RESUMO
BACKGROUND: Sparse published data exist on outcomes in daclizumab-treated cardiac transplant patients. One trial observed an increased mortality risk 6 and 12 months posttransplant in patients receiving daclizumab plus mycophenolate mofetil (MMF), cyclosporine, and steroids. This study further investigates the safety profile of daclizumab with this same immunosuppressive regimen from a large registry. METHODS: Data obtained at hospital discharge on all adult cardiac transplants performed in the USA between January 1998 and October 2003 for patients receiving MMF plus cyclosporine and steroids were accessed from the Scientific Registry of Transplant Recipients. Patients were selected based on induction treatment: daclizumab (n = 684) or no induction (n = 2525). Outcomes were evaluated at 6 months, 12 months, and 3 years posttransplant. Univariate Kaplan-Meier and multivariate Cox models were used to evaluate the effect of treatment on outcomes. Patient survival and infectious death were the primary endpoints. Secondary endpoints included rejection within the first year posttransplant (acute rejection; AR) and total rejection episodes over time. The two treatment groups shared similar demographics and transplant procedure details. RESULTS: Daclizumab (vs no induction) patients had no increased risk of patient death nor infectious death. Daclizumab patients had a lower incidence of AR at 6 months (P = .005) and 12 months (P < .001); the adjusted risk for AR at 12 months (hazards ratio [HR] = 0.77; P = .89) and over 3 years (HR 0.83, P = .006) was also lower in daclizumab-treated patients. CONCLUSIONS: In cardiac transplant patients, daclizumab (vs no induction) does not result in increased mortality or infectious death, and is associated with a lower incidence of AR.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Rejeição de Enxerto/prevenção & controle , Transplante de Coração/imunologia , Imunoglobulina G/uso terapêutico , Imunossupressores/uso terapêutico , Adulto , Anticorpos Monoclonais Humanizados , Daclizumabe , Quimioterapia Combinada , Feminino , Rejeição de Enxerto/epidemiologia , Transplante de Coração/mortalidade , Humanos , Incidência , Infecções/epidemiologia , Infecções/mortalidade , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Complicações Pós-Operatórias/classificação , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/mortalidade , Sistema de Registros , Análise de Sobrevida , Fatores de Tempo , Estados UnidosRESUMO
Mycophenolate mofetil (MMF) used in a triple-drug regimen has been shown to decrease acute rejection rates, compared to a double-drug regimen. The impact of MMF on late acute rejection (LAR) episodes has not been well described. To investigate the risk of LAR (rejection > or = 6 months post-transplantation) data from the Scientific Registry of Transplant Recipients (SRTR) were used. We studied adult primary liver transplant recipients transplanted between June 1, 1995, and April 30, 2004, with hepatitis C virus (HCV) (n = 3356), hepatitis B virus (HBV) (n = 550) or a nonviral (n = 5740) primary cause of liver disease who were recorded as receiving continuous 3-(MMF + Tacro + steroids) versus 2-drug (Tacro + steroids) therapy for at least 6 months immediately post transplantation. Kaplan-Meier analysis showed significantly lower LAR rates 4 years post-transplant in 3- versus 2-drug HCV, HBV and nonviral disease patients. Multivariate regression confirmed 3- versus 2-drug therapy to be associated with a decreased risk of LAR. Late graft survival was significantly lower at 4 years post-transplant for patients with LAR 6-12 months post-transplantation versus patients with early rejection (78.0% vs. 87.0%, p < 0.001) and no rejection (88.1%, p < 0.001). Three-drug versus 2-drug therapy for a minimum of 6 months may offer a better treatment strategy to avoid the consequences and expense of LAR episodes.
