RESUMO

OBJECTIVE: To investigate the effect of a single oral dose of 200,000 IU of vitamin D3 on antiphospholipid antibodies in hospitalized patients with moderate to severe COVID-19. METHODS: This is a post-hoc, exploratory analysis from a double-blind, placebo-controlled, randomized clinical trial performed in two centers in Sao Paulo, Brazil. Hospitalized patients with COVID-19 were randomly assigned to receive either vitamin D3 (n = 97) or placebo (n = 97). In this post-hoc analysis, the endpoints were titers and frequency of anti-ß2-Glycoprotein-I (aß2-GP) and Anticardiolipin (aCL) antibodies [Immunoglobulin G, M and A (IgG, IgM and IgA)]. RESULTS: Overall mean (SD) age was 55.3 (13.9) years, Body Mass Index (BMI) was 32.2 (7.1 kg/m2), and 106 participants (54.6 %) were male. There was a significant group by time interaction (p = 0.046) for frequency of aCL IgG, with increased values from baseline to discharge in the placebo group [n (%), from 13 (13.4) to 25 (25.8)] compared to the vitamin D3 [from 25 (25.8) to 29 (29.9)]. However, the frequency of aCL IgG did not change between the groups on discharge. No significant differences between vitamin D3 and placebo groups were found for any other autoantibodies. CONCLUSION: These findings do not support the use of a single oral dose of 200,000 IU of vitamin D3 to modulate autoantibodies in hospitalized patients with moderate to severe COVID-19.

Assuntos

Anticorpos Antifosfolipídeos , COVID-19 , Colecalciferol , Humanos , Masculino , Colecalciferol/uso terapêutico , Colecalciferol/administração & dosagem , Feminino , Pessoa de Meia-Idade , Método Duplo-Cego , COVID-19/imunologia , Anticorpos Antifosfolipídeos/sangue , Idoso , Adulto , Índice de Gravidade de Doença , Hospitalização/estatística & dados numéricos , SARS-CoV-2/imunologia , Tratamento Farmacológico da COVID-19 , Vitaminas/uso terapêutico , Vitaminas/administração & dosagem , Anticorpos Anticardiolipina/sangue , Brasil , Imunoglobulina G/sangue , beta 2-Glicoproteína I/imunologia , Resultado do Tratamento

RESUMO

Introduction: Polyarticular juvenile idiopathic arthritis (pJIA) is a childhood-onset autoimmune disease. Immune cells contribute to persistent inflammation observed in pJIA. Despite the crucial role of monocytes in arthritis, the precise involvement of classical monocytes in the pathogenesis of pJIA remains uncertain. Here, we aimed to uncover the transcriptomic patterns of classical monocytes in pJIA, focusing on their involvement in disease mechanism and heterogeneity. Methods: A total of 17 healthy subjects and 18 premenopausal women with pJIA according to ILAR criteria were included. Classical monocytes were isolated, and RNA sequencing was performed. Differential expression analysis was used to compare pJIA patients and healthy control group. Differentially expressed genes (DEGs) were identified, and gene set enrichment analysis (GSEA) was performed. Using unsupervised learning approach, patients were clustered in two groups based on their similarities at transcriptomic level. Subsequently, these clusters underwent a comparative analysis to reveal differences at the transcriptomic level. Results: We identified 440 DEGs in pJIA patients of which 360 were upregulated and 80 downregulated. GSEA highlighted TNF-α and IFN-γ response. Importantly, this analysis not only detected genes targeted by pJIA therapy but also identified new modulators of immuno-inflammation. PLAUR, IL1B, IL6, CDKN1A, PIM1, and ICAM1 were pointed as drivers of chronic hyperinflammation. Unsupervised learning approach revealed two clusters within pJIA, each exhibiting varying inflammation levels. Conclusion: These findings indicate the pivotal role of immuno-inflammation driven by classical monocytes in pJIA and reveals the existence of two subclusters within pJIA, regardless the positivity of rheumatoid factor and anti-CCP, paving the way to precision medicine.

Assuntos

Artrite Juvenil , Perfilação da Expressão Gênica , Inflamação , Monócitos , Transcriptoma , Adulto , Criança , Feminino , Humanos , Anticorpos Antiproteína Citrulinada , Artrite Juvenil/classificação , Artrite Juvenil/genética , Artrite Juvenil/imunologia , Artrite Juvenil/patologia , Estudos de Casos e Controles , Doença Crônica , Análise por Conglomerados , Inflamação/genética , Inflamação/imunologia , Inflamação/patologia , Mediadores da Inflamação/imunologia , Interferon gama/imunologia , Monócitos/imunologia , Monócitos/metabolismo , Fenótipo , Medicina de Precisão , Pré-Menopausa , Ligação Proteica , Mapas de Interação de Proteínas , Fator Reumatoide , Análise de Sequência de RNA , Transcriptoma/genética , Fator de Necrose Tumoral alfa/imunologia , Aprendizado de Máquina não Supervisionado

