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1.
Osteoarthritis Cartilage ; 31(2): 228-237, 2023 02.
Artículo en Inglés | MEDLINE | ID: mdl-36379393

RESUMEN

OBJECTIVE: Hand osteoarthritis (OA) is a frequent musculoskeletal disorder with an increasing prevalence during ageing. This study aimed to evaluate circulating microRNAs (miRNAs) in the plasma of patients with hand OA compared with age- and sex-matched healthy control subjects. METHODS: In total, 238 participants (96 with erosive and 73 with non-erosive hand OA patients and 69 healthy control subjects) were included in this study. All patients underwent clinical examinations, including self-reported measures (AUSCAN and Algofunctional index). Radiographs of both hands were scored with the Kallman scale. The profile of miRNAs in plasma was screened using TaqMan™ Low-Density Array, and candidate miRNAs were validated on two quantitative real-time PCR (qRT-PCR) systems (QuantStudio and SmartChip). RESULTS: Of all the 754 miRNAs, 40 miRNAs were different between hand OA patients and healthy control subjects in the screening cohort. Following the two-phase validation process, three miRNAs (miR-23a-3p, miR-146a-5p, and miR-652-3p) were increased in patients with hand OA compared with healthy control subjects and were associated with the AUSCAN sum score and AUSCAN pain. Furthermore, an inverse correlation of miR-222-3p with the Kallman radiographic score was found. The expression of miRNAs did not differ between erosive and non-erosive hand OA. CONCLUSION: The profile of circulating miRNAs could unveil candidate biomarkers associated with hand OA symptoms. Longitudinal studies are required to determine the role of miRNAs in hand OA.


Asunto(s)
MicroARN Circulante , MicroARNs , Osteoartritis , Humanos , Osteoartritis/diagnóstico por imagen , Osteoartritis/genética , Dolor , Biomarcadores
2.
J Physiol ; 599(1): 207-229, 2021 01.
Artículo en Inglés | MEDLINE | ID: mdl-33063873

RESUMEN

KEY POINTS: Regular exercise improves muscle functional capacity and clinical state of patients with idiopathic inflammatory myopathy (IIM). In our study, we used an in vitro model of human primary muscle cell cultures, derived from IIM patients before and after a 6-month intensive supervised training intervention to assess the impact of disease and exercise on lipid metabolism dynamics. We provide evidence that muscle cells from IIM patients display altered dynamics of lipid metabolism and impaired adaptive response to saturated fatty acid load compared to healthy controls. A 6-month intensive supervised exercise training intervention in patients with IIM mitigated disease effects in their cultured muscle cells, improving or normalizing their capacity to handle lipids. These findings highlight the putative role of intrinsic metabolic defects of skeletal muscle in the pathogenesis of IIM and the positive impact of exercise, maintained in vitro by yet unknown epigenetic mechanisms. ABSTRACT: Exercise improves skeletal muscle function, clinical state and quality of life in patients with idiopathic inflammatory myopathy (IIM). Our aim was to identify disease-related metabolic perturbations and the impact of exercise in skeletal muscle cells of IIM patients. Patients underwent a 6-month intensive supervised training intervention. Muscle function, anthropometric and metabolic parameters were examined and muscle cell cultures were established (m. vastus lateralis; Bergström needle biopsy) before and after training from patients and sedentary age/sex/body mass index-matched controls. [14 C]Palmitate was used to determine fat oxidation and lipid synthesis (thin layer chromatography). Cells were exposed to a chronic (3 days) and acute (3 h) metabolic challenge (the saturated fatty acid palmitate, 100 µm). Reduced oxidative (intermediate metabolites, -49%, P = 0.034) and non-oxidative (diglycerides, -38%, P = 0.013) lipid metabolism was identified in palmitate-treated muscle cells from IIM patients compared to controls. Three days of palmitate exposure elicited distinct regulation of oxidative phosphorylation (OxPHOS) complex IV and complex V/ATP synthase (P = 0.012/0.005) and adipose triglyceride lipase in patients compared to controls (P = 0.045) (immunoblotting). Importantly, 6 months of training in IIM patients improved lipid metabolism (CO2 , P = 0.010; intermediate metabolites, P = 0.041) and activation of AMP kinase (P = 0.007), and nearly normalized palmitate-induced changes in OxPHOS proteins in myotubes from IIM patients, in parallel with improvements of patients' clinical state. Myotubes from IIM patients displayed altered dynamics of lipid metabolism and impaired response to metabolic challenge with saturated fatty acid. Our observations suggest that metabolic defects intrinsic to skeletal muscle could represent non-immune pathomechanisms, which can contribute to muscle weakness in IIM. A 6-month training intervention mitigated disease effects in muscle cells in vitro, indicating the existence of epigenetic regulatory mechanisms.


Asunto(s)
Metabolismo de los Lípidos , Miositis , Humanos , Fibras Musculares Esqueléticas/metabolismo , Músculo Esquelético/metabolismo , Miositis/metabolismo , Calidad de Vida
3.
Scand J Rheumatol ; 49(5): 361-370, 2020 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-32468892