Assuntos
Rejeição de Enxerto/patologia , Rejeição de Enxerto/prevenção & controle , Transplante de Fígado , Ácido Micofenólico/análogos & derivados , Doença Aguda , Adolescente , Adulto , Idoso , Feminino , Seguimentos , Rejeição de Enxerto/imunologia , Hepacivirus/efeitos dos fármacos , Hepacivirus/fisiologia , Hepatite B/tratamento farmacológico , Hepatite B/imunologia , Hepatite B/cirurgia , Hepatite B/virologia , Vírus da Hepatite B/efeitos dos fármacos , Vírus da Hepatite B/fisiologia , Hepatite C/tratamento farmacológico , Hepatite C/imunologia , Hepatite C/cirurgia , Hepatite C/virologia , Humanos , Transplante de Fígado/imunologia , Masculino , Pessoa de Meia-Idade , Ácido Micofenólico/farmacologia , Fatores de Risco , Fatores de TempoRESUMO
Immunosuppression is often incriminated for the increased risk of post-transplant malignancies. To examine whether triple- (MMF+Tacro+CS) versus dual-drug therapy (Tacro+CS) is associated with an increased incidence of malignancy, or death due to malignancy, data from a large registry of liver transplant recipients were analyzed. Data from adult primary liver recipients reported to the Scientific Registry of Transplant Recipients between June 1, 1995, and April 30, 2004, and recorded at transplant on triple-drug (n = 9180) or dual-drug (n = 10 099) therapy were included. Kaplan-Meier survival analysis showed no significant differences in death due to malignancy 4 years post-transplantation between the treatment groups. Multivariable analysis using Cox proportional hazard models confirmed no differences in risk of death due to malignancy between the groups (HR: 0.83, p = 0.107). Incidence of any post-transplant malignancy was also not significantly different. Older recipient age and cause of liver disease were significantly associated with an increased risk of malignancy-related death. These data utilizing relatively short follow-up suggest the addition of MMF to Tacro+CS at transplant is not associated with death due to malignancy, at least in the short term. Individual recipient factors appear to be important risk factors for malignancy-related death; elucidating these risk factors can assist in identifying who should be monitored most aggressively for post-transplant malignancies.
Assuntos
Corticosteroides/administração & dosagem , Rejeição de Enxerto/tratamento farmacológico , Imunossupressores/administração & dosagem , Transplante de Fígado/mortalidade , Ácido Micofenólico/análogos & derivados , Tacrolimo/administração & dosagem , Adolescente , Adulto , Idoso , Quimioterapia Combinada , Feminino , Rejeição de Enxerto/mortalidade , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Ácido Micofenólico/administração & dosagem , Neoplasias/mortalidade , Sistema de Registros/estatística & dados numéricos , Fatores de Risco , Análise de SobrevidaRESUMO
The present study investigated the safety of induction therapy with daclizumab (compared with no induction treatment), in adult renal transplant patients reported to the Scientific Registry of Transplant Recipients (SRTR) database between January 1, 1998 and July 27, 2003. Patients who were discharged from the hospital on mycophenolate mofetil, azathioprine, or sirolimus were divided into two groups: induction treatment with daclizumab (n = 8203) and no induction treatment (n = 25,368). Patient survival, death due to infection and death due to malignancy were evaluated at 1 and 3 yr post-transplantation. Rejection and graft survival were also examined. Kaplan-Meier and Cox regression models were used to evaluate outcomes. No significant differences were found between patients treated with daclizumab compared with patients who received no induction therapy for death due to infection or malignancy at 1 and 3 yr post-transplantation. Patients treated with daclizumab (compared with no induction treatment) had statistically significantly better survival rates at 1 (96.9% vs. 96.2%, p = 0.003) and 3 yr (92.4% vs. 91.4%, p = 0.004) although absolute differences were minimal. This was confirmed in the multivariable Cox regression analysis for patient death at 1 (HR = 0.77, p < 0.001) and 3 yr (HR = 0.83, p = 0.001) post-transplantation. Patients treated with daclizumab compared to no induction had lower rejection rates at 1 (13.1% vs. 17.3%, p < 0.001) and 3 yr post-transplantation (16.7% vs. 21.3%, p < 0.001). Cox regression confirmed a decreased risk for rejection at 1 (HR = 0.74, p < 0.001) and 3 yr (HR = 0.75, p < 0.001). Treatment with daclizumab was associated with reduced risk for graft loss at 1 (HR = 0.82, p < 0.001) and 3 years (HR = 0.86, p < 0.001). In conclusion, daclizumab was associated with a significantly reduced risk for rejection and graft loss compared with no induction treatment, and improved patient survival. In addition, daclizumab was not associated with an increase in risk of death due to infection or malignancy, when compared with no induction therapy. These findings demonstrate the short and long-term safety and efficacy of daclizumab in patients transplanted between January 1998 and July 2003.