RESUMO

We ascertained the fracture risk factors stratified by vertebral and non-vertebral sites in rheumatoid arthritis (RA) females. Bone/muscle features, but not disease activity, were the main markers for fractures in this long-standing RA population: low trabecular bone score (TBS) for vertebral fracture and decreased appendicular muscle mass for non-vertebral fracture. PURPOSE: To assess risk factors for fractures, including clinical, laboratory and dual energy X-ray absorptiometry (DXA) parameters (bone mass, trabecular bone score-TBS, muscle mass) in women with established rheumatoid arthritis (RA). METHODS: Three hundred females with RA (ACR, 2010) were studied. Clinical data were obtained by questionnaire and disease activity by composite indices (DAS28, CDAI, SDAI), C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR). Bone mineral density (BMD), TBS, body composition and Vertebral Fracture Assessment (VFA) were performed by DXA. Logistic regression models were constructed to identify factors independently associated with vertebral (VF) and non-vertebral fractures (NVF), separately. RESULTS: Through rigorous eligibility criteria, a total of 265 women were yielded for final data analysis (median age, 55 [22-86] years; mean disease duration, 16.2 years). Prevalence of VF and NVF were 30.6% and 17.4%, respectively. In multivariate analyzes, TBS (OR = 1.6, 95%CI = 1.09-2.36, p = 0.017), CRP (OR = 1.54, 95%CI = 1.15-2.08, p = 0.004), and parathormone (OR = 1.24, 95%CI = 1.05-1.45, p = 0.009) were risk factors for VF, whereas low appendicular muscle mass (OR = 2.71; 95%CI = 1.01-7,28; p = 0.048), body mass index (BMI) (OR = 0.90, 95%CI = 0.82-0.99; p = 0.025), ESR (OR = 1.18, 95%CI = 1.01-1,38, p = 0,038) and hip BMD (OR = 1.82, 95%CI = 1.10-3.03, p = 0.02) were associated with NVF. CONCLUSION: In women with long-term RA, markers of fractures differed between distinct skeletal sites (vertebral and non-vertebral). The magnitude of association of bone/muscle parameters with fracture (TBS for VF and appendicular muscle mass for NVF) was greater than that of the association between RA activity and fracture. TBS seems to have greater discriminative power than BMD to identify subjects with VF in long-standing RA.

Assuntos

Artrite Reumatoide , Fraturas por Osteoporose , Fraturas da Coluna Vertebral , Humanos , Feminino , Pessoa de Meia-Idade , Fraturas da Coluna Vertebral/epidemiologia , Osso Esponjoso/diagnóstico por imagem , Vértebras Lombares/diagnóstico por imagem , Densidade Óssea/fisiologia , Absorciometria de Fóton , Fatores de Risco , Artrite Reumatoide/complicações , Fraturas por Osteoporose/etiologia , Fraturas por Osteoporose/complicações

RESUMO

Abstract Objective: To investigate the effect of a single oral dose of 200,000 IU of vitamin D3 on antiphospholipid antibodies in hospitalized patients with moderate to severe COVID-19. Methods: This is a post-hoc, exploratory analysis from a double-blind, placebo-controlled, randomized clinical trial performed in two centers in São Paulo, Brazil. Hospitalized patients with COVID-19 were randomly assigned to receive either vitamin D3 (n = 97) or placebo (n = 97). In this post-hoc analysis, the endpoints were titers and frequency of anti-β2-Glycoprotein-I (aβ2-GP) and Anticardiolipin (aCL) antibodies [Immunoglobulin G, M and A (IgG, IgM and IgA)]. Results: Overall mean (SD) age was 55.3 (13.9) years, Body Mass Index (BMI) was 32.2 (7.1 kg/m²), and 106 participants (54.6 %) were male. There was a significant group by time interaction (p = 0.046) for frequency of aCL IgG, with increased values from baseline to discharge in the placebo group [n (%), from 13 (13.4) to 25 (25.8)] compared to the vitamin D3 [from 25 (25.8) to 29 (29.9)]. However, the frequency of aCL IgG did not change between the groups on discharge. No significant differences between vitamin D3 and placebo groups were found for any other autoantibodies. Conclusion: These findings do not support the use of a single oral dose of 200,000 IU of vitamin D3 to modulate autoantibodies in hospitalized patients with moderate to severe COVID-19.

RESUMO

OBJECTIVES: To analyze longstanding polyarticular juvenile idiopathic arthritis (pJIA) for possible associations between localized bone damage (erosions), and systemic bone loss. Besides, to compare the systemic bone mass of pJIA with healthy controls. METHODS: Thirty-four pJIA women and 99 healthy controls (HC) were included. Radius and tibia of all subjects were scanned by HR-pQCT. Volumetric bone mineral density (vBMD), bone microarchitecture, and -finite element parameters were analyzed. Patients underwent HR-pQCT of 2nd and 3rd metacarpophalangeal (MCP) and proximal interphalangeal (PIP) joints of the dominant hand, for bone erosions quantification. RESULTS: The mean age of patients was 31.5 ± 7.4yrs with a mean disease duration of 21.7 ± 9.2yrs. Bone erosions were detectable in 79% of patients. The number of bone erosions was positively correlated with cortical porosity (Ct.Po) at tibia (r = 0.575, p = 0.001), and radius (r = 0.423, p = 0.018); and negatively correlated with cortical vBMD at tibia (r=-0.420, p = 0.015). In a logistic regression analysis, adjusted for anti-CCP, the presence of bone erosions was independently associated with Ct.Po at radius (p = 0.018) and cortical vBMD at tibia (p = 0.020). Moreover, cortical and trabecular vBMD, trabecular number, and µ-finite element parameters were decreased in patients compared to HC (p < 0.05). CONCLUSION: Bone erosions in longstanding pJIA women were associated with decreased cortical bone parameters, and these patients showed systemic bone impairment at peripheral sites compared with healthy controls.

Assuntos

Artrite Juvenil , Osteoporose , Humanos , Feminino , Adulto Jovem , Adulto , Artrite Juvenil/complicações , Artrite Juvenil/diagnóstico por imagem , Densidade Óssea , Rádio (Anatomia) , Tomografia Computadorizada por Raios X , Tíbia/diagnóstico por imagem , Absorciometria de Fóton

RESUMO

Patients with systemic mastocytosis (SM) are at high risk of bone deterioration. However, the evaluation of bone microarchitecture in this disease remains unclear. We aimed to assess bone microarchitecture in patients with SM. This was a cross-sectional study of 21 adult patients with SM conducted in a quaternary referral hospital in Sao Paulo, Brazil. A healthy, age-, weight-, and sex-matched cohort of 63 participants was used to provide reference values for bone microarchitecture, assessed by high resolution peripheral quantitative computed tomography (HR-pQCT). Total volumetric bone mineral density (vBMD), cortical vBMD, and cortical thickness at the radius were significantly lower in the control group compared with the SM group (all P < 0.001). Patients with aggressive SM had significantly lower trabecular number (Tb.N) (P = 0.035) and estimated failure load (F.load) (P = 0.032) at the tibia compared with those with indolent SM. Handgrip strength was significantly higher in patients who had more Tb.N at the radius (ρ, 0.46; P = 0.036) and tibia (ρ, 0.49; P = 0.002), and lower who had more trabecular separation at the radius (ρ, -0.46; P = 0.035) and tibia (ρ, -0.52; P = 0.016). Strong and positive associations between F.load (ρ, 0.75; P < 0.001) and stiffness (ρ, 0.70; P < 0.001) at the radius, and between F.load at the tibia (ρ, 0.45; P = 0.038) were observed with handgrip strength. In this cross-sectional study, aggressive SM was more susceptible to bone deterioration compared with indolent SM. In addition, the findings demonstrated that handgrip strength was associated with bone microarchitecture and bone strength.

