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1.
Mult Scler ; 21(1): 48-56, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24866201

RESUMO

BACKGROUND: Natalizumab is approved for treatment of active forms of relapsing-remitting multiple sclerosis (MS) based on a pivotal phase III study comprising patients aged 18-50 years. The effect of natalizumab has not been specifically studied in older patients. OBJECTIVE: We analyzed age-dependent effects on treatment-related outcome measures in 1872 patients, 189 of whom were aged 50 or more, included in the Swedish post-marketing natalizumab surveillance program. METHODS: In three MS centers registry data for patients aged >50 years were validated. RESULTS: At baseline older patients had longer disease duration, higher Expanded Disability Status Scale (EDSS) and lower Symbol Digit Modality Test (SDMT) scores than younger patients. The influence from natalizumab on outcome measures was significantly reduced and 18.7% of patients >50 years stopped treatment for lack of effect compared to 7.7% in the younger age group. At baseline, the cerebrospinal fluid levels of the chemokine CXCL13 and the leukocyte cell count were negatively correlated with age in a smaller subgroup of patients. CONCLUSION: These results were in agreement with previous findings suggesting that inflammation is more pronounced in younger patients and therefore the beneficial effects of potent anti-inflammatory treatments are subsiding with older ages.


Assuntos
Anticorpos Monoclonais Humanizados/farmacologia , Esclerose Múltipla/tratamento farmacológico , Avaliação de Resultados em Cuidados de Saúde , Sistema de Registros , Adulto , Fatores Etários , Anticorpos Monoclonais Humanizados/administração & dosagem , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/líquido cefalorraquidiano , Natalizumab , Adulto Jovem
2.
Neurology ; 83(23): 2153-7, 2014 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-25361781

RESUMO

OBJECTIVE: To assess whether pretreatment-lymphocyte counts, treatment before fingolimod, age, sex, or body mass index (BMI) affects the risk of fingolimod-induced lymphopenia in patients with relapsing-remitting multiple sclerosis (RRMS). METHODS: Data were obtained from a German multicenter, single-arm, open-label study of patients with RRMS treated with fingolimod, and findings were validated in an independent Swedish national pharmacovigilance study. RESULTS: Four hundred eighteen patients with RRMS from Germany and 438 patients from Sweden were included. A nadir ≤0.2 × 10(9) lymphocytes/L was reached in 15% (95% confidence interval [CI] 12%-17%) of all 856 patients. Patients with lower starting lymphocyte counts (below 1.6 × 10(9)/L) and patients with BMI lower than 18.5 kg/m(2) (women only) were at higher risk of developing lymphopenia with values ≤0.2 × 10(9)/L in the combined analysis, increasing the risk in these subgroups to 26% (95% CI 20%-31%) or 46% (95% CI 23%-71%), respectively. In the German cohort, infection rates were similar in patients who developed severe lymphopenia and those who did not. CONCLUSIONS: Our findings suggest that patients with low baseline lymphocyte counts and underweight women in which fingolimod treatment will be initiated should possibly be monitored more closely.


Assuntos
Índice de Massa Corporal , Imunossupressores/efeitos adversos , Linfopenia/induzido quimicamente , Esclerose Múltipla/tratamento farmacológico , Propilenoglicóis/efeitos adversos , Esfingosina/análogos & derivados , Adulto , Idoso , Estudos de Coortes , Feminino , Cloridrato de Fingolimode , Humanos , Imunossupressores/uso terapêutico , Contagem de Linfócitos , Pessoa de Meia-Idade , Propilenoglicóis/uso terapêutico , Esfingosina/efeitos adversos , Esfingosina/uso terapêutico
3.
J Neurol Neurosurg Psychiatry ; 84(11): 1199-205, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-23463870

RESUMO

BACKGROUND: The anti-JC virus (JCV) antibody status has been introduced to stratify patients with multiple sclerosis (MS) for higher or lower risk of progressive multifocal leukoencephalopathy (PML). OBJECTIVE: To assess the potential utility of anti-JCV antibody levels for earlier diagnosis or prediction of PML. METHODS: An analytically validated antibody assay was used to determine serological status, normalised optical density values, and dilution titres for anti-JCV antibodies. The method was applied to stored sera of 1157 patients with MS including five cases of PML, all enrolled in the Swedish pharmacovigilance study for natalizumab (NAT). Anticytomegalovirus (CMV) and antivaricella-zoster (VZV) antibody levels served as controls. RESULTS: Prior to treatment with NAT, anti-JCV antibody levels were stable in the anti-JCV positive patients. During therapy, a slight decrease in anti-JCV and anti-VZV antibody levels, but not anti-CMV antibody levels, was observed. All five patients who developed PML showed a mild to moderate increase in anti-JCV antibody levels at time of PML diagnosis; pre-PML samples suggested that this increase might start already prior to diagnosis of PML. CONCLUSIONS: Treatment initiation with NAT may lead to a slight decrease in anti-JCV and anti-VZV antibody levels, suggestive of a mild suppressive effect of NAT on antibody levels. Our findings in five cases of PML demonstrate that the onset of PML can be accompanied by increasing anti-JCV antibodies in serum. Monitoring of anti-JCV antibody levels could potentially be used as a tool for prediction or earlier diagnosis of PML during NAT treatment for MS. Further studies are warranted.


