Asunto(s)
Enfermedades Autoinmunes/tratamiento farmacológico , Hemofilia A/tratamiento farmacológico , Lenalidomida/uso terapéutico , Autoanticuerpos/inmunología , Enfermedades Autoinmunes/complicaciones , Enfermedades Autoinmunes/patología , Erupciones por Medicamentos/etiología , Sustitución de Medicamentos , Factor VIII/inmunología , Hemofilia A/complicaciones , Hemofilia A/patología , Hemorragia/complicaciones , Humanos , Inmunosupresores/efectos adversos , Inmunosupresores/uso terapéutico , Lenalidomida/efectos adversos , Masculino , Persona de Mediana Edad , Paraplejía/etiología , Médula Espinal/irrigación sanguíneaRESUMEN
Animal epidemiological and clinical studies suggest that cholesterol is a risk factor for Alzheimer's disease (AD). Nevertheless, the relation of cholesterol to mild cognitive impairment (MCI), influence of APOE genotype and its changes in lifespan is controversial. We investigated the potential impact of plasma total cholesterol (TC) on development of MCI and AD in the interdisciplinary longitudinal study on adult development and aging, a representative birth cohort (born 1930-1932), examined in 1993/1994 (VT1), 1997/1998 (VT2), and 2005/2007 (VT3). Of 500 participants at baseline, 381 survived and were examined at VT3. After exclusion of participants with lifetime prevalence of major psychiatric diseases or mild cognitive disorder due to a medical condition, 222 participants were included in the analysis. At VT3, 82 participants had MCI, 22 participants had AD, and 118 were in good health. Participants with MCI and AD at VT3 evidenced higher TC levels at VT1 than those who were healthy. Higher TC levels at baseline were associated with an increased risk for cognitive disorders at VT3 (highest vs. lowest quartile: OR 2.64, 95 % CI 1.12-6.23, p < 0.05). Over the 14 year follow-up, TC levels declined in those with MCI and AD, but remained stable in those who remained healthy. These findings were not modified by APOE genotype or use of cholesterol-lowering medications. Our findings demonstrate that higher TC levels are observed long before the clinical manifestation of MCI and AD in patients without psychiatric or somatic comorbidities and are independent of APOE genotype.
Asunto(s)
Enfermedad de Alzheimer/sangre , Colesterol/sangre , Disfunción Cognitiva/sangre , Adulto , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/genética , Apolipoproteínas E/genética , Atención , Disfunción Cognitiva/genética , Estudios de Cohortes , Femenino , Humanos , Masculino , Memoria , Persona de Mediana Edad , Pruebas Neuropsicológicas , Escalas de Valoración Psiquiátrica , Análisis de Supervivencia , Pensamiento , Aprendizaje Verbal , Percepción Visual , Adulto JovenRESUMEN
It is only possible to diagnose an adjustment disorder if there is an explicit connection to a stressful life event. Clinically this disorder is marked by a wide variability of symptoms (e.g. depressive mood, anxiety). The prodromal symptoms have not been unequivocally differentiated from those of other mental disorders and normal adaptation processes. Nevertheless, the diagnosis is often made in clinical practice and, in particular, in primary care. Against this background, its significance is to be examined in association with internal medicine diseases.
Asunto(s)
Trastornos de Adaptación/diagnóstico , Trastornos de Adaptación/terapia , Depresión/diagnóstico , Depresión/terapia , Medicina Interna/tendencias , Estrés Psicológico/diagnóstico , Estrés Psicológico/terapia , Trastornos de Adaptación/complicaciones , Depresión/complicaciones , Humanos , Estrés Psicológico/complicacionesRESUMEN
Activated CD4+ T-cells are found in joints of patients with rheumatoid arthritis and are involved in the joint destroying autoimmune response. Besides proinflammatory cytokine production T-cells are indispensable for the activation of B-cells, the so-called T-cell help for B-cells. However, the recognition of autoantigens by T-cells seems of utmost importance for the pathogenesis of rheumatoid arthritis. Selective inhibition of this process is therefore one of the most interesting therapeutic targets for the future.