Assuntos

Mastocitose Sistêmica , Adulto , Humanos , Estudos Transversais , Força da Mão , Brasil , Osso e Ossos , Densidade Óssea , Rádio (Anatomia)/diagnóstico por imagem , Tíbia , Absorciometria de Fóton

RESUMO

OBJECTIVE: To evaluate inactivated CoronaVac prime vaccination, antibody decay, booster dose, and safety in ANCA-Associated Vasculitis (AAV) patients. METHODS: Fifty-three AAV patients and 106 Controls (CG) received CoronaVac on days: D0 (first dose), D28(second dose), and D210 (booster dose, 32 AAV: 32 CG). The primary outcome was immunogenicity after the second vaccine dose (day 69) assessed by Seroconversion Rates (SC) of anti-SARS-CoV-2 S1/S2 IgG and Neutralizing Antibodies (NAb). Secondary outcomes were safety, immunogenicity (D28/D240), 6-months antibody decay (D210) and the booster dose response (D240). RESULTS: At D69 SC (65.1% vs. 96.8%, p = 0.0001), GMT (21.3 UA/mL vs. 67.7 UA/mL, p < 0.001) and NAb- positivity (53.7% vs. 80.6%, p = 0.001) were moderate but lower in naïve-AAV patients than CG. Patients without SC used more often IS (93.3% vs. 53.3%, p = 0.015), mycophenolate mofetil (20% vs. 0%, p = 0.037) and prednisone (60.0% vs. 28.6%, p = 0.057) than seroconverted. NAb negativity in AAV patients was associated with prednisone treatment (57.9% vs. 18.2%, p = 0.015) and IS (84.2% vs. 55.0%, p = 0.046). Logistic regression analysis models showed that only prednisone was associated with lower seroconversion (OR = 0.2, 0,95% CI 0.05‒0.86, p = 0.030) and with lower NAb positivity (OR = 0.2, 0,95% CI 0.05‒0.88, p = 0.034). After six months (D69‒D210) a decrease in IgG positivity occurred in 32 AAV patients (15.7%, p = 0.074) and 32 CG (18.7%, p = 0.041). For the NAb positivity, the 6-month decrease was not significant (p = 0.114) whereas a major reduction occurred for CG (p < 0.001). A booster dose (D240) resulted in an increment in IgG-positivity (21.9%, p = 0.023) and NAb-positivity (34.4%, p = 0.006) in AAV patients. No moderate/severe adverse events attributable to the vaccine were observed. CONCLUSION: This study provides novel data on the excellent safety and moderate immunogenicity of CoronaVac in AAV patients. A six-month mild antibody waning was observed with a good response to the booster dose, although levels remained lower than CG (CoronavRheum-NCT04754698).

Assuntos

Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos , COVID-19 , Humanos , Anticorpos Antivirais , Imunoglobulina G , Prednisona

RESUMO

Abstract Objective: To evaluate inactivated CoronaVac prime vaccination, antibody decay, booster dose, and safety in ANCA-Associated Vasculitis (AAV) patients. Methods: Fifty-three AAV patients and 106 Controls (CG) received CoronaVac on days: D0 (first dose), D28(second dose), and D210 (booster dose, 32 AAV: 32 CG). The primary outcome was immunogenicity after the second vaccine dose (day 69) assessed by Seroconversion Rates (SC) of anti-SARS-CoV-2 S1/S2 IgG and Neutralizing Antibodies (NAb). Secondary outcomes were safety, immunogenicity (D28/D240), 6-months antibody decay (D210) and the booster dose response (D240). Results: At D69 SC (65.1% vs. 96.8%, p = 0.0001), GMT (21.3 UA/mL vs. 67.7 UA/mL, p < 0.001) and NAb- positivity (53.7% vs. 80.6%, p = 0.001) were moderate but lower in naïve-AAV patients than CG. Patients without SC used more often IS (93.3% vs. 53.3%, p = 0.015), mycophenolate mofetil (20% vs. 0%, p = 0.037) and prednisone (60.0% vs. 28.6%, p = 0.057) than seroconverted. NAb negativity in AAV patients was associated with prednisone treatment (57.9% vs. 18.2%, p = 0.015) and IS (84.2% vs. 55.0%, p = 0.046). Logistic regression analysis models showed that only prednisone was associated with lower seroconversion (OR = 0.2, 0,95% CI 0.05-0.86, p = 0.030) and with lower NAb positivity (OR = 0.2, 0,95% CI 0.05-0.88, p = 0.034). After six months (D69-D210) a decrease in IgG positivity occurred in 32 AAV patients (15.7%, p = 0.074) and 32 CG (18.7%, p = 0.041). For the NAb positivity, the 6-month decrease was not significant (p = 0.114) whereas a major reduction occurred for CG (p < 0.001). A booster dose (D240) resulted in an increment in IgG-positivity (21.9%, p = 0.023) and NAb-positivity (34.4%, p = 0.006) in AAV patients. No moderate/severe adverse events attributable to the vaccine were observed. Conclusion: This study provides novel data on the excellent safety and moderate immunogenicity of CoronaVac in AAV patients. A six-month mild antibody waning was observed with a good response to the booster dose, although levels remained lower than CG (CoronavRheum-NCT04754698).