RESUMEN

Objective: SB4, SB2, and SB5 are biosimilars of etanercept (ETN), infliximab (INF), and adalimumab (ADA), respectively. This pooled analysis evaluated the immunogenicity of these treatments across three phase III randomized controlled trials of patients with rheumatoid arthritis (RA). Methods: Patients had to have at least one anti-drug antibody (ADAb) assessment up to the time of the primary endpoint from each study (week 24 in SB4 and SB5 studies; week 30 in SB2 study). The effect of ADAbs on American College of Rheumatology 20% (ACR20) response and the incidences of injection-site reactions (ISRs)/infusion-related reactions (IRRs) were evaluated. Results: The study included 1709 patients. The cumulative incidences of ADAbs were 30.3% in the all-treatments-combined group, 29.1% in the biosimilars combined group, and 31.5% in the reference products combined group. ACR20 response rates were significantly lower in ADAb-positive patients in the all-treatments-combined [odds ratio (95% confidence interval) 1.77 (1.37, 2.27), p < 0.0001], biosimilars combined [2.24 (1.53, 3.30), p < 0.0001], and reference products combined [1.49 (1.06, 2.09), p = 0.0225] groups. ADAb-positive patients also had a higher likelihood of developing ISRs/IRRs in the all-treatments-combined group [0.56 (0.31, 1.01), p = 0.0550], predominantly due to the results observed with SB2 + INF combined rather than with SB4 + ETN or SB5 + ADA combined. Conclusion: In this pooled analysis, ADAbs were associated with reduced efficacy in patients with RA treated with biosimilars (SB4, SB2, and SB5) or their reference products (ETN, INF, and ADA). ADAbs were associated with an increased incidence of ISRs/IRRs in those treated with SB2 + INF. Clinical trial registration numbers: NCT01936181 (SB2 study), NCT01895309 (SB4 study), and NCT02167139 (SB5 study).


Asunto(s)
Antirreumáticos/uso terapéutico , Artritis Reumatoide/tratamiento farmacológico , Biosimilares Farmacéuticos/uso terapéutico , Etanercept/uso terapéutico , Inhibidores del Factor de Necrosis Tumoral/uso terapéutico , Adalimumab/efectos adversos , Adalimumab/uso terapéutico , Adulto , Anticuerpos , Antirreumáticos/efectos adversos , Biosimilares Farmacéuticos/efectos adversos , Etanercept/efectos adversos , Femenino , Humanos , Infliximab/efectos adversos , Infliximab/uso terapéutico , Masculino , Persona de Mediana Edad , Resultado del Tratamiento , Inhibidores del Factor de Necrosis Tumoral/efectos adversos
4.
J Autoimmun ; 101: 48-55, 2019 07.
Artículo en Inglés | MEDLINE | ID: mdl-30992170

RESUMEN

OBJECTIVES: To determine prevalence and co-existence of myositis specific autoantibodies (MSAs) and myositis associated autoantibodies (MAAs) and associated clinical characteristics in a large cohort of idiopathic inflammatory myopathy (IIM) patients. METHODS: Adult patients with confirmed IIM recruited to the EuroMyositis registry (n = 1637) from four centres were investigated for the presence of MSAs/MAAs by radiolabelled-immunoprecipitation, with confirmation of anti-MDA5 and anti-NXP2 by ELISA. Clinical associations for each autoantibody were calculated for 1483 patients with a single or no known autoantibody by global linear regression modelling. RESULTS: MSAs/MAAs were found in 61.5% of patients, with 84.7% of autoantibody positive patients having a sole specificity, and only three cases (0.2%) having more than one MSA. The most frequently detected autoantibody was anti-Jo-1 (18.7%), with a further 21 specificities each found in 0.2-7.9% of patients. Autoantibodies to Mi-2, SAE, TIF1, NXP2, MDA5, PMScl and the non-Jo-1 tRNA-synthetases were strongly associated (p < 0.001) with cutaneous involvement. Anti-TIF1 and anti-Mi-2 positive patients had an increased risk of malignancy (OR 4.67 and 2.50 respectively), and anti-SRP patients had a greater likelihood of cardiac involvement (OR 4.15). Interstitial lung disease was strongly associated with the anti-tRNA synthetases, anti-MDA5, and anti-U1RNP/Sm. Overlap disease was strongly associated with anti-PMScl, anti-Ku, anti-U1RNP/Sm and anti-Ro60. Absence of MSA/MAA was negatively associated with extra-muscular manifestations. CONCLUSIONS: Myositis autoantibodies are present in the majority of patients with IIM and identify distinct clinical subsets. Furthermore, MSAs are nearly always mutually exclusive endorsing their credentials as valuable disease biomarkers.


Asunto(s)
Autoanticuerpos/inmunología , Susceptibilidad a Enfermedades/inmunología , Miositis/epidemiología , Miositis/inmunología , Adulto , Anciano , Estudios de Cohortes , Comorbilidad , Dermatomiositis/epidemiología , Dermatomiositis/inmunología , Europa (Continente)/epidemiología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Miositis/diagnóstico , Oportunidad Relativa , Polimiositis/epidemiología , Polimiositis/inmunología , Prevalencia
5.
Scand J Immunol ; 84(2): 100-9, 2016 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-27173897

RESUMEN

Myositis is a heterogeneous group of autoimmune diseases, with different pathogenic mechanisms contributing to the different subsets of disease. The aim of this study was to test whether the autoantibody profile in patients with myositis is associated with a type I interferon (IFN) signature, as in patients with systemic lupus erythematous (SLE). Patients with myositis were prospectively enrolled in the study and compared to healthy controls and to patients with SLE. Autoantibody status was analysed using an immunoassay system and immunoprecipitation. Type I IFN activity in whole blood was determined using direct gene expression analysis. Serum IFN-inducing activity was tested using peripheral blood cells from healthy donors. Blocking experiments were performed by neutralizing anti-IFNAR or anti-IFN-α antibodies. Patients were categorized into IFN high and IFN low based on an IFN score. Patients with autoantibodies against RNA-binding proteins had a higher IFN score compared to patients without these antibodies, and the IFN score was related to autoantibody multispecificity. Patients with dermatomyositis (DM) and inclusion body myositis (IBM) had a higher IFN score compared to the other subgroups. Serum type I IFN bioactivity was blocked by neutralizing anti-IFNAR or anti-IFN-α antibodies. To conclude, a high IFN score was not only associated with DM, as previously reported, and IBM, but also with autoantibody monospecificity against several RNA-binding proteins and with autoantibody multispecificity. These studies identify IFN-α in sera as a trigger for activation of the type I IFN pathway in peripheral blood and support IFN-α as a possible target for therapy in these patients.


