismo , Receptores Depuradores de Clase B/metabolismo , Factores de Empalme Serina-Arginina/metabolismoRESUMEN
Objectives: To characterize hand synovial manifestations assessed by power Doppler ultrasonography (PDUS) in a cohort of unselected patients fulfilling the 2013 ACR/EULAR classification criteria for SSc and to evaluate the associations of these synovial manifestations with the main general clinical and biological features of SSc. Methods: One hundred and three SSc patients were consecutively included and underwent PDUS evaluation of both hands assessing synovial and tenosynovial manifestations according to the OMERACT definitions. Clinical, biological and immunological SSc characteristics were recorded at the same time. Results: Thirty-three patients (32%) had ultrasonographic synovial/tenosynovial involvement. The two main PDUS features were Doppler-positive/inflammatory synovitis (n = 18, 17.5%) and sclerosing tenosynovitis (TS) (n = 19, 18.4%). Inflammatory synovitis was more frequent in the wrist and MCP joints. Sclerosing TS was more frequent in men [odds ratio (OR) = 6.32, 95% CI: 2.17, 18.41; P = 0.001] and was associated with anti-RNA polymerase III antibodies (OR = 10.93, 95% CI: 1.84, 65.12; P = 0.01), diffuse SSc (OR = 18.24, 95% CI: 4.80, 69.32; P < 0.0001), interstitial lung disease (OR = 6.09, 95% CI: 1.86, 19.98; P = 0.001) and inflammatory arthralgia (OR = 14.64, 95% CI: 2.58, 83.10; P = 0.002). Inflammatory TS or synovitis were associated with CRP levels >5 mg/l (OR = 5.50, 95% CI: 1.81, 16.70; P = 0.001), pericarditis (OR = 7.81, 95% CI: 1.58, 38.71; P = 0.017) and inflammatory arthralgia (OR = 15.96, 95% CI: 2.80, 91.02; P = 0.002). Inflammatory synovitis and sclerosing TS were not significantly associated within an individual patient (OR = 2.77, 95% CI: 0.88, 8.70; P > 0.05). Conclusions: Ultrasonographic synovial involvement is frequent in patients fulfilling the 2013 ACR/EULAR classification criteria and PDUS may have a part to play in a more accurate and precise description of musculoskeletal manifestations of the disease, especially as the question of a treat-to-target approach is arising for SSc.
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Esclerodermia Sistémica/diagnóstico por imagen , Membrana Sinovial/diagnóstico por imagen , Sinovitis/diagnóstico por imagen , Tenosinovitis/diagnóstico por imagen , Adulto , Anciano , Estudios Transversales , Femenino , Articulaciones de la Mano/diagnóstico por imagen , Humanos , Masculino , Persona de Mediana Edad , Índice de Severidad de la Enfermedad , Ultrasonografía Doppler , Articulación de la Muñeca/diagnóstico por imagenRESUMEN
Macrophages play a central role in the pathogenesis of inflammatory and fibrotic lung diseases. However, alveolar macrophages (AM) are poorly available in humans to perform in vitro studies due to a limited access to broncho-alveolar lavage (BAL). In this study, to identify the best alternative in vitro model for human AM, we compared the phenotype of AM obtained from BAL of patients suffering from three lung diseases (lung cancers, sarcoidosis and Systemic Sclerosis (SSc)-associated interstitial lung disease) to human blood monocyte-derived macrophages (MDMs) differentiated with M-CSF or GM-CSF. The expression of eight membrane markers was evaluated by flow cytometry. Globally, AM phenotype was closer to GM-CSF MDMs. However, the expression levels of CD163, CD169, CD204, CD64 and CD36 were significantly higher in SSc-ILD than in lung cancers. Considering the expression of CD204 and CD36, the phenotype of SSc-AM was closer to MDMs, from healthy donors or SSc patients, differentiated by M-CSF rather than GM-CSF. The comparative secretion of IL-6 by SSc-MDMs and SSc-AM is concordant with these phenotypic considerations. Altogether, these results support the M-CSF MDM model as a relevant in vitro alternative to simulate AM in fibrotic disorders such as SSc.