RESUMO

Purpose: The aim of this study was to investigate the reported persistent or new symptoms 1 year after a single dose of 200,000 IU of vitamin D3 and hospitalization in patients with moderate to severe COVID-19. Methods: This is a post-hoc, exploratory analysis from a multicenter, double-blind, placebo-controlled, randomized clinical trial from two hospitals in São Paulo, Brazil, registered in ClinicalTrials.gov, NCT04449718. Discharged patients were followed for up to 1 year and evaluated by telephone interviews at 6 and 12 months. The primary and secondary outcomes were previously published. These post-hoc exploratory secondary outcomes are the persistent or new symptoms and quality of life (QoL) at the post-viral stage of COVID-19. Generalized estimating equations (GEE) for repeated measures with Bonferroni's adjustment were used for testing outcomes. Results: Between 2 June and 27 August 2020, we randomized 240 patients of which 144 were included in this study [the vitamin D3 (n = 71) or placebo (n = 73) group]. The mean (SD) age was 54.3 (13.1) years, and body mass index (BMI) was 32.4 (6.5) kg/m2. Fever demonstrated a significant main effect of time (P < 0.001) with a reduction from baseline to 6 (52-0) and 12 months (52-0). No significant differences between groups were observed for fever, cough, fatigue, fever, myalgia, joint pain, runny nose, nasal congestion, sore throat, hypertension, diabetes, cardiovascular disease, rheumatic disease, asthma, chronic obstructive pulmonary, chronic kidney disease, QoL, and new or persistent symptoms up to 1-year of follow-up. Conclusion: The findings do not support the use of 200,000 IU of vitamin D3 compared to placebo for the management of persistence or new symptoms, and QoL reported by moderate to severe patients after hospitalization for COVID-19.

RESUMO

BACKGROUND: The modulating effect of vitamin D on cytokine concentrations in severe coronavirus disease 2019 (COVID-19) remains unknown. OBJECTIVES: We aimed to investigate the effect of a single high dose of vitamin D3 on cytokines, chemokines, and growth factor in hospitalized patients with moderate to severe COVID-19. METHODS: This is a post hoc, ancillary, and exploratory analysis from a multicenter, double-blind, placebo-controlled, randomized clinical trial. Patients with moderate to severe COVID-19 were recruited from 2 hospitals in São Paulo, Brazil. Of 240 randomly assigned patients, 200 were assessed in this study and randomly assigned to receive a single oral dose of 200,000 IU vitamin D3 (n = 101) or placebo (n = 99). The primary outcome was hospital length of stay, which has been published in our previous study. The prespecified secondary outcomes were serum concentrations of IL-1ß, IL-6, IL-10, TNF-α, and 25-hydroxyvitamin D. The post hoc exploratory secondary outcomes were IL-4, IL-12p70, IL-17A, IFN-γ, granulocyte-macrophage colony-stimulating factor (GM-CSF), IL-8, IFN-inducible protein-10 (IP-10), macrophage inflammatory protein-1ß (MIP-1ß), monocyte chemoattractant protein-1 (MCP-1), vascular endothelial growth factor (VEGF), and leukocyte count. Generalized estimating equations for repeated measures, with Bonferroni's adjustment, were used for testing all outcomes. RESULTS: The study included 200 patients with a mean ± SD age of 55.5 ± 14.3 y and BMI of 32.2 ± 7.1 kg/m2, of which 109 (54.5%) were male. GM-CSF concentrations showed a significant group-by-time interaction effect (P = 0.04), although the between-group difference at postintervention after Bonferroni's adjustment was not significant. No significant effects were observed for the other outcomes. CONCLUSIONS: The findings do not support the use of a single dose of 200,000 IU vitamin D3, compared with placebo, for the improvement of cytokines, chemokines, and growth factor in hospitalized patients with moderate to severe COVID-19.This trial was registered at clinicaltrials.gov as NCT04449718.

Assuntos

Tratamento Farmacológico da COVID-19 , Quimiocinas/efeitos dos fármacos , Colecalciferol/administração & dosagem , Citocinas/efeitos dos fármacos , Fator Estimulador de Colônias de Granulócitos e Macrófagos/efeitos dos fármacos , Fator A de Crescimento do Endotélio Vascular/efeitos dos fármacos , Vitaminas/administração & dosagem , Adulto , Idoso , Brasil , COVID-19/imunologia , Método Duplo-Cego , Feminino , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/sangue , Masculino , Pessoa de Meia-Idade , SARS-CoV-2/imunologia

RESUMO

OBJECTIVE: To evaluate premenopausal women with longstanding rheumatoid arthritis (RA) for potential associations between parameters of localized bone involvement and parameters of systemic bone involvement in the affected joints. METHODS: Eighty consecutively evaluated premenopausal women with RA were included in the study, along with 160 healthy female control subjects who were matched to the patients by age and body mass index. Volumetric bone mineral density (vBMD), bone microarchitecture, and finite elements of biomechanical bone strength (bone stiffness and estimated failure load) at the distal radius and distal tibia were analyzed by high-resolution peripheral quantitative computed tomography (HR-pQCT) in patients with RA compared to healthy controls. In addition, in patients with RA, localized bone involvement in the metacarpophalangeal and proximal interphalangeal joints was analyzed by HR-pQCT, to identify bone erosions and osteophytes. RESULTS: Among the 80 premenopausal women with longstanding RA, the mean ± SD age was 39.4 ± 6.7 years and mean ± SD disease duration was 9.8 ± 5.3 years. Trabecular and cortical bone parameters and bone strength at the distal radius and distal tibia were all impaired in patients with RA compared to healthy controls (each P < 0.05). In total, 75% of RA patients had evidence of bone erosions, and 41.3% of RA patients had detectable osteophytes on HR-pQCT. RA patients with bone erosions, as compared to RA patients without bone erosions, had lower cortical vBMD (at the distal radius, mean ± SD 980 ± 72 mg HA/cm3 versus 1,021 ± 47 mg HA/cm3 [P = 0.03]; at the distal tibia, 979 ± 47 mg HA/cm3 versus 1,003 ± 34 mg HA/cm3 [P = 0.04]) and higher cortical bone porosity (at the distal radius, mean ± SD 2.8 ± 2.5% versus 1.8 ± 1.6% [P = 0.04]; at the distal tibia, 3.7 ± 1.6% versus 2.7 ± 1.6% [P = 0.01]). In patients with RA, osteophyte volume at the distal radius was positively correlated with trabecular vBMD (r = 0.392, P = 0.02), trabecular number (r = 0.381, P = 0.03), and trabecular stiffness (r = 0.411, P = 0.02), and negatively correlated with trabecular separation (r = -0.364, P = 0.04), as determined by Pearson's or Spearman's correlation test. CONCLUSION: The findings show that premenopausal women with longstanding RA have systemic bone fragility at peripheral joint sites. Moreover, the presence of bone erosions is mainly associated with cortical bone fragility at the distal radius and tibia, and presence of osteophytes is associated with repair of trabecular bone at the distal radius.