Asunto(s)
Especificidad de Anticuerpos , Autoanticuerpos/inmunología , Dermatomiositis/inmunología , Interferón Tipo I/metabolismo , Miositis por Cuerpos de Inclusión/inmunología , Anciano , Células Cultivadas , Femenino , Humanos , Lupus Eritematoso Sistémico/inmunología , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Proteínas de Unión al ARN/inmunología , Transducción de Señal
6.
Genes Immun ; 16(7): 470-80, 2015 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-26291516

RESUMEN

Autoimmune muscle diseases (myositis) comprise a group of complex phenotypes influenced by genetic and environmental factors. To identify genetic risk factors in patients of European ancestry, we conducted a genome-wide association study (GWAS) of the major myositis phenotypes in a total of 1710 cases, which included 705 adult dermatomyositis, 473 juvenile dermatomyositis, 532 polymyositis and 202 adult dermatomyositis, juvenile dermatomyositis or polymyositis patients with anti-histidyl-tRNA synthetase (anti-Jo-1) autoantibodies, and compared them with 4724 controls. Single-nucleotide polymorphisms showing strong associations (P<5×10(-8)) in GWAS were identified in the major histocompatibility complex (MHC) region for all myositis phenotypes together, as well as for the four clinical and autoantibody phenotypes studied separately. Imputation and regression analyses found that alleles comprising the human leukocyte antigen (HLA) 8.1 ancestral haplotype (AH8.1) defined essentially all the genetic risk in the phenotypes studied. Although the HLA DRB1*03:01 allele showed slightly stronger associations with adult and juvenile dermatomyositis, and HLA B*08:01 with polymyositis and anti-Jo-1 autoantibody-positive myositis, multiple alleles of AH8.1 were required for the full risk effects. Our findings establish that alleles of the AH8.1 comprise the primary genetic risk factors associated with the major myositis phenotypes in geographically diverse Caucasian populations.


Asunto(s)
Alelos , Antígenos HLA/genética , Miositis/genética , Adolescente , Adulto , Autoanticuerpos/inmunología , Estudios de Casos y Controles , Dermatomiositis/genética , Femenino , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Haplotipos , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Polimiositis/genética , Factores de Riesgo , Población Blanca
7.
Rheumatol Int ; 33(1): 259-63, 2013 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-22038193

RESUMEN

Neuropsychiatric manifestations are present in 30-40% of patients with systemic lupus erythematosus (SLE). Recently, antibodies to aquaporin-4 (termed AQP4-Ab, or NMO-IgG), a water channel protein, were reported to be present in a subset of patients with SLE and neurological involvement. To evaluate the syndrome specificity and prevalence of serum NMO-IgG/anti-AQP4 antibodies in patients with neuropsychiatric systemic lupus erythematosus (NPSLE). Sera of 76 patients with SLE and neurological symptoms, 50 of whom met the ACR case definitions of NPSLE, were tested for AQP4-Ab in an indirect immunofluorescence assay employing HEK293 cells transfected with recombinant human AQP4. Only one of the examined sera was positive for NMO-IgG/AQP4-Ab. This patient suffered from TM, ranging over two vertebral segments on spinal MRI. None of the 75 NPSLE without TM was found to be seropositive for NMO-IgG/AQP4-Ab. NMO-IgG/AQP4-Ab in NPSLE were present only in a patient with TM and were not detectable in NPSLE patients with other neurological manifestations. Testing for NMO-IgG/AQP4-Ab positivity should be considered in patients presenting with SLE and TM. Non-longitudinally extensive lesions do no not exclude NMO-IgG/AQP4-Ab in patients presenting with SLE and TM.


Asunto(s)
Acuaporina 4/análisis , Inmunoglobulina G/análisis , Vasculitis por Lupus del Sistema Nervioso Central/epidemiología , Mielitis Transversa/epidemiología , Acuaporina 4/sangre , Biomarcadores/análisis , Biomarcadores/sangre , Comorbilidad , República Checa/epidemiología , Técnica del Anticuerpo Fluorescente Indirecta , Células HEK293 , Humanos , Inmunoglobulina G/sangre , Vasculitis por Lupus del Sistema Nervioso Central/diagnóstico , Vasculitis por Lupus del Sistema Nervioso Central/inmunología , Mielitis Transversa/diagnóstico , Mielitis Transversa/inmunología , Prevalencia , Proteínas Recombinantes , Estudios Seroepidemiológicos
8.
Folia Biol (Praha) ; 59(1): 47-50, 2013.
Artículo en Inglés | MEDLINE | ID: mdl-23537528

RESUMEN

The sampling procedure is a crucial step in every kind of experiment. This is also true in gene expression profiling experiments, where high quality and sufficient quantity of extracted RNA plays a significant role in the experimental outcome. We have compared five different RNA extraction protocols from peripheral blood/PBMCs with the aim to define the most suitable method for the miRNA expression profiling experiments. Convincing results in terms of highest quantity and quality were obtained by the TRIzol-chloroform extraction method. The total RNA obtained using this method contained the highest portion of good-quality miRNA molecules, which was also confirmed by gene-specific real-time PCR experiments.