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Neoplasias Pulmonares/inmunología , Macrófagos Alveolares/inmunología , Sarcoidosis Pulmonar/inmunología , Esclerodermia Sistémica/inmunología , Anciano , Antígenos CD/análisis , Líquido del Lavado Bronquioalveolar/citología , Líquido del Lavado Bronquioalveolar/inmunología , Citocinas/análisis , Femenino , Factor Estimulante de Colonias de Granulocitos y Macrófagos/análisis , Humanos , Factor Estimulante de Colonias de Macrófagos/análisis , Macrófagos Alveolares/química , Masculino , Persona de Mediana Edad , Cultivo Primario de CélulasAsunto(s)
Enfermedades Autoinmunes , Enfermedades del Tejido Conjuntivo , Esclerodermia Sistémica , Síndrome de Sjögren , Humanos , Glándulas Salivales/diagnóstico por imagen , Esclerodermia Sistémica/complicaciones , Esclerodermia Sistémica/diagnóstico por imagen , Síndrome de Sjögren/complicaciones , Síndrome de Sjögren/diagnóstico por imagenRESUMEN
BACKGROUND: Tinzaparin could be easier to manage than unfractionated heparin in patients with severe renal impairment. However, clinical and pharmacologic data regarding its use in such patients are lacking. OBJECTIVES: The aims of this study were to determine, in patients with estimated glomerular filtration rate (eGFR) of <30 mL.minâ»1, tinzaparin pharmacokinetics (PK) parameters using a population PK approach and bleeding and thrombotic complications. METHODS: We performed a retrospective observational single-center study, including in-patients with eGFR of <30 mL.minâ»1 receiving prophylactic (4500 IU.dâ»1) or therapeutic (175 IU.kgâ»1.dâ»1) tinzaparin. Measured anti-Xa levels were analyzed using a nonlinear mixed-effects modeling approach. Individual predicted tinzaparin exposure markers at steady state were calculated for each patient and dosing regimen. The PK was also evaluated through Monte Carlo simulations based on the final covariate model parameter estimates. RESULTS: Over a 22-month period, 802 tinzaparin treatment periods in 623 patients were analyzed: two-thirds received a prophylactic dose, 66% had an eGFR of <20 mL.minâ»1, and 25% were on renal replacement therapy. In patients for whom anti-Xa measurements were performed (n = 199; 746 values), PK parameters, profiles, and maximum plasma concentrations were comparable with those in patients without renal impairment or in healthy volunteers. In the whole population, major bleeding occurred in 2.4% and 3.5% of patients receiving prophylactic and therapeutic doses over a median 9- and 7-day treatment period, respectively. No patients had thrombotic complications. CONCLUSION: Tinzaparin PK parameters and profiles were not affected by renal impairment. This suggests that tinzaparin, at therapeutic or prophylactic dose, could be an alternative to unfractionated heparin in hospitalized patients with severe renal impairment.
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Apixaban and rivaroxaban have first-line use for many patients needing anticoagulation for venous thromboembolism (VTE). The pharmacokinetics of these drugs in non-obese subjects have been extensively studied, and, while changes in pharmacokinetics have been documented in obese patients, data remain scarce for these anticoagulants. The aim of this study was to perform an external validation of published population pharmacokinetic (PPK) models of apixaban and rivaroxaban in a cohort of obese patients with VTE. A literature search was conducted in the PubMed/MEDLINE, Scopus, and Embase databases following the PRISMA statement. External validation was performed using MonolixSuite software, using prediction-based and simulation-based diagnostics. An external validation dataset from the university hospitals of Brest and Rennes, France, included 116 apixaban pharmacokinetic samples from 69 patients and 121 rivaroxaban samples from 81 patients. Five PPK models of apixaban and 16 models of rivaroxaban were included, according to the inclusion criteria of the study. Two of the apixaban PPK models presented acceptable performances, whereas no rivaroxaban PPK model did. This study identified two published models of apixaban applicable to apixaban in obese patients with VTE. However, none of the rivaroxaban models evaluated were applicable. Dedicated studies appear necessary to elucidate rivaroxaban pharmacokinetics in this population.