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Rejeição de Enxerto/prevenção & controle , Imunoglobulina G/uso terapêutico , Imunossupressores/uso terapêutico , Transplante de Rim/imunologia , Adulto , Anticorpos Monoclonais Humanizados , Daclizumabe , Feminino , Humanos , Transplante de Rim/mortalidade , Masculino , Pessoa de Meia-Idade , Análise de SobrevidaRESUMO
We have investigated the expression of vascular adhesion molecules during the first stage of chronic inflammation in experimental autoimmune encephalomyelitis in the SJL/J mouse. Immunocytochemical analysis of frozen sections of inflamed versus noninflamed brains and spinal cords showed that the vascular endothelium in brains and spinal cords from diseased animals expressed high levels of vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) but no detectable mucosal addressin or peripheral lymph node addressin. In frozen section assays, anti-alpha 4 integrin and anti-VCAM-1 monoclonal antibodies inhibited binding of mouse peripheral lymphocytes to inflamed brains at both 4 C and 20 C. Antilymphocyte function-associated antigen-1 and anti-ICAM-1 monoclonal antibodies inhibited binding of mouse peripheral lymphocytes to inflamed brains at 20 C. These results are consistent with an important role for the vascular adhesion molecules VCAM-1 and ICAM-1 and for their lymphocytes receptors in lymphocyte recruitment to the central nervous system.
Assuntos
Doenças Autoimunes , Química Encefálica , Linfócitos T CD4-Positivos/fisiologia , Moléculas de Adesão Celular/fisiologia , Encefalomielite , Endotélio Vascular/química , Medula Espinal/química , Animais , Doenças Autoimunes/imunologia , Doenças Autoimunes/patologia , Encéfalo/irrigação sanguínea , Encéfalo/imunologia , Linfócitos T CD4-Positivos/patologia , Adesão Celular/fisiologia , Moléculas de Adesão Celular/análise , Linhagem Celular , Movimento Celular/fisiologia , Encefalomielite/imunologia , Encefalomielite/patologia , Endotélio Vascular/fisiologia , Feminino , Humanos , Molécula 1 de Adesão Intercelular , Linfonodos/citologia , Linfonodos/fisiologia , Linfoma , Camundongos , Camundongos Endogâmicos BALB C , Fenótipo , Medula Espinal/irrigação sanguínea , Medula Espinal/imunologia , Molécula 1 de Adesão de Célula VascularRESUMO
The expression of cell adhesion molecules (CAMs) in the choroid plexus was studied in normal brain and during experimental autoimmune encephalomyelitis (EAE) in the SJL/J mouse during inflammation induced by intracerebral injection of killed Corynebacterium parvum in the C3H/He mouse. Both ICAM-1 and VCAM-1, but not MAdCAM-1, were constitutively expressed on choroid plexus epithelium but not on the fenestrated capillary endothelial cells within the choroid plexus. During EAE, we observed an up-regulation of ICAM-1 and VCAM-1 and de novo expression of MAdCAM-1 on choroid plexus epithelial cells. In contrast, endothelial cells in the choroid plexus were not induced to express any of the investigated CAMs. In in situ hybridization analysis we demonstrated that ICAM-1, VCAM-1, and MAdCAM-1 were locally synthesized and that the amount of their mRNAs increased in the inflamed choroid plexus. In vitro, primary choroid plexus epithelial cells could be induced to express ICAM-1, VCAM-1, and MAdCAM-1 on their surface after treatment with proinflammatory cytokines such as tumor necrosis factor-alpha, interleukin-1, interferon-gamma, and lipopolysaccharide. To investigate the functional status of the expressed CAMs we performed Stamper-Woodruff binding assays on frozen sections of inflamed and naive brains. ICAM-1, VCAM-1, and MAdCAM-1 expressed in choroid plexus epithelial cells mediated binding of lymphocytes via their known ligands LFA-1 and alpha4-integrin, respectively. The expression of ICAM-1, VCAM-1, and MAdCAM-1 on choroid plexus epithelial cells together with the lack of their expression on the fenestrated choroid plexus endothelium raises the possibility that the epithelial blood-cerebrospinal-fluid barrier plays an important role in the immunosurveillance of the central nervous system.