Asunto(s)
Artritis Reumatoide/inmunología , Articulaciones/inmunología , Activación de Linfocitos/inmunología , Modelos Inmunológicos , Linfocitos T/inmunología , Animales , HumanosRESUMEN
Rheumatoid arthritis (RA) is a chronic rheumatic disease of unknown aetiology and variable severity. It is now well known that several risk factors are involved in its pathogenesis, including genetic factors and sex hormones as well as environmental factors, i.e. infections and stress. In particular stress is now recognised as an important risk factor for the onset and even more for the modulation of disease activity in RA. Many studies have clearly shown that chronic mild stress (family or professional stress) may lead to proinflammatory effects, increasing disease activity. Furthermore, a positive correlation between the stress level at the onset of RA and radiological progression could be demonstrated. The onset of RA was associated with moderate stress at work, underlining the possible interactions between the various stress systems and the immune system. In this respect it could be demonstrated that coping strategies reduce stress episodes and change stress management with a positive impact on disease activity in RA. However, more studies are warranted to further explore the pathophysiological implications of stress on onset and activity of chronic autoimmune diseases.
Asunto(s)
Artritis Reumatoide/psicología , Estrés Psicológico/complicaciones , Adaptación Psicológica , Adolescente , Adulto , Artritis Juvenil/inmunología , Artritis Juvenil/psicología , Artritis Juvenil/terapia , Artritis Reumatoide/inmunología , Artritis Reumatoide/terapia , Niño , Progresión de la Enfermedad , Humanos , Psiconeuroinmunología , Terapia por Relajación , Factores de Riesgo , Rol del Enfermo , Estrés Psicológico/inmunología , Estrés Psicológico/terapiaRESUMEN
We reported earlier that two mitochondrial gene polymorphisms, UCP2 -866 G/A (rs659366) and mtDNA nt13708 G/A (rs28359178), are associated with multiple sclerosis (MS). Here we aim to investigate whether these functional polymorphisms contribute to other eight chronic inflammatory diseases, including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), Wegener' granulomatosis (WG), Churg-Strauss syndrome (CSS), Crohn's disease (CD), ulcerative colitis (UC), primary sclerosing cholangitis (PSC) and psoriasis. Compared with individual control panels, the UCP2 -866 G/A polymorphism was associated with RA and SLE, and the mtDNA nt13708 G/A polymorphism with RA. Compared with combined controls, the UCP2 -866 G/A polymorphism was associated with SLE, WG, CD and UC. When all eight disease panels and the original MS panel were combined in a meta-analysis, the UCP2 was associated with chronic inflammatory diseases in terms of either alleles (odds ratio (OR)=0.91, 95% confidence interval (95% CI): 0.86-0.96), P=0.0003) or genotypes (OR=0.88, (95% CI: 0.82-0.95), P=0.0008), with the -866A allele associated with a decreased risk to diseases. As the -866A allele increases gene expression, our findings suggest a protective role of the UCP2 protein in chronic inflammatory diseases.