Assuntos

Artrite Reumatoide/diagnóstico por imagem , Densidade Óssea/fisiologia , Osteófito/diagnóstico por imagem , Rádio (Anatomia)/diagnóstico por imagem , Tíbia/diagnóstico por imagem , Adulto , Osso Esponjoso/diagnóstico por imagem , Osso Cortical/diagnóstico por imagem , Feminino , Humanos , Pessoa de Meia-Idade , Pré-Menopausa , Tomografia Computadorizada por Raios X

RESUMO

Despite the well-established association of gene expression deregulation with low muscle mass (LMM), the associated biological mechanisms remain unclear. Transcriptomic studies are capable to identify key mediators in complex diseases. We aimed to identify relevant mediators and biological mechanisms associated with age-related LMM. LMM-associated genes were detected by logistic regression using microarray data of 20 elderly women with LMM and 20 age and race-matched controls extracted from our SPAH Study (GSE152073). We performed weighted gene co-expression analysis (WGCNA) that correlated the identified gene modules with laboratorial characteristics. Gene enrichment analysis was performed and an LMM predictive model was constructed using Support Vector Machine (SVM). Overall, 821 discriminating transcripts clusters were identified (|beta coefficient| >1; p-value <0.01). From this list, 45 predictors of LMM were detected by SVM and validated with 0.7 of accuracy. Our results revealed that the well-described association of inflammation, immunity and metabolic alterations is also relevant at transcriptomic level. WGCNA highlighted a correlation of genes modules involved in immunity pathways with vitamin D level (R = 0.63, p = 0.004) and the Agatston score (R = 0.51, p = 0.02). Our study generated a predicted regulatory network and revealed significant metabolic pathways related to aging processes, showing key mediators that warrant further investigation.

Assuntos

Envelhecimento , Redes Reguladoras de Genes , Sistema Imunitário , Inflamação , Músculo Esquelético , Sarcopenia/metabolismo , Transcriptoma , Idoso , Idoso de 80 Anos ou mais , Feminino , Perfilação da Expressão Gênica , Humanos , Inflamação/genética , Inflamação/metabolismo , Modelos Logísticos , Redes e Vias Metabólicas , Sarcopenia/genética , Máquina de Vetores de Suporte , Vitamina D/sangue

RESUMO

BACKGROUND: Vitamin D acts as a mediator in the immune system regulating antiviral mechanisms and inflammatory processes. Vitamin D insufficiency has been suggested as a potential risk factor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, although its impact on the prognosis of hospitalized patients with coronavirus disease 2019 (COVID-19) remains unclear. OBJECTIVE: This multicenter prospective cohort study was designed to investigate whether serum 25-hydroxyvitamin D [25(OH)D] concentration is associated with hospital length of stay and prognosis in hospitalized patients with COVID-19. METHODS: Patients with moderate to severe COVID-19 (n = 220) were recruited from 2 hospitals in Sao Paulo, Brazil. Serum 25(OH)D concentrations were categorized as follows: <10 ng/mL, 10 to <20 ng/mL, 20 to <30 ng/mL, and ≥30 ng/mL, and <10 ng/mL and ≥10 ng/mL. The primary outcome was hospital length of stay and the secondary outcomes were the rate of patients who required invasive mechanical ventilation and mortality. RESULTS: There were no significant differences in hospital length of stay when the 4 25(OH)D categories were compared (P = 0.120). Patients exhibiting 25(OH)D <10 ng/mL showed a trend (P = 0.057) for longer hospital length of stay compared with those with 25(OH)D ≥10 ng/mL [9.0 d (95% CI: 6.4, 11.6 d) vs. 7.0 d (95% CI: 6.6, 7.4 d)]. The multivariable Cox proportional hazard models showed no significant associations between 25(OH)D and primary or secondary outcomes. CONCLUSIONS: Among hospitalized patients with moderate to severe COVID-19, those with severe 25(OH)D deficiency (<10 ng/mL) exhibited a trend for longer hospital length of stay compared with patients with higher 25(OH)D concentrations. This association was not significant in the multivariable Cox regression model. Prospective studies should test whether correcting severe 25(OH)D deficiency could improve the prognosis of patients with COVID-19.

