RESUMO
We described a case of IPEX syndrome successfully controlled with dupilumab, an anti-IL4 receptor alpha subunit inhibitor. IPEX syndrome is a rare and generally fatal genetic disorder characterized by immune dysregulation, polyendocrinopathy and enteropathy, mostly diagnosed in early childhood. Nonetheless, cases reported in the last 20 years demonstrated that IPEX clinical spectrum encompasses more than the classical triad of early-onset intractable diarrhea, type 1 diabetes and eczema. Atypical cases of IPEX include patients with late-onset of symptoms, single-organ involvement, mild disease phenotypes or rare clinical features. A 21-year-old caucasian man presented with immune dysregulation (hypereosinophilia and elevated IgE), protein-losing enteropathy, polyendocrinopathy (thyroiditis, osteoporosis, delayed puberty), weight loss, eczema manifestations and celiac disease. IPEX syndrome was diagnosed because of the presence of a hemizygous mutation in FOXP3 gene (c.543C>T (p.S181S) in the exon 5). During the course of the disease, the patient developed erosive proctitis, pyoderma gangrenosum, and erythema nodosum. Symptoms improved only after enteral and parenteral corticosteroid therapy and the patient soon developed steroid-dependence. Notwithstanding various therapies including azathioprine, sirolimus, tacrolimus, adalimumab, vedolizumab, the patient failed to achieve a good control of symptoms without steroids. Almost exclusive enteral nutrition with a hypoallergenic, milk-protein free, amino acid-based food for special medical purposes. He continued to lose weight (BMI 14.5 kg/m2) with a consequent high limitation of physical activity and a progressive worsening of the quality of life. In consideration of the poor response to conventional immunosuppressants and the presence of type 2 inflammatory manifestations, treatment with dupilumab at an initial dose of 600 mg, followed by a maintenance dose of 300 mg every other week, according to atopic dermatitis labeled dose, was started and combined to oral budesonide 6 mg/day and 6-mercaptopurine 75 mg/day. The patient experienced a rapid improvement in bowel and skin symptoms, leading to a progressive tapering of steroids. By our knowledge, this is the first report of IPEX syndrome successfully treated by antiIL-4/IL-13 therapy. In this case dupilumab demonstrated to be an effective, safe and steroid-sparing option.
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Dermatite Atópica , Diabetes Mellitus Tipo 2 , Eczema , Humanos , Masculino , Eczema/complicações , Eczema/diagnóstico , Eczema/tratamento farmacológico , Qualidade de Vida , Adulto JovemRESUMO
BACKGROUND: Mepolizumab (MEP) is the first anti Interleukin (IL)-5 add-on therapy approved for the treatment of severe refractory eosinophilic asthma. CASE PRESENTATION: We describe here the case of a 49 years-old woman with Aspirin-exacerbated respiratory disease (AERD), chronic rhinosinusitis, nasal polyposis and eosinophilic gastroenteritis successfully treated with MEP. Several laboratory and clinical items improved during therapy; moreover MEP showed to be useful as steroid sparing agent. CONCLUSIONS: This case supports that the use of mepolizumab can be effective also in other eosinophilic conditions different from asthma and this opens to new therapeutic perspectives.
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OBJECTIVES: To define baseline clinical and immunological characteristics [anti-citrullinated peptide antibodies (ACPAs), immunoglobulin M (IgM)- and IgA-rheumatoid factor (RF), and interleukin-6 (IL-6) levels] involved in determining baseline erosiveness, outcome, and radiographic progression among seropositive and seronegative early rheumatoid arthritis (ERA) patients. METHOD: The 408 ERA patients enrolled in the study were monitored every 3 months according to the treat-to-target strategy. At baseline and after 12 months, hand and foot radiographs were evaluated using the Sharp/van der Heijde erosion score. RESULTS: At diagnosis, seronegative patients were older and had higher Disease Activity Scores (DASs) than seropositive patients. A higher risk of erosiveness at baseline was conferred by IgA-RF positivity and IL-6 plasma levels ≥7.6 pg/mL, particularly when simultaneously present. In multivariate analysis, disease duration and IL-6 plasma levels ≥7.6 pg/mL arose as independent variables associated with presence of erosions at onset. Radiographic progression at 1 year follow-up, which occurred in 11.1% of ERA patients, was predicted by ACPA positivity, together with higher age at diagnosis. Despite similar percentages of good European League Against Rheumatism response, DAS and Boolean remission being observed over time among seropositive and seronegative patients and between erosive and non-erosive subjects, ERA patients who were erosive at onset, IgA-RF seropositive, and simultaneously having high baseline IL-6 plasma levels (≥7.6 pg/mL) were treated to a greater extent with tumour necrosis factor blockers after 12 months. CONCLUSION: IgA-RF positivity and IL-6 plasma levels are crucial for baseline erosiveness, while ACPA positivity represents the strongest risk factor for developing radiographic progression in ERA.