Asunto(s)
Artritis Reumatoide/genética , ADN Mitocondrial/genética , Canales Iónicos/genética , Lupus Eritematoso Sistémico/genética , Proteínas Mitocondriales/genética , Polimorfismo de Nucleótido Simple/genética , Artritis Reumatoide/epidemiología , Artritis Reumatoide/inmunología , Estudios de Casos y Controles , Colangitis Esclerosante/epidemiología , Colangitis Esclerosante/genética , Colangitis Esclerosante/inmunología , Enfermedad Crónica , Síndrome de Churg-Strauss/epidemiología , Síndrome de Churg-Strauss/genética , Síndrome de Churg-Strauss/inmunología , Colitis Ulcerosa/epidemiología , Colitis Ulcerosa/genética , Colitis Ulcerosa/inmunología , Enfermedad de Crohn/epidemiología , Enfermedad de Crohn/genética , Enfermedad de Crohn/inmunología , Genotipo , Alemania/epidemiología , Humanos , Lupus Eritematoso Sistémico/epidemiología , Lupus Eritematoso Sistémico/inmunología , Metaanálisis como Asunto , Esclerosis Múltiple/epidemiología , Esclerosis Múltiple/genética , Esclerosis Múltiple/inmunología , Psoriasis/epidemiología , Psoriasis/genética , Psoriasis/inmunología , Factores de Riesgo , Países Escandinavos y Nórdicos/epidemiología , Proteína Desacopladora 2RESUMEN
OBJECTIVES: To analyse the distribution of single nucleotide polymorphisms (SNPs) in the 5'-regulatory region of the DNASE2 gene, in patients with rheumatoid arthritis (RA) and healthy controls. METHODS: A total of 906 patients with RA and 878 healthy controls were genotyped. All subjects were of German Caucasian origin. Genotyping was performed by real-time polymerase chain reaction technology, using a TaqMan 5'-allele discrimination assay. RESULTS: In the initial analysis of unrelated case-control samples, three DNASE2 SNP alleles in the 5'-regulatory region were significantly more frequent in patients with RA than in healthy controls. The strongest association was found for the -1066G allele (33.5% vs 27.2%, p = 0.007, odds ratio (OR) = 1.34). Homozygosity for this allele (genotype GG) resulted in an additional increase in disease susceptibility (12.5% vs 6.2%, OR = 2.17). The association was replicated in a second case-control series of 483 patients with RA from two German multicentre studies and 474 controls. The association of DNASE2 -1066 GG homozygosity with RA was limited to rheumatoid factor-positive disease, but was not influenced by the presence of anti-cyclic citrullinated peptide or antinuclear antibodies. Similarly, the presence or absence of the HLA-DRB1 shared epitope or the RA-associated PTPN22 allele had no influence on this association. CONCLUSIONS: The association of SNPs in the 5'-regulatory region of the DNA degrading enzyme DNASE2 with RA implies a role for this enzyme in the pathogenesis of this autoimmune disease.
Asunto(s)
Artritis Reumatoide/genética , Endodesoxirribonucleasas/genética , Polimorfismo de Nucleótido Simple , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Antinucleares/sangre , Artritis Reumatoide/inmunología , Autoanticuerpos/sangre , Biomarcadores/sangre , Estudios de Casos y Controles , Femenino , Predisposición Genética a la Enfermedad , Genotipo , Homocigoto , Humanos , Masculino , Persona de Mediana Edad , Péptidos Cíclicos/inmunología , Secuencias Reguladoras de Ácidos Nucleicos/genética , Factor Reumatoide/sangre , Adulto JovenRESUMEN
Genome-wide association studies have dramatically increased our knowledge about the genetic contribution to autoimmune diseases. The identified genes are indicators for signal transduction pathways involved in disease pathogenesis and could contribute to potential new therapeutic approaches.