Assuntos

COVID-19 , Mortalidade Hospitalar , Tempo de Internação , Respiração Artificial , Índice de Gravidade de Doença , Deficiência de Vitamina D/complicações , Vitamina D/análogos & derivados , Adulto , Idoso , Brasil/epidemiologia , COVID-19/sangue , COVID-19/diagnóstico , COVID-19/mortalidade , Feminino , Hospitais , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Modelos de Riscos Proporcionais , Estudos Prospectivos , SARS-CoV-2 , Vitamina D/sangue , Deficiência de Vitamina D/sangue , Vitaminas

RESUMO

Importance: The efficacy of vitamin D3 supplementation in coronavirus disease 2019 (COVID-19) remains unclear. Objective: To investigate the effect of a single high dose of vitamin D3 on hospital length of stay in patients with COVID-19. Design, Setting, and Participants: This was a multicenter, double-blind, randomized, placebo-controlled trial conducted in 2 sites in Sao Paulo, Brazil. The study included 240 hospitalized patients with COVID-19 who were moderately to severely ill at the time of enrollment from June 2, 2020, to August 27, 2020. The final follow-up was on October 7, 2020. Interventions: Patients were randomly assigned to receive a single oral dose of 200 000 IU of vitamin D3 (n = 120) or placebo (n = 120). Main Outcomes and Measures: The primary outcome was length of stay, defined as the time from the date of randomization to hospital discharge. Prespecified secondary outcomes included mortality during hospitalization; the number of patients admitted to the intensive care unit; the number of patients who required mechanical ventilation and the duration of mechanical ventilation; and serum levels of 25-hydroxyvitamin D, total calcium, creatinine, and C-reactive protein. Results: Of 240 randomized patients, 237 were included in the primary analysis (mean [SD] age, 56.2 [14.4] years; 104 [43.9%] women; mean [SD] baseline 25-hydroxyvitamin D level, 20.9 [9.2] ng/mL). Median (interquartile range) length of stay was not significantly different between the vitamin D3 (7.0 [4.0-10.0] days) and placebo groups (7.0 [5.0-13.0] days) (log-rank P = .59; unadjusted hazard ratio for hospital discharge, 1.07 [95% CI, 0.82-1.39]; P = .62). The difference between the vitamin D3 group and the placebo group was not significant for in-hospital mortality (7.6% vs 5.1%; difference, 2.5% [95% CI, -4.1% to 9.2%]; P = .43), admission to the intensive care unit (16.0% vs 21.2%; difference, -5.2% [95% CI, -15.1% to 4.7%]; P = .30), or need for mechanical ventilation (7.6% vs 14.4%; difference, -6.8% [95% CI, -15.1% to 1.2%]; P = .09). Mean serum levels of 25-hydroxyvitamin D significantly increased after a single dose of vitamin D3 vs placebo (44.4 ng/mL vs 19.8 ng/mL; difference, 24.1 ng/mL [95% CI, 19.5-28.7]; P < .001). There were no adverse events, but an episode of vomiting was associated with the intervention. Conclusions and Relevance: Among hospitalized patients with COVID-19, a single high dose of vitamin D3, compared with placebo, did not significantly reduce hospital length of stay. The findings do not support the use of a high dose of vitamin D3 for treatment of moderate to severe COVID-19. Trial Registration: ClinicalTrials.gov Identifier: NCT04449718.

Assuntos

Tratamento Farmacológico da COVID-19 , Colecalciferol/administração & dosagem , Tempo de Internação , Vitaminas/administração & dosagem , Adulto , Brasil , COVID-19/mortalidade , COVID-19/terapia , Método Duplo-Cego , Feminino , Mortalidade Hospitalar , Humanos , Unidades de Terapia Intensiva , Masculino , Pessoa de Meia-Idade , Respiração Artificial , Falha de Tratamento , Vitamina D/análogos & derivados , Vitamina D/sangue , Deficiência de Vitamina D/tratamento farmacológico

RESUMO

BACKGROUND: Rheumatoid arthritis (RA) is a chronic autoimmune disease depicted by synovial inflammation leading to local and systemic bone loss. The aim of this study was to evaluate by a HR-pQCT (High Resolution Peripheral Quantitative Computed Tomography) study which parameters are associated with volume of bone erosions including bone mineral density (BMD) around erosions (VOI 1 to 4 = volume of interest), BMD of metacarpophalangeal (MCP) head, BMD of radius, presence of osteophytes and joint space width (JSW). METHODS: Fifty female RA patients (18-50 years) were enrolled in this study. Demographic and disease-specific data, laboratory inflammatory parameters and handgrip test were performed. All patients underwent HR-pQCT of 2nd and 3rd MCP joints and distal radius, according to established protocols. The volume of bone erosions was evaluated by MIAF (Medical Image Analysis Framework) software. Osteophytes were analyzed by manual method. RESULTS: The mean of age and disease duration were 40.0 ± 6.0 yrs. and 10.8 ± 4.8 yrs., respectively. According to DAS-28 (Disease Activity Score), 54% (27) of the sample were in remission. However, when SDAI (Simplified Disease Activity Index) was used, only 18% (9) were under remission. The mean of HAQ (Health Assessment Questionnaire), ESR (Erythrocyte sedimentation rate) and CRP (C reactive protein) were 0.9 ± 0.7, 13.9 ± 12.2 mm and 5.6 ± 7.5 mg/mL, respectively. Forty-six bone erosions (0.9 ± 1.2 erosion/patient) and 14 osteophytes (0.3 ± 0.7 osteophyte/patient) were found in 2nd MCP head. The median (IQR-Interquartile range) of volume of erosion and volume of osteophytes were 14.9 (5.7;35.9)mm3 and 3.1 (2.1, 4.3)mm3, respectively. The mean of JSW was 80.5 ± 34.2 mm3. The volume of bone erosions was negatively correlated with BMD of 2nd MCP head, VOI-4 and JSW; and it was positively correlated with osteophytes number. Regarding absence or presence of erosion in 2nd MCP head, a significant difference was found between BMD of MCP head, osteophyte number and JSW. Multiple linear regression analysis showed that only BMD of 2nd MCP head was independently associated with volume of bone erosions. CONCLUSION: BMD of MCP head was independently associated with volume of bone erosion, suggesting that this parameter should be used to analyze and monitoring bone destruction, as well as to evaluate treatment response in RA patients.