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Anticorpos Antiproteína Citrulinada/sangue , Artrite Reumatoide/sangue , Interleucina-6/sangue , Fator Reumatoide/sangue , Adulto , Idoso , Antirreumáticos/uso terapêutico , Artrite Reumatoide/diagnóstico por imagem , Artrite Reumatoide/patologia , Biomarcadores/sangue , Progressão da Doença , Feminino , Seguimentos , Humanos , Imunoglobulina A/sangue , Imunoglobulina M/sangue , Masculino , Pessoa de Meia-Idade , Curva ROC , Índice de Gravidade de DoençaRESUMO
Acute inflammation is a complex and tightly regulated homeostatic process that includes leucocyte migration from the vasculature into tissues to eliminate the pathogen/injury, followed by a pro-resolving response promoting tissue repair. However, if inflammation is uncontrolled as in chronic diseases such as rheumatoid arthritis (RA), it leads to tissue damage and disability. Synovial tissue inflammation in RA patients is maintained by sustained activation of multiple inflammatory positive-feedback regulatory pathways in a variety of cells, including myeloid cells. In this review, we will highlight recent evidence uncovering biological mechanisms contributing to the aberrant activation of myeloid cells that contributes to perpetuation of inflammation in RA, and discuss emerging data on anti-inflammatory mediators contributing to sustained remission that may inform a novel category of therapeutic targets.
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Artrite Reumatoide/patologia , Autoimunidade/imunologia , Células Mieloides/metabolismo , Membrana Sinovial/patologia , Artrite Reumatoide/imunologia , Citocinas/imunologia , Células Dendríticas/imunologia , Humanos , Inflamação/imunologia , Inflamação/patologia , Mediadores da Inflamação/metabolismo , Macrófagos/imunologia , Membrana Sinovial/imunologiaRESUMO
High-mobility group box 1 (HMGB1) has been implicated in angiogenesis and rheumatoid arthritis (RA). The aim of this study was to define more clearly the role of HMGB1 in the synovial angiogenesis and pathogenesis of an immune model of arthritis. BALB/c mice were injected with monoclonal anti-collagen antibody cocktail followed by lipopolysaccharide to induce arthritis. HMGB1 and vascular endothelial growth factor (VEGF) were over-expressed in the areas of the synovium where more inflammation and neoangiogenesis were present. The selective blockade of HMGB1 or VEGF resulted alternatively in a lower severity of arthritis evaluated by the arthritis index. Furthermore, exogenous HMGB1 administration caused a worsening of arthritis, associated with VEGF up-regulation and increased synovial angiogenesis. The selective inhibition of VEGF also resulted in no induction of arthritis in mice receiving exogenous HMGB1. Cytokine enzyme-linked immunosorbent assay (ELISA) analyses performed on peripheral blood and synovial fluid demonstrated a significant reduction of interleukin (IL)-1ß, IL-6 and tumour necrosis factor (TNF)-α in mice where HMGB1 and VEGF pathways were blocked. Interestingly, the selective blockade of HMGB1 and VEGF resulted in an increase of the peripheral IL-17A concentration. The development of arthritis mediated by HMGB1 and the synovial angiogenesis can be blocked by inhibiting the VEGF activity. The proinflammatory and proangiogenic cytokine IL-17A was increased when HMGB1 is inhibited, but the synovial angiogenesis was nevertheless reduced in this model of arthritis. Taken together, these findings shed new light on the role of this nuclear protein in the pathogenesis of arthritis in an RA-like model.
Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Anticorpos/sangue , Artrite Experimental/tratamento farmacológico , Proteína HMGB1/imunologia , Peptídeos/farmacologia , Fator A de Crescimento do Endotélio Vascular/imunologia , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/farmacologia , Animais , Artrite Experimental/genética , Artrite Experimental/imunologia , Artrite Experimental/patologia , Colágeno Tipo II/sangue , Colágeno Tipo II/imunologia , Expressão Gênica , Proteína HMGB1/antagonistas & inibidores , Proteína HMGB1/genética , Proteína HMGB1/farmacologia , Interleucina-17/genética , Interleucina-17/imunologia , Interleucina-1beta/genética , Interleucina-1beta/imunologia , Interleucina-6/genética , Interleucina-6/imunologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Neovascularização Patológica/genética , Neovascularização Patológica/imunologia , Neovascularização Patológica/patologia , Neovascularização Patológica/prevenção & controle , Índice de Gravidade de Doença , Membrana Sinovial/efeitos dos fármacos , Membrana Sinovial/imunologia , Membrana Sinovial/patologia , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologia , Fator A de Crescimento do Endotélio Vascular/agonistas , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Fator A de Crescimento do Endotélio Vascular/genéticaRESUMO
OBJECTIVE: Several studies underline the relevance of the genetic background for the response to therapy. We evaluated the relationship between the polymorphism of the HS1,2A enhancer, located in the 3' regulatory region of the heavy immunoglobulin chain (IgH), and the response to B cell depletion therapy (BCDT) with Rituximab (RTX). METHODS: Fifty rheumatoid arthritis (RA) patients (42 women; disease duration 13.9 ± 10.6 years) treated with RTX, not responsive to previous DMARDs and/or TNFα inhibitors therapies, and 220 healthy subjects were enrolled in the study. Patients were genotyped for HS1,2A enhancer polymorphism, as previously described. Disease activity was assessed every three months according to the European League Against Rheumatism's (EULAR) criteria. RESULTS: All RA patients were seropositive for at least one of the tested autoantibodies: rheumatoid factor (FR IgA, FR IgM e FR IgG), anti-cyclic citrullinated peptides (anti-CCP IgA, anti-CCP IgM e anti-CCP IgG) and anti-vimentin antibodies. RA patients had an increased frequency of the allele*2 (60.0%) of the HS1,2A enhancer compared to healthy subjects (42.0%; OR(95%ICs): 2.07 (1.33-3.22)). Patients with a good EULAR response at 6 months follow-up visit had an increased frequency of genotype 2/2 (47.1%) compared to poor-responders RA patients (genotype 2/2: 18.2%, OR(95%ICs): 4.00 (1.09-14.68)). All the patients with a good EULAR response had the allele*2, thus showing a possible association with the allele in this population. CONCLUSIONS: The presence of allele*2 seems to be related to a good response to BCDT with RTX in seropositive RA patients, thus highlighting the role of the HS1,2A enhancer in B cell maturation and class-switch recombination.
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Artrite Reumatoide/terapia , Genes de Imunoglobulinas , Cadeias Pesadas de Imunoglobulinas/genética , Depleção Linfocítica , Regiões 3' não Traduzidas/genética , Adulto , Idoso , Alelos , Anticorpos Monoclonais Murinos/uso terapêutico , Artrite Reumatoide/genética , Artrite Reumatoide/imunologia , Autoanticorpos/sangue , Autoantígenos/imunologia , Linfócitos B/efeitos dos fármacos , Sedimentação Sanguínea , Proteína C-Reativa/análise , Citrulina/imunologia , Feminino , Genótipo , Humanos , Imunoglobulinas/análise , Masculino , Pessoa de Meia-Idade , Fator Reumatoide/sangue , Rituximab , Inquéritos e Questionários , Resultado do TratamentoRESUMO
OBJECTIVE: To investigate the role of the HS1,2 enhancer polymorphisms as a new candidate marker for rheumatoid arthritis (RA) and to define the possible association with autoantibody positivity and clinical outcome. METHODS: Genomic DNA was obtained from two cohorts of patients with RA (100 with early RA (ERA) and 114 with longstanding RA (LSRA)) and from 248 gender-matched controls from the same geographical area. Clinical and immunological characteristics were recorded for all the patients. RESULTS: The percentage of the 2/2 genotype was higher in patients with ERA (27.0%), and in patients with LSRA (34.2%), than in controls (14.9%) (ERA: OR = 2.11 (95% CI 1.20 to 3.70) vs controls; LSRA: OR = 2.96 (95% CI 1.76 to 5.00) vs controls). A lower representation of allele *3 was present in patients with ERA (2.0%) than in controls (6.0%; OR = 0.32 (95% CI 0.11 to 0.91)). No significant associations were found between polymorphisms and autoantibodies positivity. CONCLUSION: The HS1,2A allele *2 associates with early and longstanding RA.