Asunto(s)
Enfermedades Autoinmunes/genética , Análisis por Conglomerados , Ligamiento Genético/genética , Marcadores Genéticos/genética , Predisposición Genética a la Enfermedad/genética , Pruebas Genéticas/métodos , Polimorfismo de Nucleótido Simple/genética , Enfermedades Autoinmunes/diagnóstico , Heterocigoto , Humanos , Modelos GenéticosRESUMEN
OBJECTIVE: In the present work, the frequency of inherited polymorphisms of the beta2 adrenergic receptor (beta2AR) gene and their association with rheumatoid arthritis (RA) as well as human leukocyte antigen (HLA)-DRB1 alleles was examined. METHODS: An allele-specific polymerase chain reaction was used to determine the common variants of the beta2AR at positions 16, 27 and 164 in patients with RA (n=310) and ethnically matched healthy controls (n=305) from Germany. HLA-DRB1 genotyping was performed by oligonucleotide hybridisation of enzymatically amplified DNA allowing low-resolution HLA-DRB1 genotyping comprising specificities DRB1*01 to DRB1*17. RESULTS: Arginine (Arg) at codon 16 was present in 278 patients with RA (89.7%) compared to 202 controls (66.2%; odds ratio (OR) 4.43, 95% CI 2.81 to 7.02, p<0.001). Homozygosity for Arg16 was found in 107 patients with RA (34.5%) compared to 14 controls (4.6%; OR 10.9, CI 5.9 to 20.5, p<0.001). Stratifying patients for their HLA-DR status revealed that homozygosity for Arg16 exhibited the greatest risk for RA in combination with HLA-DRB1*04 (OR 17.1, 95% CI 1.71 to 414.4, p=0.004). Interestingly, patients with the Arg16 allele have a younger mean (SD) age at disease onset compared to patients without Arg16 (46.1 (2.0) vs 53.1 (2.7) respectively, p<0.05). Furthermore, 93.3% patients with homozygosity for Arg16 were positive for anti-cyclic citrullinated peptide (CCP) antibodies vs 75% patients with homozygosity for Gly16 (p<0.05). CONCLUSION: There was a highly significant distortion between patients with RA and controls in the distribution of beta2AR polymorphisms at codon 16, contributing (together with the HLA-DR alleles) to the genetic background of RA.
Asunto(s)
Artritis Reumatoide/genética , Antígenos HLA-DR/genética , Polimorfismo Genético , Receptores Adrenérgicos beta 2/genética , Adulto , Estudios de Casos y Controles , Femenino , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Genotipo , Cadenas HLA-DRB1 , Heterocigoto , Humanos , Masculino , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa/métodos , Índice de Severidad de la EnfermedadRESUMEN
Growing evidence supports the hypothesis that alterations of the stress response and interactions between the neuroendocrine and immune systems contribute to the pathogenesis of rheumatic diseases such as rheumatoid arthritis (RA). In particular, the hypothalamus-pituitary-adrenal (HPA) axis and the autonomic nervous system (ANS) are of special interest. Polymorphisms of the corticotropin-releasing hormone (CRH)-regulating region have been described recently. These polymorphisms are differentially distributed in RA patients and healthy subjects of various ethnic origin, thus supporting the hypothesis that they represent a new genetic marker for RA susceptibility. The decreased expression of beta(2)-adrenergic receptors (beta(2)-R) on lymphatic cells in rheumatic diseases like RA, together with an impaired influence of catecholamines on immune function in these patients, further underlines the concept of a dysfunction of the ANS in rheumatic diseases. Results from work in this field will provide more insight into the pathogenesis of RA and help to establish novel therapies for this chronic rheumatic disease.