Assuntos

Artrite Reumatoide , Densidade Óssea , Artrite Reumatoide/diagnóstico por imagem , Feminino , Força da Mão , Humanos , Articulação Metacarpofalângica/diagnóstico por imagem , Articulação do Punho

RESUMO

OBJECTIVE: To assess the body composition (BC) of patients with granulomatosis with polyangiitis (GPA) compared to healthy controls, emphasizing visceral adipose tissue (VAT) and associated BC parameters with disease activity, the damage index, and inflammatory parameters in patients with GPA. METHODS: This study was conducted in 43 patients with GPA and 43 healthy controls matched by sex, age, and body mass index (BMI). BC was analyzed using dual-energy X-ray absorptiometry (DXA). The fat mass parameters evaluated were total fat mass (FM), adiposity (%), the fat mass index (FMI: fat mass/ht2), and VAT (g, cm2, cm3). Disease activity was assessed by the Birmingham Vasculitis Activity Score (BVAS). Damage was assessed by the Vasculitis Damage Index (VDI). C-reactive protein (CRP) and the erythrocyte sedimentation rate (ESR) were measured. RESULTS: Comparing patients with GPA with healthy controls, patients had a significantly greater VAT (VAT in g: 685.81 ± 306.10 vs. 581.21 ± 235.57, p = 0.04; VAT in cm2: 142.23 ± 63.48 vs. 119.84 ± 49.54, p = 0.03; VAT in cm3: 741.33 ± 330.97 vs. 628.44 ± 254.66, p = 0.04). Patients with higher VAT (≥ 768 g) had an increased value of ESR (22.77 ± 26.79 vs. 11.57 ± 11.30 mm/1st hour, p = 0.04) and an increased value of BVAS (3.18 ± 4.15 vs. 0.90 ± 1.70, p = 0.01) when compared to patients with less VAT (< 768 g). CONCLUSION: Patients with GPA have altered BC compared to healthy controls. Moreover, higher VAT was associated with disease activity and higher inflammatory markers, suggesting a relationship between GPA activity and adiposity parameters. Key points • Granulomatosis with polyangiitis patients have increased visceral adipose tissue when compared to health controls; • Granulomatosis with polyangiitis patients with higher values of visceral adipose tissue have worse disease activity and higher inflammatory markers; • This paper represents important contribution to the well-studied association between vasculitis and inflammatory markers, adding the role of adipose visceral tissue in the disease physiopathology.

Assuntos

Granulomatose com Poliangiite , Gordura Intra-Abdominal , Absorciometria de Fóton , Tecido Adiposo/diagnóstico por imagem , Adiposidade , Composição Corporal , Granulomatose com Poliangiite/complicações , Humanos , Gordura Intra-Abdominal/diagnóstico por imagem

RESUMO

BACKGROUND: Vertebral fractures (VFs) are the most common clinical manifestation of osteoporosis associated with high morbimortality. A personal/familiar history of fractures increases the risk of fractures. The purpose of this study is to identify possible molecular markers associated with osteoporotic VFs in elderly women from community. METHODS: Transcriptomic analysis using Affymetrix HTA2 microarray was performed using whole blood samples of 240 subjects from a population-based survey (Sao Paulo Ageing & Health [SPAH] study). Only elderly women with osteoporosis diagnosis by densitometry were analyzed, and divided in two groups: VF: women with osteoporosis and VFs versus no vertebral fracture (NVF): women with osteoporosis and NVFs. They were matched for age, chronic disease, medication use, and bone mineral density (BMD). The logistic regression model adjusted for age was applied for transcriptome data analysis. SYBR green-based quantitative polymerase chain reaction (qPCR) was used to validate the most significant expression changes obtained in the microarray experiment. RESULTS: Microarray analysis identified 142 differentially expressed genes (DEGs, p < .01), 57 upregulated and 85 downregulated, compared VF versus NVF groups. The DEG with the greatest expression difference was the Gamma2-Syntrophin (SNTG2) (ß = 31.88, p = .005). Validation by qPCR confirmed increased expression in VF group of Syntrophin (SNTG2, fold change = 2.79, p = .009), TRAF3 Interacting Protein2 (TRAF3IP2, fold change = 2.79, p = .020), and Integrin Subunit Alpha 6 (ITGA6, fold change = 2.86, p = .038). CONCLUSION: Our data identified and validated the association of SNTG2 (608715), TRAF3IP2 (607043), and ITGA6 (147556) with osteoporotic VF in elderly women, independently of BMD. These results suggest that these transcripts have potential clinical significance and may help to explain the molecular mechanisms and biological functions of vertebral fracture.

Assuntos

Proteínas Adaptadoras de Transdução de Sinal/genética , Integrina alfa6/genética , Proteínas de Membrana/genética , Proteínas Musculares/genética , Fraturas por Osteoporose/genética , Fraturas da Coluna Vertebral/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Idoso de 80 Anos ou mais , Feminino , Humanos , Integrina alfa6/metabolismo , Proteínas de Membrana/metabolismo , Proteínas Musculares/metabolismo , Fraturas por Osteoporose/metabolismo , Fraturas da Coluna Vertebral/metabolismo , Transcriptoma , Regulação para Cima

RESUMO

Defective KLOTHO gene expression in mice led to a syndrome resembling human ageing. This study evaluated three KLOTHO polymorphisms, namely G395A, C1818T, and C370S, in an elderly population (mean age of 73 years) and their associations with ageing-related outcomes (cardiovascular events, kidney function, osteoporosis, sarcopenia) and mortality. Estimated glomerular filtration rates (eGFR) was lower in subjects with 1818TT (P = 0.047) and 370SS (P = 0.046) genotypes. The 1818TT genotype (P = 0.006) and 1818T allele were associated with higher frequency of myocardial infarction (MI) (CC:1.7% vs. CT + TT:7.0%; P = 0.002). The 370SS genotype was associated with lower stroke frequency (P = 0.001). MI (OR 3.35 [95% CI: 1.29-8.74]) and stroke (OR 3.64 [95% CI: 1.48-8.97]) were associated with mortality. Regarding MI, logistic regression showed 1818T allele was a risk factor for death-related MI (OR 4.29 [95% CI: 1.60-11.52]; P = 0.003), while 370C was protective (OR 0.03 [95% CI: 0.01-0.08]; P < 0.001). Regarding stroke, the 395A and 370C alleles were protective factors (respectively: OR 0.28 [95% CI: 0.20-0.80]; P = 0.018; OR 0.10 [95% CI: 0.05-0.18]; P < 0.001). This is the first study to determine potential associations between common ageing-related outcomes/mortality and KLOTHO polymorphisms. The 1818T allele was a risk factor for MI-related death. The 395A and 370C alleles were protective factors for stroke-related death in elderly from community.