Assuntos
Alelos , Artrite Reumatoide/genética , Cadeias Pesadas de Imunoglobulinas/genética , Adulto , Idoso , Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/imunologia , Autoanticorpos/sangue , Estudos de Coortes , Elementos Facilitadores Genéticos , Feminino , Marcadores Genéticos , Predisposição Genética para Doença , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Sequências Reguladoras de Ácido Nucleico , Fator Reumatoide/sangue , Índice de Gravidade de Doença , Resultado do TratamentoRESUMO
OBJECTIVE: To evaluate the role of the single-nucleotide polymorphism (SNP) at position -670 in the FAS gene promoter (FAS-670G>A) in influencing the susceptibility, clinical features and severity of systemic sclerosis (SSc). METHODS: 350 white Italian SSc patients (259 with limited cutaneous SSc (lcSSc) and 91 with diffuse cutaneous SSc (dcSSc)) and 232 healthy individuals were studied. Patients were assessed for the presence of autoantibodies (anticentromere, anti-topoisomerase I (anti-Scl-70) antibodies), interstitial lung disease (ILD), pulmonary arterial hypertension and scleroderma renal crisis. FAS-670G>A SNP was genotyped by PCR restriction fragment length polymorphism assay. Serum levels of soluble FAS (sFAS) were analysed by ELISA. RESULTS: A significant difference in FAS-670 genotype distribution was observed between SSc patients and healthy individuals (p = 0.001). The frequency of the FAS-670A allele was significantly greater in SSc than in controls (p = 0.001). No significant difference in genotype distribution and allele frequencies was observed between lcSSc and dcSSc, although a greater frequency of the FAS-670A allele was found in dcSSc. The FAS-670AA genotype significantly influenced the predisposition to SSc (OR 1.97, 95% CI 1.35 to 2.88, p = 0.001) and to both lcSSc (OR 1.84, 95% CI 1.23 to 2.75, p = 0.003) and dcSSc (OR 2.37, 95% CI 1.41 to 3.99, p = 0.001). FAS-670A allele frequency was greater, although not significantly, in anti-Scl-70 antibody-positive dcSSc and ILD dcSSc. sFAS was significantly higher in patients and controls carrying the FAS-670AA genotype compared with those carrying the FAS-670GG genotype (p = 0.003 in SSc, p = 0.004 in controls). CONCLUSION: The FAS-670A allele is significantly associated with susceptibility to SSc, suggesting a role for a genetic control of apoptosis in the pathogenesis of the disease.
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Polimorfismo de Nucleotídeo Único , Regiões Promotoras Genéticas , Escleroderma Sistêmico/genética , Receptor fas/genética , Apoptose , Autoanticorpos/sangue , Estudos de Casos e Controles , Ensaio de Imunoadsorção Enzimática/métodos , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , Itália , Masculino , Pessoa de Meia-Idade , Polimorfismo de Fragmento de Restrição , Escleroderma Sistêmico/imunologia , Escleroderma Sistêmico/patologiaRESUMO
Rheumatoid arthritis is a chronic inflammatory disease characterized by synovial inflammation and pannus formation leading to destruction of cartilage and bone. Several self proteins have been suggested to be disease-driving autoantigens. Proteins are encoded by a limited number of genes in our genome. Post-translational modifications such as citrullination of the arginine residues, can increase the morphological and the functional diversity of the proteome. The positivity of anti-citrullinated peptides autoantibodies occurs then at an early stage of the disease development. Several factors, among which the synovial tissue inflammatory and the nitric oxide reaction, are involved in the regulation of the citrullination reaction. All of them have to be analysed and considered to understand the loss of tolerance and the development of autoimmunity leading to the disease.