Assuntos
Anticorpos Antivirais/sangue , Vírus JC/imunologia , Leucoencefalopatia Multifocal Progressiva/diagnóstico , Leucoencefalopatia Multifocal Progressiva/virologia , Esclerose Múltipla/diagnóstico , Esclerose Múltipla/virologia , Adulto , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/uso terapêutico , Citomegalovirus/imunologia , Diagnóstico Precoce , Feminino , Herpesvirus Humano 3/imunologia , Humanos , Interferons/uso terapêutico , Leucoencefalopatia Multifocal Progressiva/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/imunologia , Natalizumab , Farmacovigilância , Vigilância de Produtos Comercializados , Fatores de Risco
4.
Mult Scler ; 17(6): 708-19, 2011 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-21228027

RESUMO

BACKGROUND: A post marketing surveillance study was conducted to evaluate safety and efficacy of natalizumab in Swedish multiple sclerosis (MS) patients since its introduction in August 2006 until March 2010. METHODS: Patients were registered in the web-based Swedish MS-registry at 40 locations and evaluated every 6 months. Adverse events and clinical outcomes were recorded. RESULTS: One thousand one hundred and fifty-two patients were included (71.4% female) and 149 patients stopped treatment; the main reason was planned pregnancy. Anti-natalizumab antibodies were found in 4.5% (52 patients) of which 1.6% displayed persistent antibodies. Serious adverse events were rare, but included three cases with progressive multifocal leukoencephalopathy (PML). There were seven fatal cases, probably unrelated to the natalizumab treatment. For relapsing-remitting MS patients (n=901), mean Expanded Disability Status Scale (EDSS, -10.7%), Multiple Sclerosis Severity Scale (MSSS, -20.4%), Multiple Sclerosis Impact Scale (MSIS-29, physical -9.9%, psychological -13.3%) and Symbol Digit Modalities Test (SDMT, +10.7%) all showed significant improvements during 24 months of treatment with natalizumab. The Swedish web-based MS quality registry proved to function as a platform for post-marketing MS drug surveillance, providing long-term data regarding drug effects and adverse events beyond clinical trials. CONCLUSIONS: Our results indicate that natalizumab is generally well tolerated and has sustained efficacy for patients with active MS, though the risk of PML is still an important concern.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Fatores Imunológicos/uso terapêutico , Esclerose Múltipla Crônica Progressiva/tratamento farmacológico , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Adolescente , Adulto , Idoso , Análise de Variância , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais Humanizados , Avaliação da Deficiência , Feminino , Humanos , Fatores Imunológicos/efeitos adversos , Leucoencefalopatia Multifocal Progressiva/induzido quimicamente , Leucoencefalopatia Multifocal Progressiva/mortalidade , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla Crônica Progressiva/diagnóstico , Esclerose Múltipla Crônica Progressiva/mortalidade , Esclerose Múltipla Recidivante-Remitente/diagnóstico , Esclerose Múltipla Recidivante-Remitente/mortalidade , Natalizumab , Testes Neuropsicológicos , Vigilância de Produtos Comercializados , Sistema de Registros , Índice de Gravidade de Doença , Suécia/epidemiologia , Fatores de Tempo , Resultado do Tratamento , Adulto Jovem
5.
J Am Soc Nephrol ; 18(9): 2497-508, 2007 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-17699811