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OBJECTIVE: To define a semiquantitative classification of finger pulp blood flow (FPBF) and to evaluate whether this classification could be used to assess FPBF in healthy controls and in systemic sclerosis (SSc) patients. METHODS: Thirty controls and 86 SSc patients were consecutively included. A classification of FPBF including 5 grades (from grade 0 [no signal] to 4 [signal detected on the entire finger pulp, including the subepidermal vascular network]) was evaluated. This classification was explored in basal conditions and after hand baths in hot and cold water in controls. Its relevance was also assessed at room temperature in SSc patients. RESULTS: In controls, power Doppler ultrasonography (PDUS) of FPBF was improved after hot challenge (P = 0.024), whereas cold challenge decreased FPBF (P = 0.001). FPBF correlated with the vasodilation status assessed by the resistivity index of radial arteries (Spearman's correlation coefficient = -0.50, P = 0.0049). Grade 0 was more frequent in SSc patients than in controls (22.1% versus 3.3%; P < 0.05). In SSc patients, grade 0 was associated with severity markers of the digital vasculopathy such as digital ulcers (DUs) (current or past) (P < 0.05) or ulnar artery occlusion (P < 0.05). On the other hand, DUs were less frequent in patients with grade 4 (P < 0.05). A pathologic threshold of <2 (grade 0 or 1) was significantly associated with DUs (odds ratio 6.67 [95% confidence interval 2.31-19.21], P < 0.0001). CONCLUSION: PDUS allowed a semiquantitative evaluation of FBPF in SSc patients and controls. Further studies are warranted to validate these results in independent SSc populations and to compare PDUS to existing tools assessing digital blood flow.
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Arteriopatías Oclusivas , Esclerodermia Sistémica , Úlcera Cutánea , Humanos , Proyectos Piloto , Ultrasonografía , Esclerodermia Sistémica/complicaciones , Dedos/diagnóstico por imagen , Dedos/irrigación sanguíneaAsunto(s)
Factor de Transcripción GATA2/deficiencia , Pulmón/patología , Proteinosis Alveolar Pulmonar/complicaciones , Fibrosis Pulmonar/complicaciones , Adulto , Femenino , Factor de Transcripción GATA2/genética , Humanos , Mutación , Proteinosis Alveolar Pulmonar/diagnóstico , Proteinosis Alveolar Pulmonar/genética , Fibrosis Pulmonar/genética , Espirometría , Tomografía Computarizada por Rayos XRESUMEN
Side effects of long-term oral corticosteroid therapy. Systemic corticosteroid therapy has been used for over 70 years, and is still the cornerstone of the treatment of many conditions, in particular systemic, autoimmune or inflammatory diseases. Side effects of corticosteroids are numerous, and for most of them well known by prescribers. Nonetheless, guidelines for the prevention of corticosteroids toxicity are scarce, and the implementation of protective measures by prescribers is heterogenous. Hence, corticosteroids related complications entail a significant morbidity, which, importantly, could be largely prevented. We conducted therefore a systematic literature, through the Medline database, the Cochrane database and the grey literature until January 2021. After recalling the history of the discovery of corticosteroid therapy and its main pharmacological properties, we present the various complications associated with long-term corticosteroid therapy, and discuss the relevance of the preventive measures that may be proposed in daily practice in the light of available scientific evidence. This work highlights the importance of multidisciplinary follow-up, but above all of a thorough screening of the risk factors of complications at treatment initiation, and of a repeated evaluation of the complications all along the treatment course, in order to reduce the significant burden of morbidity associated with long-term corticosteroid therapy and to improve patient quality of life.