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Arginina/metabolismo , Artrite Reumatoide/imunologia , Artrite Reumatoide/metabolismo , Citrulina/metabolismo , Artrite Reumatoide/genética , Humanos , Articulações/metabolismoRESUMO
OBJECTIVE: To investigate the relationship of the polymorphic enhancer HS1,2 central to the 3' enhancer complex regulatory region (IgH3'EC) of the immunoglobulin heavy chain genes with systemic sclerosis (SSc) disease and compare it with HLA-DR and DQ associations. METHODS: A total of 116 patients with SSc were classified as diffuse (dSSc) or limited (lSSc), and as carriers of antitopoisomerase I (anti-Scl70) or anticentromere (ACA) antibodies. Allele and genotype frequencies were assessed in the population as a whole and in the two major subsets, dSSc and lSSc. The concentration of peripheral blood immunoglobulin levels was also determined and analysed according to the genotypes. RESULTS: The analysis of genotypes for the four alleles of the HS1,2A enhancer showed an increased frequency of allele *2 in the SSc cohort highly significant versus controls (57% vs. 40%, p<0.0001). Considering the autoantibody pattern, we found that the frequency of the 2/2 genotype was increased in ACA+ patients (42%) and anti-Scl70+ patients (31%) compared with the control group (15%). The differences of allelic frequencies among dSSc versus lSSc or ACA+ versus anti-Scl70+ patients were not significant, although highly significant when comparing each subgroup with the control group. HLA-DRB1*11 and DQB1*03 associated with SSc. No association was seen between HS1,2A enhancer polymorphism and HLA alleles. CONCLUSIONS: These data confirm there was an increased risk of having SSc in carriers of allele *2, suggesting an intriguing function of this polymorphism for B-cell regulation.
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Elementos Facilitadores Genéticos , Cadeias Pesadas de Imunoglobulinas/genética , Polimorfismo Genético , Escleroderma Sistêmico/imunologia , Adulto , Idoso , Autoanticorpos/sangue , Esôfago/patologia , Feminino , Frequência do Gene , Predisposição Genética para Doença , Genótipo , Antígenos HLA-DQ , Antígenos HLA-DR , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Escleroderma Sistêmico/genética , Escleroderma Sistêmico/patologia , Estatísticas não Paramétricas , Estômago/patologiaRESUMO
Preliminary pharmacogenetic data suggest that germline genetic informations might be of value in individualizing disease-modifying antirheumatic drugs (DMARDs) therapy in various autoimmune chronic inflammatory diseases. Either DMARDs small molecules (DMARDs-SM) or DMARDs biological therapies (DMARDs-BT) might be selected for their lower toxicity or better efficacy based on single-nucleotide polymorphisms (SNPs) of genes governing the metabolism of drugs, or the response of immune cells to proinflammatory molecules, or the proinflammatory molecular activity of immune cells. Data available for one DMARDs-SM, methotrexate, suggest that a careful assessment of the SNPs of four enzymes involved in the folate metabolism allow one to construct a genetic index of toxicity (toxicogenetic index) that might be employed in daily practice to find the patient's most at risk. Only the full knowledge of the various gene polymorphisms controlling the phenotypic manifestations of the inflammatory-immunological milieu of each rheumatic disease will allow one to obtain the clear definition of a personalized medicine. Few different cytokine gene SNPs seem to be of importance in determining the susceptibility to diseases, or the aggressiveness of diseases. The role of genetics in affecting a possible clinical response to DMARDs-BT targeting specific inflammatory molecules or their receptors still has to be defined. However, the available data suggest that cytokine (and/or receptors) gene SNPs might indeed play a role in determining the biological effects, hence the clinical effectiveness of DMARDs-BT. Crucial to this aim will be the prospective analysis of clinical benefits and safety on the basis of the at baseline stratification of gene SNPs in each chronic inflammatory rheumatic disease before starting any new DMARDs-SM or DMARDs-BT.