RESUMO

The pathogenic role of anti-endothelial cell antibodies (AECA) in vascular injury is debated. It was previously shown that many patients with Wegener's granulomatosis (WG) have AECA that react with human kidney microvascular endothelial cells (EC). In addition, during active disease, renal endothelium strongly expresses the inflammatory molecules vascular adhesion protein-1 (VAP-1) and MHC class I-related antigen A (MICA). This study sought to determine whether AECA mediates this upregulation of VAP-1 and MICA and to define better the signaling pathways that are activated by these autoantibodies upon binding to EC in the kidney. Stimulation of human kidney microvascular EC with AECA IgG upregulated surface expression of MICA and VAP-1, elicited a rapid Ca2+ flux, induced high levels of the chemokines monocyte chemoattractant protein-1 and granulocyte chemotactic protein-2, induced specific phosphorylation of stress-activated protein kinase (SAPK)/c-Jun N-terminal kinase (JNK) and the transcription factors c-Jun and activating transcription factor-2, and activated NF-kappaB. Specific inhibitors of SAPK/JNK significantly reduced AECA-induced chemokine production and phosphorylation of c-Jun and activating transcription factor-2 and abrogated protein expression of MICA but not VAP-1. In kidney sections from patients with WG, infiltrating cells that expressed the ligand for MICA (NKG2D+) were identified, as were CD8+ and 32 gamma delta+ T cells. In conclusion, AECA may be involved in the pathogenesis of WG, and the SAPK/JNK pathway and the endothelial inflammatory protein VAP-1 may be novel therapeutic targets for vasculitis.


Assuntos
Autoanticorpos/metabolismo , Células Endoteliais/imunologia , Granulomatose com Poliangiite/metabolismo , Sistema de Sinalização das MAP Quinases , Idoso , Idoso de 80 Anos ou mais , Amina Oxidase (contendo Cobre)/metabolismo , Antígenos/imunologia , Autoanticorpos/imunologia , Moléculas de Adesão Celular/metabolismo , Células Cultivadas , Quimiocinas/metabolismo , Ativação Enzimática/efeitos dos fármacos , Feminino , Granulomatose com Poliangiite/imunologia , Antígenos de Histocompatibilidade Classe I/metabolismo , Humanos , Imunoglobulina G/química , Imunoglobulina G/imunologia , Imunoglobulina G/farmacologia , Proteínas Quinases JNK Ativadas por Mitógeno/antagonistas & inibidores , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Rim/irrigação sanguínea , Rim/metabolismo , Masculino , Microcirculação , Pessoa de Meia-Idade , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Mieloblastina/deficiência , Regulação para Cima
6.
Blood Purif ; 24(2): 196-202, 2006.
Artigo em Inglês | MEDLINE | ID: mdl-16373998

RESUMO

BACKGROUND: Patients with chronic kidney disease (CKD) display endothelial dysfunction and are at a high risk for atherosclerotic cardiovascular disease (CVD). Recent studies suggest that circulating detached endothelial cells (CECs) and stimulated endothelial progenitor cells (EPCs) from the bone marrow may reflect endothelial damage. METHODS: We correlated the levels of CECs expressing the endothelial cell inflammation marker (MICA+ cells) and EPCs (Tie-2+ or VEGFR-2+ cells) in a population of 19 (55 +/- 3 years; 42% males) patients with advanced CKD (median glomerular filtration rate 8 ml/min). In addition, the levels of CD-31+ cells were investigated. Twenty healthy age- (49 +/- 2 years) and gender- (50% men) matched subjects served as controls. RESULTS: CECs expressing MICA were increased (7.6 +/- 2.7 vs. 1.6 +/- 0.3%; p < 0.05) in CKD patients, however EPCs expressing Tie-2 or VEGFR-2 were significantly decreased (0.16 +/- 0.07 vs. 0.53 +/- 0.15%; p < 0.05, and 0.42 +/- 0.10 vs. 2.80 +/- 0.72%; p < 0.01, respectively) as compared to controls. Furthermore, we also found that the levels of CD-31+ cells were significantly elevated (22.8 +/- 4.2 vs. 9.4 +/- 0.8%; p < 0.01) in CKD patients. Patients on angiotensin-converting enzyme (ACE) inhibitors tended (p = 0.06) to have higher levels of VEGFR-2+ cells (0.57 +/- 0.14 vs. 0.16 +/- 0.11%). CONCLUSION: Our results suggest that there is a marked imbalance between the CEC and EPC numbers in patients with CKD. Further research is needed to evaluate the independent role of inflammatory endothelial markers as well as the effects of ACE inhibitors on mobilization of EPCs in patients with advanced CKD.