Effets indésirables de la corticothérapie orale au long cours. La corticothérapie systémique est utilisée depuis plus de 70 ans et reste la pierre angulaire du traitement de nombreuses affections. Ses effets indésirables sont nombreux et, pour la plupart, bien connus. Pour autant, les recommandations concernant leur prévention sont parfois manquantes, et souvent hétérogènes, y compris dans leur mise en Åuvre par les prescripteurs. De ce fait, les complications induites par la corticothérapie sont à l'origine d'une morbidité importante, la plupart du temps évitables. Nous avons donc réalisé une revue systématique de la littérature, à travers les bases Medline, Cochrane et la littérature grise, jusqu'à janvier 2021. Après avoir rappelé l'histoire de la découverte de la corticothérapie et ses principales caractéristiques pharmacologiques, nous présentons les différentes complications associées à une corticothérapie au long cours et les mesures de prévention disponibles, en discutant leur efficacité et leur pertinence à la lumière des recommandations actuelles ou, à défaut, des dernières données scientifiques disponibles. Ce travail met en évidence l'importance du suivi multidisciplinaire des patients traités par corticothérapie systémique au long cours, mais surtout celle d'un dépistage préalable des facteurs associés à la survenue de complications et de réévaluations répétées de ces complications sous traitement, afin de diminuer le poids très important de la morbidité qui y est associée et ainsi d'améliorer la qualité de vie des patients.
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Corticoesteroides , Calidad de Vida , Corticoesteroides/efectos adversos , Glucocorticoides/efectos adversos , HumanosRESUMEN
BACKGROUND: to compare three existing screening algorithms of pulmonary arterial hypertension (PAH) in systemic sclerosis (SSc) with the results of a multidisciplinary team (MDT) meeting from a tertiary center. METHODS: we conducted a monocentric longitudinal study from 2015 to 2018. All patients with SSc according to LeRoy's classification were eligible. Patients were excluded in the case of missing data required by any of the three screening algorithms. The algorithms were applied for each patient at inclusion. Right heart catheterization (RHC) was performed based on the MDT decision. MDT members were all blinded from the results of the three algorithms regarding RHC recommendations. The RHC recommendations of each algorithm were compared with the MDT decision, and the impact on diagnosis and management was evaluated. RESULTS: 117 SSc patients were consecutively included in the study, and 99 had follow-up data over the three-year duration of the study (10 deaths). Among the 117 patients, the MDT suggested RHC for 16 patients (14%), DETECT algorithm for 28 (24%), ASIG for 48 (41%) and ESC/ERS 2015 for 20 (17%). Among the 16 patients who had RHC, SSc-PAH was diagnosed in seven. Among patients with an initial recommendation of RHC based on at least one algorithm but not according to the MDT meeting, no SSc-PAH was diagnosed during the three-year follow-up. Results were unchanged when the new 2018 definition of PAH was applied instead of the previous definition. CONCLUSION: a MDT approach appears interesting for the screening of SSc-PAH, with a significant reduction of RHC performed in comparison with dedicated algorithms. The specific relevance of a MDT for the management and follow-up of patients with RHC recommended by existing algorithms but with no PAH warrants further studies.
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BACKGROUND: Direct oral anticoagulants (DOAC) use remains challenging in obese patients treated for Venous-Thrombo-Embolism (VTE) due to the paucity of prospective and dedicated studies. OBJECTIVE: To assess rivaroxaban and apixaban concentrations at different time-points after intake, in obese patients followed at a thrombosis center and treated for VTE; to define factors associated with DOAC levels outside the on-therapy ranges; and to evaluate bleeding and thrombosis rates during follow-up. METHODS: Observational prospective study in two French University hospitals. Apixaban or rivaroxaban concentrations were measured after the first visit, regardless of last intake in obese patients receiving DOAC for VTE. Concentrations were compared to published reference values for non-obese patients. Demographic, clinical, biological and therapeutic data were collected. Univariate and multivariate analyses were performed to identify factors associated to DOAC concentrations outside the on-therapy ranges. RESULTS: Out of the 146 patients included, 22 (15%) had DOAC concentrations outside the on-therapy ranges, mainly in the rivaroxaban group (n = 17). Age ≤ 63 years, use of rivaroxaban and time since last intake ≤8 h were associated with DOAC concentrations outside the on-therapy ranges, in multivariable analysis. During the median follow-up of 16 months, two (1%) patients receiving apixaban had recurrent VTE. No patient had major bleeding, 11 (8%) patients had minor bleeding. CONCLUSION: In this specific prospective bi-centric study dedicated to VTE obese patients, use of DOACs at fixed doses led to concentrations similar to those of non-obese patients in a high proportion of patients, without any effect of the BMI, and with risk-benefit profile comparable to non-obese patients.