Asunto(s)
Sistema Hipotálamo-Hipofisario/fisiopatología , Neuroinmunomodulación/fisiología , Enfermedades Reumáticas/etiología , Alelos , Animales , Artritis Reumatoide/etiología , Artritis Reumatoide/inmunología , Artritis Reumatoide/patología , Artritis Reumatoide/fisiopatología , Enfermedades Autoinmunes/etiología , Enfermedades Autoinmunes/inmunología , Enfermedades Autoinmunes/patología , Enfermedades Autoinmunes/fisiopatología , Catecolaminas/farmacología , Catecolaminas/fisiología , División Celular/efectos de los fármacos , Cromosomas Humanos Par 8/genética , Hormona Liberadora de Corticotropina/genética , Regulación hacia Abajo , Etnicidad , Predisposición Genética a la Enfermedad , Humanos , Linfocitos/química , Linfocitos/efectos de los fármacos , Tejido Linfoide/inervación , Modelos Biológicos , Polimorfismo Genético , Receptores Adrenérgicos beta 2/análisis , Receptores Adrenérgicos beta 2/genética , Secuencias Reguladoras de Ácidos Nucleicos , Enfermedades Reumáticas/inmunología , Enfermedades Reumáticas/fisiopatología , Sistema Nervioso Simpático/fisiopatologíaRESUMEN
The expression of beta2-adrenergic receptors (beta2-R) on B lymphocytes and agonist-induced cAMP production is reduced in patients with rheumatoid arthritis (RA). To further study functional consequences of the diminished beta2-R density on B lymphocytes in RA patients, agonist-induced cell death was evaluated and compared to healthy controls. B lymphocytes from patients with RA and healthy controls were activated with anti-IgM-antibody. Coincubation was carried out with isoprenaline (iso, 0.001-10 microM). Apoptotic and necrotic cells were determined using Annexin-V and propidium-iodide staining. beta2-R-induced cell death in B cells from healthy volunteers was stimulated after 24 h (medium, 21.2 +/- 1.6%; iso, 34.6 +/- 4.4%; increase 59.3 +/- 10.1%). However, in RA patients the increase in cell death following beta2-R stimulation (21.8 +/- 8.9%) was significantly impaired (p = 0.02). Our data demonstrate that catecholamine-induced cell death after stimulation of beta2-R on B lymphocytes is decreased in RA patients, possibly contributing to the pathogenesis of the disease.
Asunto(s)
Agonistas Adrenérgicos beta/farmacología , Apoptosis/efectos de los fármacos , Artritis Reumatoide/patología , Enfermedades Autoinmunes/patología , Linfocitos B/patología , Anexina A5/análisis , Anticuerpos Antiidiotipos/farmacología , Artritis Reumatoide/inmunología , Enfermedades Autoinmunes/inmunología , Biomarcadores , Caspasa 3 , Caspasas/análisis , Células Cultivadas/efectos de los fármacos , Resistencia a Medicamentos , Epinefrina/farmacología , Humanos , Isoproterenol/farmacología , Receptores Adrenérgicos beta 2/efectos de los fármacos , Terbutalina/farmacologíaRESUMEN
PURPOSE: T-cell-located CD4 antigen represents one of the therapeutic targets in rheumatoid arthritis (RA). However, up to now there is no established imaging tool to visualize this target in vivo. The aim of our study was to assess the safety and tolerability of a technetium-99m labelled murine anti-human CD4 IgG1-Fab fragment ([(99m)Tc]-anti-CD4-Fab, [(99m)Tc]-EP1645) in patients with active synovitis due to RA, and to evaluate its potential as a marker of disease activity. METHODS: In the present phase I proof of principle study five patients with RA were examined. Planar scans of the whole body, hands, and feet were taken 30 min up to 24h after application of 550 ± 150 MBq [(99m)Tc]-anti-CD4-Fab, followed by visual analyses, comparison with clinical data in 68 joints per patient and semiquantitative analysis of hand and wrist joints. RESULTS: Neither infusion related adverse events nor adverse events during follow up were observed. No increase in human anti-murine antibody titres was seen. All patients had positive scans in almost 70% of clinically affected joints. Positive scans were also found in 8% of joints without evidence of swelling or tenderness. CONCLUSION: Scintigraphy with [(99m)Tc]-anti-CD4-Fab is a promising technique for evaluation of inflammatory activity in patients with RA, pre-therapeutical evaluation of CD4 status and therapy control. Tracer uptake in clinically inconspicuous joints strongly indicates diagnostic potential of [(99m)Tc]-anti-CD4-Fab. Whether this technique is eligible as a prognostic factor in RA needs to be analysed in further studies as well as the pathophysiological background of clinically affected joints lacking tracer uptake.