Asunto(s)
Perfilación de la Expresión Génica , MicroARNs/genética , Biología Molecular/métodos , Animales , Regulación de la Expresión Génica , Humanos , MicroARNs/metabolismo , Reproducibilidad de los Resultados
9.
Ann Rheum Dis ; 71(1): 71-4, 2012 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-21900287

RESUMEN

OBJECTIVE: Dickkopf-1 (DKK-1) is an inhibitor of osteoblastogenesis, and its lower levels are linked to new bone formation. The aim of this study was therefore to explore serum levels of DKK-1 and to evaluate DKK-1's association with the severity of spinal involvement in diffuse idiopathic skeletal hyperostosis (DISH). METHODS: Serum levels of total and functional DKK-1 and C-reactive protein (CRP) were measured in 37 patients with DISH and 22 healthy age and sex-matched controls. Plain radiographs of the cervical and thoracic spine were performed, and the diagnosis of DISH was defined using the Resnick criteria. Patients were divided into three groups based on spinal involvement. Bone mineral density (BMD) and bone turnover markers were evaluated in patients with DISH. RESULTS: The levels of total serum DKK-1 were significantly lower in patients with DISH than in healthy controls (p<0.0001). Importantly, low serum levels of DKK-1 were associated with more severe spinal involvement in DISH, independent of age, sex, disease duration, CRP, bone turnover markers or BMD. However, these findings were less significant for functional DKK-1. CONCLUSION: These observations indicate that DKK-1 may play a significant role in bone formation during DISH.


Asunto(s)
Hiperostosis Esquelética Difusa Idiopática/sangre , Péptidos y Proteínas de Señalización Intercelular/sangre , Anciano , Biomarcadores/sangre , Densidad Ósea/fisiología , Remodelación Ósea/fisiología , Proteína C-Reactiva/metabolismo , Estudios de Casos y Controles , Femenino , Humanos , Hiperostosis Esquelética Difusa Idiopática/diagnóstico por imagen , Hiperostosis Esquelética Difusa Idiopática/fisiopatología , Masculino , Persona de Mediana Edad , Radiografía , Índice de Severidad de la Enfermedad , Vértebras Torácicas/diagnóstico por imagen
10.
Ann Rheum Dis ; 71(6): 961-5, 2012 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-22186711

RESUMEN

OBJECTIVES: HLA-DRB1*03 is strongly associated with anti-Jo-1-positive idiopathic inflammatory myopathies (IIM) and there is now increasing evidence that Jo-1 antigen is preferentially expressed in lung tissue. This study examined whether smoking was associated with the development of anti-Jo-1 antibodies in HLA-DRB1*03-positive IIM. METHODS: IIM cases were selected with concurrent information regarding HLA-DRB1 status, smoking history and anti-Jo-1 antibody status. DNA was genotyped at DRB1 using a commercial sequence-specific oligonucleotide kit. Anti-Jo-1 antibody status was established using a line blot assay or immunoprecipitation. RESULTS: 557 Caucasian IIM patients were recruited from Hungary (181), UK (99), Sweden (94) and Czech Republic (183). Smoking frequency was increased in anti-Jo-1-positive IIM cases, and reached statistical significance in Hungarian IIM (45% Jo-1-positive vs 17% Jo-1-negative, OR 3.94, 95% CI 1.53 to 9.89, p<0.0001). A strong association between HLA-DRB1*03 and anti-Jo-1 status was observed across all four cohorts (DRB1*03 frequency: 74% Jo-1-positive vs 35% Jo-1-negative, OR 5.55, 95% CI 3.42 to 9.14, p<0.0001). The frequency of HLA-DRB1*03 was increased in smokers. The frequency of anti-Jo-1 was increased in DRB1*03-positive smokers vs DRB1*03-negative non-smokers (42% vs 8%, OR 7.75, 95% CI 4.21 to 14.28, p<0.0001) and DRB1*03-positive non-smokers (42% vs 31%, p=0.08). In DRB1*03-negative patients, anti-Jo-1 status between smokers and non-smokers was not significantly different. No significant interaction was noted between smoking and DRB1*03 status using anti-Jo-1 as the outcome measure. CONCLUSION: Smoking appears to be associated with an increased risk of possession of anti-Jo-1 in HLA-DRB1*03-positive IIM cases. The authors hypothesise that an interaction between HLA-DRB1*03 and smoking may prime the development of anti-Jo-1 antibodies.


Asunto(s)
Anticuerpos Antinucleares/inmunología , Cadenas HLA-DRB1/inmunología , Miositis/epidemiología , Miositis/inmunología , Fumar/epidemiología , Fumar/inmunología , Adulto , Edad de Inicio , Anticuerpos Antinucleares/sangre , Europa (Continente)/epidemiología , Femenino , Genotipo , Cadenas HLA-DRB1/genética , Humanos , Masculino , Persona de Mediana Edad , Miositis/genética , Factores de Riesgo , Estudios Seroepidemiológicos , Fumar/genética , Población Blanca/genética , Población Blanca/estadística & datos numéricos
11.
Ann Rheum Dis ; 71(1): 4-12, 2012 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-21953336

RESUMEN

BACKGROUND: Psoriatic arthritis (PsA) is a clinically heterogeneous disease. Clear consensual treatment guidance focused on the musculoskeletal manifestations of PsA would be advantageous. The authors present European League Against Rheumatism (EULAR) recommendations for the treatment of PsA with systemic or local (non-topical) symptomatic and disease-modifying antirheumatic drugs (DMARD). METHODS: The recommendations are based on evidence from systematic literature reviews performed for non-steroidal anti-inflammatory drugs (NSAID), glucocorticoids, synthetic DMARD and biological DMARD. This evidence was discussed, summarised and recommendations were formulated by a task force comprising 35 representatives, and providing levels of evidence, strength of recommendations and levels of agreement. RESULTS: Ten recommendations were developed for treatment from NSAID through synthetic DMARD to biological agents, accounting for articular and extra-articular manifestations of PsA. Five overarching principles and a research agenda were defined. CONCLUSION: These recommendations are intended to provide rheumatologists, patients and other stakeholders with a consensus on the pharmacological treatment of PsA and strategies to reach optimal outcomes, based on combining evidence and expert opinion. The research agenda informs directions within EULAR and other communities interested in PsA.