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Antirreumáticos/uso terapêutico , Farmacogenética , Doenças Reumáticas/tratamento farmacológico , Doenças Reumáticas/genética , Animais , Antirreumáticos/farmacologia , Citocinas/genética , Citocinas/metabolismo , HumanosRESUMO
OBJECTIVE: To assess the relationship between tumor necrosis factor receptor II (TNF-RII) gene polymorphisms and sTNFRII plasma levels in healthy blood donors (HBDs) and in rheumatoid arthritis (RA) patients. 113 HBDs and 49 RA patients were genotyped for the T/G polymorphism in exon 6 of the TNF-RII gene. In the same cases, sTNF-RII plasma levels were determined by an enzyme-linked immunosorbent assay (ELISA) procedure. sTNF-RII levels were higher in RA patients than in HBDs (p < 0.0001). No difference in sTNF-RII levels arose between RA patients on low oral doses of glucocorticoids versus those not taking glucocorticoids. In healthy controls, we observed lower levels of the sTNF-RII in carriers of the TT genotype compared to TG/GG genotype (p = 0.04). In RA there was the same behaviour between TT and TG/GG carriers, even though the difference was not statistically significant. When analyzing the correlation between sTNF-RII plasma levels and disease activity parameters, significant correlations were seen with disease activity score (r = 0.40, p = 0.01), swollen joint count (r = 0.38, p = 0.01), and tender joint count (r = 0.42, p = 0.01), but not with erythrocyte sedimentation rate (r = 0.22, p = ns) nor with C-reactive protein (r = 0.14, p = NS). The correlation remained significant only in the RA subgroup carrying the TT genotype. Healthy donors carrying the TT genotype showed lower sTNF-RII plasma levels than carriers of the TG/GG genotypes, while in RA patients we observed only a trend.
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Artrite Reumatoide/genética , Artrite Reumatoide/imunologia , Receptores Tipo II do Fator de Necrose Tumoral/sangue , Receptores Tipo II do Fator de Necrose Tumoral/genética , Adolescente , Adulto , Idoso , Artrite Reumatoide/sangue , Estudos de Casos e Controles , Éxons , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo Genético , SolubilidadeRESUMO
OBJECTIVE: Given the role of TNF-alpha in Rheumatoid Arthritis (RA) we decided to define the characteristics of the TNF-alpha synthesis by peripheral blood mononuclear cells (PBMNCs) obtained from active-aggressive RA patients giving a particular attention to the modulation of the expression of two fundamental proteins in TNF-alpha mRNA stability regulation, Tristetraprolin (TTP) and HuR. METHODS: 11 RA patients with active disease were enrolled in the study before their entry in 2 double blind protocols: Infliximab versus MTX and Etanercept versus MTX. 9 healthy blood donors were taken as controls. PBMNCs obtained by Ficoll centrifugation and plastic adherence were stimulated with lipopolysaccharide (LPS) and TNF-alpha was measured in the supernatant during 8 hours by ELISA. At each time point the cells were harvested and analysed for TNF-alpha, TTP and HuR mRNA expression by semi-quantitative PCR. RESULTS: MNCs TNF-alpha secretion after LPS stimulation did not differ significantly between RA and control subjects, even if a tendency towards a more prompt response was observed in the patients. More importantly only the DMARDs responsive patients (DAS < 3.7 at the 6th month, with a minimal reduction of 1.2 points) disclosed precociously (at the first month) a significant change in the profile of TNF-alpha secretion and maintained it until the 6th month. The "normalization" of the synthetic behaviour was accompanied by the resetting in the regulation of the expression of the TTP, that appeared significantly different in the patients before and after therapy. CONCLUSIONS: Independently from the type of therapy, responsive patients demonstrate a rapid change in the cellular biology at the systemic level that might drive the resolution of the inflammatory process at the synovial level.