Asunto(s)
Anticuerpos Monoclonales/inmunología , Artritis Reumatoide/diagnóstico por imagen , Antígenos CD4/inmunología , Tecnecio , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales/farmacocinética , Femenino , Humanos , Inflamación/diagnóstico por imagen , Masculino , Persona de Mediana Edad , Cintigrafía , SeguridadRESUMEN
Opioids are the most potent analgesics available and are well established for the treatment of severe acute, surgical, and cancer pain. However, their use to ameliorate chronic noncancer pain (CNCP) is still controversial because of the side effects, such as tolerance, somnolence, confusion, constipation, addiction, withdrawal, and anxiety about disapproval by regulatory bodies. Chronic rheumatic diseases along with low-back pain and arthritis are among the leading causes of CNCP. This article will focus on the role of opioids in chronic rheumatic diseases. Furthermore, the peripheral effects of opioids on pain and inflammation in rheumatic diseases will be outlined.
Asunto(s)
Analgésicos Opioides/efectos adversos , Analgésicos Opioides/uso terapéutico , Artritis Reumatoide/terapia , Osteoartritis/terapia , Enfermedad Crónica/tratamiento farmacológico , Humanos , Inflamación/tratamiento farmacológico , Dolor de la Región Lumbar/tratamiento farmacológico , Dolor/tratamiento farmacológicoRESUMEN
The analysis of cytokines (i.e. interleukins, interferons and colony-stimulating factors) has only flourished in the last 25 years subsequently revealing new insights into the pathogenesis of rheumatic diseases that revolutionised the management of patients with chronic rheumatic disorders. Tumour necrosis factor-alpha (TNF-alpha), interleukin-1 (IL-1) and interleukin-6 (IL-6) have been found to play a pivotal role in rheumatic inflammation. As early as in 1992 the first proof of concept study with a monoclonal antibody against TNF was able to demonstrate positive effects in rheumatoid arthritis. Since the approval of the first anti-TNF-alpha therapy, further agents against TNF and other proinflammatory cytokines were approved and even more biological drugs are under development aimed at modulating the disturbed immune system in patients with rheumatic diseases. To date the following biologics are approved for therapy of chronic rheumatic diseases: the TNF antagonists Etanercept, Infliximab and Adalimumab; Anakinra as an IL-1 receptor antagonist; the anti-CD20 monoclonal antibody Rituximab and the anti-CD80/86 fusion protein Abatacept. In the present article, we report on biological therapy modalities in rheumatic diseases as well as the recommendations for initiation of these agents.
Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Enfermedades Reumáticas/tratamiento farmacológico , Anticuerpos Monoclonales/efectos adversos , Antígenos CD20/inmunología , Artritis Juvenil/tratamiento farmacológico , Artritis Juvenil/inmunología , Artritis Psoriásica/tratamiento farmacológico , Artritis Psoriásica/inmunología , Artritis Reumatoide/tratamiento farmacológico , Artritis Reumatoide/inmunología , Enfermedades del Colágeno/tratamiento farmacológico , Enfermedades del Colágeno/inmunología , Quimioterapia Combinada , Humanos , Interleucina-6/antagonistas & inhibidores , Receptores de Interleucina-1/antagonistas & inhibidores , Enfermedades Reumáticas/inmunología , Espondilitis Anquilosante/tratamiento farmacológico , Espondilitis Anquilosante/inmunología , Enfermedad de Still del Adulto/tratamiento farmacológico , Enfermedad de Still del Adulto/inmunología , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Vasculitis/tratamiento farmacológico , Vasculitis/inmunologíaRESUMEN
Opioids are the most potent analgesics available and are well established for the treatment of severe acute, surgical and cancer pain. Due to their high effectiveness, their use in chronic non-cancer pain (CNCP) is being propagated. However, the use of opioids is still controversial due to their side effects, such as tolerance, addiction or withdrawal, and administrative difficulties associated with their prescription. Chronic rheumatic diseases, in particular low back pain and arthritis, are the leading causes of CNCP. The present article provides a brief overview of the role of opioids in chronic rheumatic diseases, pointing out that a national guideline for opioid use in CNCP is expected at the end of 2008. Furthermore, the peripheral effects of opioids on pain and inflammation in rheumatic diseases will be outlined.