Asunto(s)
Antirreumáticos/uso terapéutico , Artritis Psoriásica/tratamiento farmacológico , Antirreumáticos/efectos adversos , Comorbilidad , Europa (Continente) , Medicina Basada en la Evidencia/métodos , Glucocorticoides/uso terapéutico , Humanos , Cooperación Internacional , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores
12.
Cesk Patol ; 47(2): 62-5, 2011 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-21598762

RESUMEN

3-nitrotyrosine (3NT) is regarded as a "footprint" of nitric oxide generation. The study aimed at documenting the presence and distribution of 3-nitrotyrosine (3NT) in muscle tissue samples from patients with idiopathic inflammatory myopathies (IIM) as well as from those with non-inflammatory myopathies to consider whether polymyositis (PM) and dermatomyositis (DM) could be distinguished based on 3NT immunohistochemistry in muscle biopsy. Cryosections prepared from muscle biopsies of 54 patients with either IIM, i.e., PM and DM, or various non-inflammatory myopathies were immunostained using monoclonal antibody against 3NT. The 3NT immunostaining was localized to endothelial cells and their close surroundings in muscle biopsies of DM and PM patients but only in those areas of tissue sections where inflammatory cell infiltrates were present. No 3NT positivity was found in tissue sections of IIM patients without inflammatory infiltrates in the studied sample as well as in muscle tissue sections of patients with non-inflammatory myopathies. However, the endothelial cells were also positive in cases of confirmed non-inflammatory myopathies with secondary lymphocytic infiltration (myodystrophies, myasthenia gravis). Despite the pathogenetic significance, the 3NT immunohistochemistry is of low diagnostic value for the differential diagnosis of IIM in muscle biopsy.


Asunto(s)
Músculo Esquelético/metabolismo , Miositis/metabolismo , Tirosina/análogos & derivados , Adulto , Anciano , Dermatomiositis/metabolismo , Dermatomiositis/patología , Endotelio/metabolismo , Femenino , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Músculo Esquelético/patología , Polimiositis/metabolismo , Polimiositis/patología , Unión Proteica , Tirosina/metabolismo
13.
Physiol Res ; 70(2): 255-264, 2021 04 30.
Artículo en Inglés | MEDLINE | ID: mdl-33676382

RESUMEN

Circulating miRNAs appear promising therapeutic and prognostic biomarkers. We aimed to investigate the predictive value of circulating miRNAs on the disease outcome following anti-TNF therapy in patients with ankylosing spondylitis (AS). Our study included 19 AS patients assessed at baseline (M0), after three (M3) and twelve months (M12) of therapy. Total RNA was isolated from plasma. A comprehensive analysis of 380 miRNAs using TaqMan Low Density Array (TLDA) was followed by a single assay validation of selected miRNAs. All AS patients had high baseline disease activity and an excellent response to anti-TNF therapy at M3 and M12. TLDA analysis revealed the dysregulation of 17 circulating miRNAs, including miR-145. Single assay validation confirmed that miR-145 is significantly downregulated at M3 compared to baseline. The decrease in the levels of miR-145 from M0 to M3 negatively correlated with the change in BASDAI from M0 to M3; and positively correlated with disease activity improvement from M3 to M12 as per BASDAI and ASDAS. The predictive value of the early change in miR-145 and levels of miR-145 at M3 were further validated by Receiver operating curves analysis. We show thatthe early change in circulating miR-145 may be a predictor for the future outcome ofAS patients treated with TNF inhibitors. Patients with a more significant decrease in miR-145 levels may show further significant improvement of disease activity after 12 months. Monitoring the expression of miR-145 in plasma in AS patients may, therefore, influence our therapeutic decision-making.


Asunto(s)
MicroARN Circulante/sangre , MicroARNs/sangre , Espondilitis Anquilosante/tratamiento farmacológico , Inhibidores del Factor de Necrosis Tumoral/uso terapéutico , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Adulto , Biomarcadores/sangre , Femenino , Humanos , Masculino , Persona de Mediana Edad , Espondilitis Anquilosante/sangre , Espondilitis Anquilosante/diagnóstico , Espondilitis Anquilosante/inmunología , Factores de Tiempo , Resultado del Tratamiento , Inhibidores del Factor de Necrosis Tumoral/efectos adversos , Adulto Joven
14.
Clin Immunol ; 136(1): 139-47, 2010 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-20359956

RESUMEN

We investigated the role of natural killer (NK) cells and CD161, their primary C-type-lectin-like receptor in rheumatoid arthritis (RA). Samples were compared with healthy donors (HD), dermatomyositic (DM), polymyositic (PM), and osteoarthritic (OA) patients. RA, PM, and DM NK cell cytotoxicities significantly decreased relative to the HD and OA NK cells (p<0.0001). These results correlated with an increased expression of NK cell inhibitory receptor CD161, in active disease RA patients. We demonstrated that NK cells are able to respond to mutated citrullinated vimentin (MCV), an RA-specific autoantigen, leading to increases in both PAD4 enzyme and CD161 mRNA expression. MGAT5 glycosidase involvement was detected in GlcNAc metabolism within the synoviocytes of RA patients. Our findings reveal a functional relationship between CD161 expression and NK cell cytotoxicity as well as reactivity to glycans and MCV, thus providing new insight into the pathogenesis of RA and confirming the involvement of surface glycosylation.