Assuntos
Células Endoteliais/patologia , Falência Renal Crônica/fisiopatologia , Células-Tronco/patologia , Contagem de Células , Feminino , Antígenos de Histocompatibilidade Classe I/metabolismo , Humanos , Falência Renal Crônica/patologia , Masculino , Pessoa de Meia-Idade , Molécula-1 de Adesão Celular Endotelial a Plaquetas/metabolismo , Receptor TIE-2/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo
7.
J Am Soc Nephrol ; 16(10): 3110-20, 2005 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-16107582

RESUMO

Impaired angiogenic function has been reported in patients with kidney failure. During vascular damage, endothelial cells may detach from the site of inflammation and be released into the peripheral blood. With the use of Wegener's granulomatosis as a study model, whether circulating inflammatory endothelial cells (IEC) can (1) be used as a disease activity marker and (2) contribute to sustained vascular damage by inducing endothelial progenitor cell (EPC) dysfunction were examined. IEC-defined as endothelial cells that express the two inflammatory-associated markers vascular-adhesion protein-1 (VAP-1) and MHC class I-related chain A (MICA)-were increased significantly in patients with active disease as compared with those in remission. IEC expressed high levels of inducible nitric oxide synthase and neutrophil-activating chemokines, such as macrophage inflammatory protein-1alpha, growth-related oncogene-alpha, epithelial neutrophil activating peptide-78, and IL-8, and induced increased neutrophil migration. IEC levels significantly correlated with C-reactive protein and extent of organ involvement. Patients with active disease had decreased numbers of EPC colony-forming units and a high expression of VAP-1 and MICA in kidney endothelium. EPC did not express VAP-1 or MICA. IEC significantly inhibited proliferation, migration, and endothelial nitric oxide synthase expression in EPC. Thus, apart from being a new disease activity marker, IEC may contribute to vascular damage by impairing the functional capacity for repair by EPC. IEC may provide a unique in vitro system to study pathogenesis of kidney and vascular diseases.


Assuntos
Células Endoteliais , Granulomatose com Poliangiite/sangue , Granulomatose com Poliangiite/imunologia , Células-Tronco , Vasculite/sangue , Vasculite/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Amina Oxidase (contendo Cobre)/biossíntese , Moléculas de Adesão Celular/biossíntese , Células Endoteliais/metabolismo , Feminino , Antígenos de Histocompatibilidade Classe I/biossíntese , Humanos , Masculino , Pessoa de Meia-Idade , Sialoglicoproteínas/biossíntese , Células-Tronco/metabolismo
8.
Am J Respir Cell Mol Biol ; 32(1): 18-27, 2005 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-15498963

RESUMO

The vast heterogeneity of endothelial cells (EC) in various organs necessitates isolation of EC from the relevant organs when defining mechanisms of site-specific pathologies. We report a novel finding that describes the presence of two heterogeneous populations of human nasal microvascular EC isolated from the inferior turbinate. Light and electron microscopy, flow cytometric analysis, and immunocytochemistry analysis demonstrated that one EC population exhibited the classic vascular endothelial markers with cobblestone-like morphology, whereas the other was sinusoidal with fusiform morphology. The sinusoidal EC (SEC) lacked surface expression of the endothelial markers CD31 and E-selectin, were discontinuous, showed fenestrae and pinocytic vesicles, and did not form tight junctions. Gene expression analysis using microarray revealed significant but limited heterogeneity between the two cell types. Immunohistochemical staining of normal nasal biopsies confirmed the presence of two distinct populations of EC. We found that CD31 was exclusively expressed on vascular EC (VEC), whereas the molecule L-SIGN was mainly expressed on SEC. Both cell types formed capillary-like tubules in matrigel in vitro. The two heterogeneous EC populations provide a unique in vitro system to study the biology of nasal VEC and SEC in normal conditions and in inflammatory processes in various nasal disorders.


Assuntos
Moléculas de Adesão Celular/metabolismo , Selectina E/metabolismo , Células Endoteliais/citologia , Lectinas Tipo C/metabolismo , Molécula-1 de Adesão Celular Endotelial a Plaquetas/metabolismo , Receptores de Superfície Celular/metabolismo , Junções Íntimas/ultraestrutura , Células Cultivadas , Células Endoteliais/metabolismo , Perfilação da Expressão Gênica , Humanos , Microscopia Eletrônica de Transmissão , Mucosa Nasal/metabolismo , Nariz/citologia , Conchas Nasais/citologia , Conchas Nasais/metabolismo , Molécula 1 de Adesão de Célula Vascular/metabolismo
9.
Circulation ; 110(24): 3699-707, 2004 Dec 14.
Artigo em Inglês | MEDLINE | ID: mdl-15381639