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Antígenos de Superfície/genética , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/metabolismo , Proteínas de Ligação a DNA/genética , Proteínas Imediatamente Precoces/genética , Proteínas de Ligação a RNA/genética , Fator de Necrose Tumoral alfa/biossíntese , Idoso , Animais , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/uso terapêutico , Antirreumáticos/administração & dosagem , Antirreumáticos/uso terapêutico , Artrite Reumatoide/sangue , Artrite Reumatoide/genética , Células Cultivadas , Intervalos de Confiança , Densitometria , Método Duplo-Cego , Proteínas ELAV , Proteína Semelhante a ELAV 1 , Eletroforese em Gel de Ágar , Ensaio de Imunoadsorção Enzimática , Etanercepte , Feminino , Seguimentos , Expressão Gênica , Humanos , Imunoglobulina G/administração & dosagem , Imunoglobulina G/uso terapêutico , Infliximab , Cinética , Lipopolissacarídeos/farmacologia , Masculino , Metotrexato/administração & dosagem , Metotrexato/uso terapêutico , Camundongos , Camundongos Knockout , Pessoa de Meia-Idade , RNA Mensageiro/análise , Receptores do Fator de Necrose Tumoral/administração & dosagem , Receptores do Fator de Necrose Tumoral/uso terapêutico , Estatísticas não Paramétricas , Fatores de Tempo , Tristetraprolina , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismoAssuntos
Lúpus Eritematoso Sistêmico/genética , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/genética , Polimorfismo Genético , Adulto , Alelos , Estudos de Coortes , Predisposição Genética para Doença , Humanos , Lúpus Eritematoso Sistêmico/complicações , Pessoa de Meia-Idade , Doença de Raynaud/etiologia , Doença de Raynaud/genéticaAssuntos
Adjuvantes Imunológicos/farmacologia , Artrite Reumatoide/imunologia , Lipopolissacarídeos/farmacologia , Monócitos/efeitos dos fármacos , Oligodesoxirribonucleotídeos/farmacologia , Adolescente , Sequência de Bases , Criança , DNA Bacteriano/imunologia , Humanos , Salmonella typhimurium , Fator de Necrose Tumoral alfa/análiseRESUMO
The detrimental effect of chronic administration of carbamazepine (CBZ) on serum and erythrocyte folates of patients has been extensively analyzed. However, at present, no data have been reported on the effect of CBZ on the intracellular content and activity of antimetabolite cytotoxic agents that can be used together with CBZ in the treatment of cancer patients. To investigate this issue, we chronically exposed in vitro the human ovarian cancer cell line SKOV-3 (grown under physiological folate concentrations) to CBZ, thus selecting SKOV-CBZ clones (SKOV-CBZ-50-2, SKOV-CBZ-50-5 and SKOV-CBZ-100-2) able to grow in the continuous presence of the antiepileptic drug. All of the SKOV-CBZ clones were more resistant to methotrexate (MTX) than the parental cells. MTX resistance index, as determined by the ratio between MTX concentrations inhibiting cell growth by 50% (MTX IC(50)) in SKOV-CBZ clones and in the parental cells, ranged between 3- and 5-fold. This resistance was related to a reduced intracellular content of MTX. No alteration activity of the cellular enzymes directly involved in MTX cytotoxicity (dihydrofolate reductase, thymidylate synthase [TS] and folylpolyglutamate synthetase) was observed. SKOV-CBZ clones were cross-resistant to the TS inhibitors tomudex and CB3717, but not to the TS inhibitor 5-fluoro-deoxy uridine and other antineoplastic drugs (cisplatin, doxorubicin, vincristine and taxol), whose cellular uptake is derived from transmembrane transport mechanisms different from folate receptor alpha (FRalpha) or reduced folate carrier (RFC). FRalpha mRNA and protein levels were significantly lower in SKOV-CBZ clones than in the parental cells. The reduced level of FRalpha in SKOV-CBZ clones was associated with a decreased binding capacity of folic acid. No variation of mRNA RFC expression in the SKOV-CBZ clones as compared to the parental cells was observed. Thus, after chronic exposure to CBZ, SKOV-CBZ clones develop resistance towards MTX due to defective MTX uptake.