Asunto(s)
Artritis Reumatoide/inmunología , Citotoxicidad Inmunológica/inmunología , Células Asesinas Naturales/inmunología , Subfamilia B de Receptores Similares a Lectina de Células NK/metabolismo , Polisacáridos/farmacología , Vimentina/farmacología , Adulto , Anciano , Artritis Reumatoide/diagnóstico , Artritis Reumatoide/tratamiento farmacológico , Autoanticuerpos/sangre , Autoanticuerpos/inmunología , Autoantígenos/farmacología , Enfermedades Autoinmunes/inmunología , Recuento de Células , Citotoxicidad Inmunológica/efectos de los fármacos , Dermatomiositis/inmunología , Femenino , Expresión Génica/efectos de los fármacos , Expresión Génica/genética , Glucocorticoides/uso terapéutico , Glicoconjugados/farmacología , Humanos , Hidrolasas/genética , Inmunosupresores/uso terapéutico , Células Asesinas Naturales/citología , Células Asesinas Naturales/efectos de los fármacos , Células Asesinas Naturales/metabolismo , Leucocitos Mononucleares/citología , Leucocitos Mononucleares/efectos de los fármacos , Leucocitos Mononucleares/inmunología , Leucocitos Mononucleares/metabolismo , Masculino , Persona de Mediana Edad , N-Acetilglucosaminiltransferasas/genética , Subfamilia B de Receptores Similares a Lectina de Células NK/agonistas , Subfamilia B de Receptores Similares a Lectina de Células NK/genética , Osteoartritis/inmunología , Polimiositis/inmunología , Arginina Deiminasa Proteína-Tipo 4 , Desiminasas de la Arginina Proteica , Líquido Sinovial/citología , Líquido Sinovial/metabolismo
15.
Clin Exp Rheumatol ; 28(6): 849-54, 2010.
Artículo en Inglés | MEDLINE | ID: mdl-21122264

RESUMEN

OBJECTIVES: Prolactin (PRL) is a hormone with cytokine-like activities that has been demonstrated to be involved in immune responses. However, there are inconsistent results related to the role of PRL in rheumatoid arthritis (RA). Therefore, the aim of this study was to evaluate the levels of PRL in serum and synovial fluid in patients with RA and osteoarthritis (OA) and examine whether PRL might be associated with laboratory and clinical disease activity of RA. METHODS: A total of 29 patients with RA and 26 patients with OA were included in the study. The concentration of PRL in the serum and synovial fluid was measured by immunoradiometric assays, and the levels of serum anti-citrullinated protein/peptide autoantibodies (ACPA) and IgM rheumatoid factor (IgM-RF) were analysed by ELISA. Disease activity score (DAS 28) and radiological (Larsen) score were assessed. RESULTS: The levels of PRL in serum (299.55±27.28 vs. 230.59±16.61 mIU/l, p=0.041) as well as in synovial fluid (338.85±33.49 vs. 245.97±21.88 mIU/l, p=0.024) were significantly higher in patients with RA than in patients with OA. A moderate correlation was found between disease activity of RA and levels of PRL in synovial fluid (r=0.485, p=0.010) and the serum PRL levels correlated significantly with the total Larsen score (r=0.484, p=0.014). CONCLUSIONS: The findings of increased prolactin levels in patients with RA lead to the assumption that prolactin may play a role in disease severity and the process of joint damage in RA.


Asunto(s)
Artritis Reumatoide/metabolismo , Artritis Reumatoide/patología , Prolactina/metabolismo , Índice de Severidad de la Enfermedad , Líquido Sinovial/metabolismo , Anciano , Artritis Reumatoide/diagnóstico por imagen , Autoanticuerpos/sangre , Femenino , Humanos , Inmunoglobulina M/sangre , Articulación de la Rodilla/diagnóstico por imagen , Articulación de la Rodilla/patología , Masculino , Persona de Mediana Edad , Osteoartritis de la Rodilla/diagnóstico por imagen , Osteoartritis de la Rodilla/metabolismo , Osteoartritis de la Rodilla/patología , Radiografía , Factor Reumatoide/sangre
16.
Physiol Res ; 69(4): 653-660, 2020 08 31.
Artículo en Inglés | MEDLINE | ID: mdl-32584134

RESUMEN

This study aimed to examine serum tenascin C (TNC) in different subsets of axial spondyloarthritis (axSpA) patients. Sixty-one patients fulfilling the Assessment of SpondyloArthritis international Society classification criteria for axSpA and 20 healthy subjects (HS) were included in study. Based on imaging, patients were classified as non-radiographic (n=16) and radiographic (n=45) axSpA. TNC serum levels were determined by ELISA. Disease-related factors including the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and C-reactive protein (CRP) levels, were determined. TNC levels were elevated in axSpA patients [535.3 (457.7-677.2) ng/ml] compared to HS [432.1 (329.1-565.9) ng/ml, p=0.007]. Dividing axSpA into radiographic and non-radiographic subsets, the difference in TNC was observed between the radiographic subset and HS [535.3 (434.5-677.2) vs. 432.1 (329.1-565.9) ng/ml, p=0.022]. TNC levels did not correlate with disease activity measures (serum CRP or BASDAI). Nevertheless, the weak correlation of TNC levels with different disease stages (r=0.25, p=0.025) was found, with the highest levels in patients with syndesmophytes. TNC levels are elevated across various subsets of axSpA, and although not related to systemic disease activity, TNC levels might reflect chronic structural spinal changes in axSpA patients. However, its specific role in bone metabolism should be elucidated in further studies.