Asunto(s)
Analgésicos Opioides/uso terapéutico , Artritis Reumatoide/tratamiento farmacológico , Osteoartritis/tratamiento farmacológico , Espondilitis Anquilosante/tratamiento farmacológico , Analgésicos Opioides/efectos adversos , Antiinflamatorios/efectos adversos , Antiinflamatorios/uso terapéutico , Encéfalo/efectos de los fármacos , Humanos , Trastornos Relacionados con Opioides/etiología , Umbral del Dolor/efectos de los fármacos , Receptores Opioides/efectos de los fármacos , TaquifilaxisRESUMEN
OBJECTIVES: The TNF superfamily member LIGHT has a T-cell co-stimulatory role and has previously been associated with inflammation and autoimmunity. To investigate its role in rheumatoid arthritis (RA), a disease where activated T cells contribute in a prominent way, we have analysed the expression of LIGHT and its receptors in RA and analysed its effects on synovial fibroblasts in vitro. METHODS: The expression of LIGHT was measured in synovial tissues and fluids and the receptors of LIGHT were detected on synovial fibroblasts derived from patients with RA and osteoarthritis (OA). The effects of recombinant LIGHT on the production of proinflammatory cytokines and proteases and on the apoptosis of synovial fibroblasts was assessed. RESULTS: LIGHT mRNA was present in synovial tissues of patients with RA but not with OA. Correspondingly, soluble LIGHT protein could be detected in RA synovial fluid samples at much higher levels than in synovial fluid from patients with OA. Immunohistochemical detection of LIGHT and analysis of synovial fluid cells by flow cytometry revealed CD4 T cells as the major source of LIGHT in the rheumatoid joint. Synovial fibroblasts from RA patients were found to express the LIGHT receptors HVEM and LTbetaR. Recombinant LIGHT induced RA synovial fibroblasts to upregulate MMP-9 mRNA, CD54 and IL-6 in an NF-kappaB-dependent fashion. In vitro, exposure of cultured synovial fibroblasts to LIGHT reduced FAS-mediated apoptosis significantly, without affecting the rate of spontaneous apoptosis. CONCLUSIONS: The results provide evidence for a novel T-cell-dependent activation of synovial fibroblasts by LIGHT in joints of patients with RA, contributing to an inflammatory and destructive phenotype.
Asunto(s)
Artritis Reumatoide/metabolismo , Líquido Sinovial/química , Membrana Sinovial/metabolismo , Miembro 14 de la Superfamilia de Ligandos de Factores de Necrosis Tumoral/metabolismo , Anciano , Apoptosis/efectos de los fármacos , Artritis Reumatoide/inmunología , Artritis Reumatoide/patología , Linfocitos T CD4-Positivos/química , Linfocitos T CD4-Positivos/metabolismo , Proliferación Celular , Supervivencia Celular , Células Cultivadas , Femenino , Fibroblastos/metabolismo , Fibroblastos/patología , Citometría de Flujo , Humanos , Inmunohistoquímica , Molécula 1 de Adhesión Intercelular/análisis , Interleucina-6/análisis , Leucotrieno B4/análisis , Leucotrieno B4/metabolismo , Masculino , Metaloproteinasa 9 de la Matriz/análisis , Persona de Mediana Edad , FN-kappa B/análisis , FN-kappa B/metabolismo , Osteoartritis/inmunología , Osteoartritis/metabolismo , Osteoartritis/patología , ARN Mensajero/análisis , Miembro 14 de Receptores del Factor de Necrosis Tumoral/análisis , Miembro 14 de Receptores del Factor de Necrosis Tumoral/metabolismo , Proteínas Recombinantes/farmacología , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Estadísticas no Paramétricas , Líquido Sinovial/inmunología , Líquido Sinovial/metabolismo , Membrana Sinovial/inmunología , Membrana Sinovial/patología , Miembro 14 de la Superfamilia de Ligandos de Factores de Necrosis Tumoral/análisis , Miembro 14 de la Superfamilia de Ligandos de Factores de Necrosis Tumoral/genéticaRESUMEN