Assuntos

Envelhecimento/genética , Doenças Cardiovasculares/mortalidade , Glucuronidase/genética , Vida Independente/estatística & dados numéricos , Polimorfismo de Nucleotídeo Único , Acidente Vascular Cerebral/mortalidade , Idoso , Doenças Cardiovasculares/genética , Doenças Cardiovasculares/patologia , Humanos , Proteínas Klotho , Masculino , Prognóstico , Fatores de Risco , Acidente Vascular Cerebral/genética , Acidente Vascular Cerebral/patologia , Taxa de Sobrevida

RESUMO

INTRODUCTION: Few studies on rheumatoid arthritis have investigated disease activity and body composition by dual-energy X-ray absorptiometry including evaluation of visceral adipose tissue. Thus, we sought to verify the association between body composition by dual-energy X-ray absorptiometry, including visceral adipose tissue, and inflammatory activity in long-standing established rheumatoid arthritis. METHODS: Seventy-eight postmenopausal women with rheumatoid arthritis (American College of Rheumatology 2010) were studied. Disease activity was assessed by composite indexes (DAS28, CDAI, SDAI) and C-reactive protein. Potential association between body composition and disease activity was analysed by Pearson correlation and Tukey´s test (p < 0.05). RESULTS: There was significant negative correlation between C-reactive protein and appendicular lean mass index (r = -0.234, p = 0.039). After adjusting for confounding variables, women with C-reactive protein >10 mg/L had a lower appendicular lean mass index than those with C-reactive protein 5-10 mg/L and <5 mg/L (6.3 ± 0.8 kg/m2 vs 7.2 ± 1.2 kg/m2 vs 6.8 ± 1.0 kg/m2, respectively; p = 0.013). Women with moderate inflammation (C-reactive protein 5-10 mg/L) had more fat than those with C-reactive protein >10 mg/L and C-reactive protein <5 mg/L (12.4 ± 3.5 kg/m2 vs 9.9 ± 3.6 kg/m2 vs 10.5 ± 2.8 kg/m2, respectively; p = 0.040), as well as more visceral adipose tissue than women with higher and lower C-reactive protein (812.5 ± 266.4 cm3 vs 604.3 ± 236.3cm3 vs 658.9 ± 255.6 cm3; p = 0.009). CONCLUSIONS: High inflammatory activity that persists after a long disease duration was associated with both lower muscle and fat mass (including visceral adipose tissue), which is suggestive of more exuberant rheumatoid cachexia. Conversely, moderate activity was associated with greater visceral adipose tissue, which is associated with increased cardiovascular risk. These results point to the existence of different body composition profiles according to inflammatory status and the importance of individualized approaches to muscle mass and adiposity according to disease activity level in long-standing rheumatoid arthritis.

Assuntos

Artrite Reumatoide/patologia , Composição Corporal , Absorciometria de Fóton , Artrite Reumatoide/diagnóstico por imagem , Proteína C-Reativa/análise , Feminino , Humanos , Gordura Intra-Abdominal/diagnóstico por imagem , Gordura Intra-Abdominal/patologia , Pessoa de Meia-Idade , Índice de Gravidade de Doença

RESUMO

INTRODUCTION: Sarcopenia is characterized by progressive loss of skeletal muscle mass, which results in decreased muscle strength, functional impairment, and increased risk of death. Few studies have performed a concomitant evaluation of clinical, laboratory, and body composition variables to accurately determine the contribution of each parameter to low muscle mass (LMM) in older subjects. This study aimed to identify risk factors (clinical, laboratory parameters, BMD, and body composition by DXA including visceral fat) for LMM in a prospective cohort of older Brazilian women. METHODS: A total of 408 women aged ≥65 yr from the São Paulo Ageing & Health study were evaluated with clinical data, laboratory bone tests, BMD, and body composition by DXA using Hologic QDR 4500A equipment. Risk factors were measured at baseline (2005-2007). After a follow-up of 4.3 ± 0.8 yr, subjects were classified according to the LMM definition of the Foundation for the National Institutes of Health criteria. LMM was defined when appendicular lean mass divided by body mass index was less than 0.512. Multivariate logistic regression models were used to identify independent risk factors for LMM. RESULTS: At the end of follow-up, 116 women (28.4%) had LMM. Age averages were 73.3 ± 4.9 yr in the LMM group and 72.5 ± 4.5 yr in the normal group (p = 0.11). Mean BMI was 30.6 ± 5.2 kg/m2 in the LMM group and 28.1 ± 4.7 kg/m2 in the normal group (p < 0.001). In multivariate analyses, predictors of LMM were: falls (OR = 1.14, p = 0.016), TSH levels (OR = 1.08, p = 0.018, per 1 µUI/L-increase), serum creatinine levels (OR = 11.11, p < 0.001, per 1 mg/dL-decrease), and visceral adipose tissue (VAT) mass (OR = 1.17, p < 0.001, per 100 g increase). CONCLUSIONS: Falls, high TSH, low creatinine, and high VAT were risk factors for LMM in older women. More attention should be paid to these factors, since they are potentially reversible with adequate intervention.

Assuntos

Acidentes por Quedas/estatística & dados numéricos , Creatinina/sangue , Gordura Intra-Abdominal , Sarcopenia/epidemiologia , Tireotropina/sangue , Idoso , Composição Corporal , Índice de Massa Corporal , Brasil/epidemiologia , Estudos de Coortes , Feminino , Humanos , Vida Independente , Modelos Logísticos , Análise Multivariada , Estudos Prospectivos , Fatores de Risco