Asunto(s)
Proteína C-Reactiva/metabolismo , Espondiloartritis/sangre , Tenascina/sangre , Adulto , Biomarcadores/sangre , Femenino , Humanos , Masculino , Índice de Severidad de la Enfermedad , Espondiloartritis/diagnóstico
17.
Ann Rheum Dis ; 68(8): 1285-9, 2009 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-19351624

RESUMEN

OBJECTIVE: To evaluate the effect of infliximab dose escalation in incomplete responders in a randomised controlled trial. METHODS: 141 rheumatoid arthritis (RA) patients treated with infliximab for 12 months (3 mg/kg; intervals 0, 2, 6 and then 8 weeks) who responded to the drug (disease activity score in 28 joints (DAS28) decrease >1.2) but who were not in remission (DAS28 >2.6) were enrolled into the study. Patients were randomly assigned into arm A, 3 mg/kg, and arm B, 5 mg/kg infliximab every 8 weeks. Outcome measures included the DAS28, its components and C-reactive protein (CRP). RESULTS: There were no significant differences in changes in the DAS28, its components, or CRP in patients in arms A and B during the 12 months of treatment. All patients showed a DAS28 decrease greater than 0.6 after 28 weeks. Eleven patients interrupted therapy in arm A and 14 in arm B. Infusion reactions and non-serious adverse events were observed in 4.2% and 28.2% of arm A patients and in 7.2% and 47.8% of arm B patients. The frequency of serious adverse events was comparable between arms A and B (16.9% and 15.9%, respectively), and the frequency of serious infections was not significantly greater in the higher dose group (5.8%) than in the lower dose group (5.6%). CONCLUSIONS: In this setting, increasing the infliximab dose from 3 mg/kg to 5 mg/kg in RA patients with residual disease activity did not improve efficacy but moderately increased toxicity. These data indicate that a switch to another biological treatment would be a more appropriate strategy in incomplete responders.


Asunto(s)
Anticuerpos Monoclonales/administración & dosificación , Antirreumáticos/administración & dosificación , Artritis Reumatoide/tratamiento farmacológico , Adulto , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales/uso terapéutico , Antirreumáticos/efectos adversos , Antirreumáticos/uso terapéutico , Artritis Reumatoide/sangre , Biomarcadores/sangre , Proteína C-Reactiva/metabolismo , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Esquema de Medicación , Femenino , Humanos , Infliximab , Masculino , Persona de Mediana Edad , Índice de Severidad de la Enfermedad , Resultado del Tratamiento
18.
Ann Rheum Dis ; 68(6): 797-804, 2009 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-19015207

RESUMEN

BACKGROUND: Certolizumab pegol is a PEGylated tumour necrosis factor inhibitor. OBJECTIVE: To evaluate the efficacy and safety of certolizumab pegol versus placebo, plus methotrexate (MTX), in patients with active rheumatoid arthritis (RA). METHODS: An international, multicentre, phase 3, randomised, double-blind, placebo-controlled study in active adult-onset RA. Patients (n = 619) were randomised 2:2:1 to subcutaneous certolizumab pegol (liquid formulation) 400 mg at weeks 0, 2 and 4 followed by 200 mg or 400 mg plus MTX, or placebo plus MTX, every 2 weeks for 24 weeks. The primary end point was ACR20 response at week 24. Secondary end points included ACR50 and ACR70 responses, change from baseline in modified Total Sharp Score, ACR core set variables and physical function. RESULTS: Significantly more patients in the certolizumab pegol 200 mg and 400 mg groups achieved an ACR20 response versus placebo (p< or =0.001); rates were 57.3%, 57.6% and 8.7%, respectively. Certolizumab pegol 200 and 400 mg also significantly inhibited radiographic progression; mean changes from baseline in mTSS at week 24 were 0.2 and -0.4, respectively, versus 1.2 for placebo (rank analysis p< or =0.01). Certolizumab pegol-treated patients reported rapid and significant improvements in physical function versus placebo; mean changes from baseline in HAQ-DI at week 24 were -0.50 and -0.50, respectively, versus -0.14 for placebo (p< or =0.001). Most adverse events were mild or moderate, with low incidence of withdrawals due to adverse events. Five patients developed tuberculosis. CONCLUSION: Certolizumab pegol plus MTX was more efficacious than placebo plus MTX, rapidly and significantly improving signs and symptoms of RA and physical function and inhibiting radiographic progression. TRIAL REGISTRATION NUMBER: NCT00175877.


Asunto(s)
Artritis Reumatoide/tratamiento farmacológico , Fragmentos Fab de Inmunoglobulinas/administración & dosificación , Inmunosupresores/administración & dosificación , Metotrexato/administración & dosificación , Polietilenglicoles/administración & dosificación , Adulto , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales Humanizados , Artritis Reumatoide/diagnóstico por imagen , Artritis Reumatoide/inmunología , Artrografía , Coagulación Sanguínea/efectos de los fármacos , Certolizumab Pegol , Método Doble Ciego , Esquema de Medicación , Quimioterapia Combinada , Femenino , Estudios de Seguimiento , Humanos , Fragmentos Fab de Inmunoglobulinas/efectos adversos , Fragmentos Fab de Inmunoglobulinas/uso terapéutico , Inmunosupresores/efectos adversos , Inmunosupresores/uso terapéutico , Masculino , Metotrexato/uso terapéutico , Polietilenglicoles/efectos adversos , Polietilenglicoles/uso terapéutico , Resultado del Tratamiento , Factor de Necrosis Tumoral alfa/inmunología
19.
Ann Rheum Dis ; 68(6): 805-11, 2009 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-19015206