RESUMO

BACKGROUND: Receptor tyrosine kinases that include vascular endothelial growth factor (VEGFR)-1, VEGFR-2, and Tie-2 regulate cardiovascular development and physiological and pathological angiogenesis. We were interested in the phenotypic and functional characterization of peripheral blood cells expressing these receptors and their therapeutic potential in vascular injury. METHODS AND RESULTS: VEGFR-1+, VEGFR-2+, and Tie-2+ cells constituted approximately 3.0+/-0.2%, 0.8+/-0.5%, and 2.0+/-0.3%, respectively, of the total population of mononuclear cells in blood. Phenotypic analysis demonstrated that all 3 cell populations mainly expressed markers of monocytic/macrophage lineage. Only VEGFR-2+ and Tie-2+ cells phenotypically, morphologically, and functionally differentiated to endothelial cells after culture, whereas VEGFR-1+ cells did not. None of the cell types proliferated in vitro. Only freshly isolated VEGFR-2+ or Tie-2+ cells but not VEGFR-2- or Tie-2- cell populations significantly contributed to efficient endothelialization of balloon-injured femoral arteries of nude mice. Furthermore, these cells also differentiated into -actin-positive smooth muscle cells. Administration of bromodeoxyuridine to animals transplanted with human endothelial progenitor cells showed that VEGFR-2+ and Tie-2+ cells proliferated in vivo. CONCLUSIONS: These data demonstrate that expression of VEGFR-2 and/or Tie-2 on peripheral blood cells defines functionally competent cell populations that proliferate in vivo and that contribute to reendothelialization. These findings may have implications for a cell-based approach in vascular diseases.


Assuntos
Endotélio Vascular/citologia , Leucócitos Mononucleares/metabolismo , Receptor TIE-2/biossíntese , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/biossíntese , Angioplastia com Balão/efeitos adversos , Animais , Biomarcadores/análise , Proliferação de Células , Quimiotaxia de Leucócito , Células Endoteliais/citologia , Células Endoteliais/metabolismo , Células Endoteliais/transplante , Artéria Femoral/citologia , Humanos , Técnicas In Vitro , Leucócitos Mononucleares/citologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Nus , Monócitos/citologia , Monócitos/metabolismo , Fenótipo , Molécula-1 de Adesão Celular Endotelial a Plaquetas/biossíntese , Receptor TIE-2/sangue , Transplante de Células-Tronco , Túnica Íntima/citologia , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/biossíntese , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/sangue , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/sangue
10.
Kidney Int ; 66(3): 1049-60, 2004 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-15327398

RESUMO

BACKGROUND: Antiendothelial cell antibodies (AECA), usually detected using human umbilical vein endothelial cells (HUVEC), are frequently observed in systemic vasculitis, but their pathogenic role is unclear. Heterogeneity of endothelial cells necessitates use of clinically relevant endothelial cells for elucidation of the role of AECA in systemic vasculitis involving small blood vessels of specific organs. METHODS: Human endothelial cells were isolated from normal tissue specimens from the nose, kidney, lung, liver, and umbilical vein. Using flow cytometry, AECA were detected against both unstimulated and cytokine-stimulated [tumor necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma)] endothelial cells. Functional capacity of AECA was determined by complement fixation assay. Sera from patients with Wegener's granulomatosis (16), limited Wegener's granulomatosis (8), renal limited disease (4), microscopic polyangiitis (MPA) (5), rheumatoid arthritis (10), and systemic lupus erythematosus (SLE) (9), and from healthy controls (20) were analyzed. RESULTS: Compared with controls (1) Wegener's granulomatosis is significantly associated with noncytotoxic AECA that selectively bind surface antigens on unstimulated nasal, kidney, and lung endothelial cells; (2) binding of Wegener's granulomatosis AECA to kidney and nasal endothelial cells in particular was lost upon treatment with IFN-gamma and TNF-alpha; (3) the two cytokines per se were cytotoxic (30%) to nasal and lung endothelial cells and lysis was further increased (60%) by addition of systemic vasculitis serum; and (4) Wegener's granulomatosis serum caused agglutination of cytokine-stimulated nasal endothelial cells. CONCLUSION: Based on these findings we suggest that AECA may be one factor involved in the initiation of Wegener's granulomatosis. Antigen identification and elucidation of the pathogenic roles of AECA and inflammatory cytokines in systemic vasculitis using these cells will be particularly important.


Assuntos
Autoanticorpos/imunologia , Células Endoteliais/imunologia , Endotélio Vascular/imunologia , Granulomatose com Poliangiite/imunologia , Testes de Fixação de Complemento , Células Endoteliais/efeitos dos fármacos , Endotélio Vascular/citologia , Humanos , Imunofenotipagem , Interferon gama/farmacologia , Rim/citologia , Rim/imunologia , Pulmão/citologia , Pulmão/imunologia , Nariz/citologia , Nariz/imunologia , Especificidade de Órgãos , Fator de Necrose Tumoral alfa/farmacologia , Veias Umbilicais/citologia
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