OBJECTIVE: To evaluate antibodies against cyclic citrullinated peptide (anti-CCP antibodies) for their predictive value for severe joint destruction in rheumatoid arthritis (RA) and to examine their relationship to shared epitope (SE)-positive DRB1 alleles. METHODS: Concentrations of anti-CCP antibodies were determined in sera from 126 patients with recent onset RA who had been followed prospectively for 6 yr. Progression of joint destruction was evaluated according to Larsen by scoring radiographs from the hand and feet taken at baseline and after 1, 2, 4 and 6 yr of observation. In addition to clinical parameters, the presence of SE-positive DRB1 alleles and of rheumatoid factor IgM and IgA was determined. RESULTS: Anti-CCP antibodies were found more frequently and in higher concentrations in both DRB1*01-positive and in DRB1*04-positive SE-positive patients compared with SE-negative patients. Severe joint destruction as defined by a Larsen score in the upper third of the study population was predicted by positivity for anti-CCP antibodies, by the presence of SE-positive DRB1*04 alleles and by the presence of erosive disease at initial presentation. Multiple logistic regression analysis revealed that SE-positive DRB1*04 alleles and anti-CCP antibodies exerted a significant influence on the progression of joint destruction. CONCLUSION: The association of anti-CCP antibodies with DRB1*01 and with SE-positive DRB1*04 alleles implies a functional role for the SE sequence motif. The determination of SE-positive DRB1*04 alleles and of anti-CCP antibody positivity facilitates the prediction of disease course and prognosis at the time of initial presentation.
Asunto(s)
Artritis Reumatoide/inmunología , Autoanticuerpos/sangre , Antígenos HLA-DR/genética , Péptidos Cíclicos/inmunología , Adulto , Alelos , Artritis Reumatoide/diagnóstico por imagen , Artritis Reumatoide/genética , Biomarcadores/sangre , Progresión de la Enfermedad , Epítopos/genética , Femenino , Cadenas HLA-DRB1 , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Estudios Prospectivos , RadiografíaRESUMEN
Approximately one third of all patients with Crohn's disease and ulcerative colitis suffer from extra-intestinal manifestations of their inflammatory bowel disease. Most commonly those symptoms occur simultaneously with the CED symptoms; they can, however, either precede them or appear later on in the course of the disease. The most frequent extra-intestinal symptoms are arthralgias of peripheral joints and spine, which are usually bland and self-limiting, while ankylosing spondylitis and erosive arthritides are rare. Skin lesion and eye affections can also parallel the bowel condition, but occasionally they precede intestinal manifestations and can be a first diagnostic clue. In addition, different extra-intestinal symptoms tend to simultaneously co-occur more frequently in some patients with CED, while others are not affected at all. Immunogenetic parameters play a role for the manifestations of the pathologic immune response both in the gut and in the musculo-skeletal systems, as indicated by associations with MHC class I alleles. Enteropathic microorganisms are also thought to be involved in the pathogenetic mechanisms.
Asunto(s)
Artritis/diagnóstico , Oftalmopatías/diagnóstico , Enfermedades Inflamatorias del Intestino/diagnóstico , Enfermedades de la Piel/diagnóstico , Espondilitis Anquilosante/diagnóstico , HumanosRESUMEN
Rheumatoid arthritis is the most common inflammatory joint disease and is characterized by chronic, symmetric, erosive synovitis of small joints of hands and feet. Prevalence in women is threefold higher than in man. Structural damage of the joints starts between the first and second year of the disease. Early therapeutic interventions can alter the course of rheumatoid arthritis by delaying the progression of radiographic joint destruction, which correlates with the grade of disability. Approval of new biologic antirheumatic drugs in the last few years improved the outcome of rheumatoid arthritis.