RESUMEN

BACKGROUND: Tumour necrosis factor alpha (TNFalpha) is a proinflammatory cytokine involved in the pathogenesis of rheumatoid arthritis (RA). Treatment with TNFalpha inhibitors reduces disease activity and improves outcomes for patients with RA. This study evaluated the efficacy and safety of certolizumab pegol 400 mg, a novel, poly-(ethylene glycol) (PEG)ylated, Fc-free TNFalpha inhibitor, as monotherapy in patients with active RA. METHODS: In this 24-week, multicentre, randomised, double-blind, placebo-controlled study, 220 patients previously failing > or =1 disease-modifying antirheumatic drug (DMARD) were randomised 1:1 to receive subcutaneous certolizumab pegol 400 mg (n = 111) or placebo (n = 109) every 4 weeks. The primary endpoint was 20% improvement according to the American College of Rheumatology criteria (ACR20) at week 24. Secondary endpoints included ACR50/70 response, ACR component scores, 28-joint Disease Activity Score Erythrocyte Sedimentation Rate 3 (DAS28(ESR)3), patient-reported outcomes (including physical function, health-related quality of life (HRQoL), pain and fatigue) and safety. RESULTS: At week 24, the ACR20 response rates were 45.5% for certolizumab pegol 400 mg every 4 weeks vs 9.3% for placebo (p<0.001). Differences for certolizumab pegol vs placebo in the ACR20 response were statistically significant as early as week 1 through to week 24 (p<0.001). Significant improvements in ACR50, ACR components, DAS28(ESR)3 and all patient-reported outcomes were also observed early with certolizumab pegol and were sustained throughout the study. Most adverse events were mild or moderate and no deaths or cases of tuberculosis were reported. CONCLUSIONS: Treatment with certolizumab pegol 400 mg monotherapy every 4 weeks effectively reduced the signs and symptoms of active RA in patients previously failing > or =1 DMARD compared with placebo, and demonstrated an acceptable safety profile. TRIAL REGISTRATION NUMBER: NCT00548834.


Asunto(s)
Artritis Reumatoide/tratamiento farmacológico , Fragmentos Fab de Inmunoglobulinas/administración & dosificación , Inmunosupresores/administración & dosificación , Polietilenglicoles/administración & dosificación , Adulto , Análisis de Varianza , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales Humanizados , Artritis Reumatoide/inmunología , Certolizumab Pegol , Método Doble Ciego , Esquema de Medicación , Femenino , Humanos , Fragmentos Fab de Inmunoglobulinas/uso terapéutico , Inmunosupresores/uso terapéutico , Inyecciones Subcutáneas , Masculino , Persona de Mediana Edad , Polietilenglicoles/uso terapéutico , Tamaño de la Muestra , Resultado del Tratamiento , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores
20.
Ann Rheum Dis ; 68(6): 836-43, 2009 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-18628284

RESUMEN

OBJECTIVE: To investigate serum levels of B cell activating factor (BAFF) in patients with myositis and correlate these to autoantibody profile, clinical phenotype and treatment. METHODS: BAFF levels in sera from 49 patients with dermatomyositis, 44 with polymyositis, 6 with inclusion body myositis and 30 matched controls were measured by ELISA. Specific autoantibodies were detected by line blot and western blot assays. RESULTS: Serum levels of BAFF were significantly higher in patients compared to healthy controls (p = 0.003). Patients with anti-Jo-1 autoantibodies had higher BAFF levels than control individuals (p<0.003) or patients without any specific autoantibodies (p<0.05). Patients with dermatomyositis had higher BAFF levels compared to polymyositis (p<0.05). Patients with interstitial lung disease (ILD) had higher BAFF levels than patients without ILD (p<0.05) or controls (p<0.01) but this could be explained by presence of anti-Jo-1 autoantibodies. BAFF levels correlated with serum creatine kinase (CK) (rs = 0.365, p = 0.0005) but not with C-reactive protein (CRP) levels. A negative correlation of BAFF levels with glucocorticoid daily dose for all patients (rs = -0.292, p = 0.003) and with cumulative glucocorticoid doses in early myositis cases (rs = -0.659, p<0.001) was recorded. CONCLUSION: Our finding of elevated serum levels of BAFF in patients with myositis with described phenotypes together with the correlations between levels of BAFF and CK and a negative correlation with dose of glucocorticoids, indicate that BAFF could be a potential therapeutic target in such cases.


Asunto(s)
Autoanticuerpos/sangre , Factor Activador de Células B/sangre , Miositis/sangre , Adolescente , Adulto , Anciano , Análisis de Varianza , Anticuerpos Antinucleares/sangre , Autoanticuerpos/inmunología , Proteína C-Reactiva/análisis , Estudios de Casos y Controles , Niño , Creatina Quinasa/sangre , Dermatomiositis/sangre , Dermatomiositis/tratamiento farmacológico , Dermatomiositis/inmunología , Femenino , Glucocorticoides/uso terapéutico , Humanos , Masculino , Persona de Mediana Edad , Miositis/tratamiento farmacológico , Miositis/inmunología , Polimiositis/sangre , Polimiositis/tratamiento farmacológico , Polimiositis/inmunología , Estadísticas no Paramétricas , Miembro 13 de la Superfamilia de Ligandos de Factores de Necrosis Tumoral/sangre , Adulto Joven
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