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2.
Am J Transplant ; 19(11): 3035-3045, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31257724

RESUMO

The limited effectiveness of rituximab plus intravenous immunoglobulin (IVIG) in desensitization may be due to incomplete B cell depletion. Obinutuzumab is a type 2 anti-CD20 antibody that induces increased B cell depletion relative to rituximab and may therefore be more effective for desensitization. This open-label phase 1b study assessed the safety, pharmacokinetics, and pharmacodynamics of obinutuzumab in highly sensitized patients with end-stage renal disease. Patients received 1 (day 1, n = 5) or 2 (days 1 and 15; n = 20) infusions of 1000-mg obinutuzumab followed by 2 doses of IVIG on days 22 and 43. Eleven patients received additional obinutuzumab doses at the time of transplant and/or at week 24. The median follow-up duration was 9.4 months. Obinutuzumab was well tolerated, and most adverse events were grade 1-2 in severity. There were 11 serious adverse events (SAEs) in 9 patients (36%); 10 of these SAEs were infections and 4 occurred after kidney transplant. Obinutuzumab plus IVIG resulted in profound peripheral B cell depletion and appeared to reduce B cells in retroperitoneal lymph nodes. Reductions in anti-HLA antibodies, number of unacceptable antigens, and the calculated panel reactive antibody score as centrally assessed using single-antigen bead assay were limited and not clinically meaningful for most patients (NCT02586051).

3.
Lupus Sci Med ; 6(1): e000308, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31080631

RESUMO

Objective: The outcome of participants with nephrotic syndrome in clinical trials of lupus nephritis has not been studied in detail. Methods: Collated data from two randomised controlled trials in lupus nephritis, Lupus Nephritis Assessment of Rituximab (LUNAR) and A Study to Evaluate Ocrelizumab in Patients With Nephritis due to Systemic Lupus Erythematosus (BELONG) were analysed. Nephrotic syndrome was defined as albumin <3 g/dL and urine protein/creatinine ratio ≥3.5 g/g at start of trial. Renal response was defined as a first morning urine protein/creatinine ratio ≤0.5 g/g in addition to ≤25% increase in creatinine from trial entry assessed at week 48. Logistic regression was used to evaluate the association of nephrotic syndrome with renal response while adjusting for treatment received and ACE inhibitor or angiotensin receptor blocker use. Results: 28 (26%) participants with nephrotic syndrome achieved renal response as compared with 130 (52.5%) of those without (p<0.001). Having nephrotic syndrome at baseline significantly lowered the likelihood of achieving renal response (OR 0.32, 95 % CI 0.19 to 0.54, p<0.001). 125 (80%) participants achieved resolution of their nephrotic syndrome in a median time of 16 weeks. Conclusions: Nephrotic syndrome at baseline decreases the likelihood of renal response at 1 year. Longer clinical trials or better short-term predictors of long-term outcomes may better assess the effect of novel therapeutic approaches on subjects with nephrotic syndrome.

4.
Artigo em Inglês | MEDLINE | ID: mdl-30295434

RESUMO

OBJECTIVE: To evaluate the long-term safety of rituximab in an observational cohort of patients with rheumatoid arthritis (RA) who had an inadequate response to ≥ 1 antitumor necrosis factor therapies in the United States (SUNSTONE Registry). METHODS: In this prospective, observational cohort study, patients received rituximab according to their physician's standard practice and were evaluated at standard-of-care follow-up visits at least every 6 months. The primary outcome was the incidence of protocol-defined significant infections. Secondary outcomes included serious adverse events potentially associated with rituximab, cardiovascular or thrombotic (CVT) events, seizures, deaths and pregnancies. Posthoc analyses assessed outcomes by concomitant medication use. RESULTS: Overall, 989 patients (safety-evaluable population) received ≥ 1 dose of rituximab, with a total follow-up of 3844 patient-years (PYs; mean duration, 3.9 years). In total, 341 significant infections occurred in 197 patients (19.9%). The incidence rates (95% CI) for significant infections, CVT events, and seizures were 8.87 (7.98, 9.86), 1.95 (1.56, 2.45), and 0.18 (0.09, 0.38) per 100 PYs, respectively. The incidence of significant infections did not increase with time or with cumulative rituximab exposure. During the study, 64 patients died (crude mortality [95% CI]: 1.66 per 100 PYs [1.30, 2.13]). The most common causes of death were infections (19 patients), malignancy (14), and cardiovascular events (13). Eight pregnancies were reported in 7 patients. CONCLUSION: In patients with RA treated with rituximab for up to 5 years, the rates of significant infections were stable over time and higher in patients who received long-term systemic steroid treatment. This article is protected by copyright. All rights reserved.

5.
Clin J Am Soc Nephrol ; 13(10): 1502-1509, 2018 10 08.
Artigo em Inglês | MEDLINE | ID: mdl-30089664

RESUMO

BACKGROUND AND OBJECTIVES: Incomplete peripheral blood B cell depletion after rituximab in lupus nephritis might correlate with inability to reduce tubulointerstitial lymphoid aggregates in the kidney, which together could be responsible for inadequate response to treatment. We utilized data from the Lupus Nephritis Assessment with Rituximab (LUNAR) study to characterize the variability of peripheral blood B cell depletion after rituximab and assess its association with complete response in patients with lupus nephritis. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We analyzed 68 participants treated with rituximab. Peripheral blood B cell depletion was defined as 0 cells/µl, termed "complete peripheral depletion," assessed over 78 weeks. Logistic regression was used to estimate the association between characteristics of complete peripheral depletion and complete response (defined as urine protein-to-creatinine ratio <0.5 mg/mg, and normal serum creatinine or an increase in creatinine <15%, if normal at baseline), assessed at week 78. RESULTS: A total of 53 (78%) participants achieved complete peripheral depletion (0 cells/µl) in a median time of 182 days (interquartile range, 80-339).The median duration of complete peripheral depletion was 71 days (interquartile range, 14-158). Twenty-five (47%) participants with complete peripheral depletion achieved complete response, compared with two (13%) without. Complete peripheral depletion was associated with complete response (unadjusted odds ratio [OR], 5.8; 95% confidence interval [95% CI], 1.2 to 28; P=0.03). Longer time to achieving complete peripheral depletion was associated with a lower likelihood of complete response (unadjusted OR, 0.89; 95% CI, 0.81 to 0.98; P=0.02). Complete peripheral depletion lasting >71 days (the median) was associated with complete response (unadjusted OR, 4.1; 95% CI, 1.5 to 11; P=0.008). CONCLUSIONS: There was substantial variability in peripheral blood B cell depletion in patients with lupus nephritis treated with rituximab from the LUNAR trial. Achievement of complete peripheral depletion, as well as the rapidity and duration of complete peripheral depletion, were associated with complete response at week 78. PODCAST: This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2018_09_06_CJASNPodcast_18_10_.mp3.


Assuntos
Linfócitos B , Fatores Imunológicos/uso terapêutico , Nefrite Lúpica/sangue , Nefrite Lúpica/tratamento farmacológico , Depleção Linfocítica , Rituximab/uso terapêutico , Adulto , Feminino , Humanos , Masculino , Indução de Remissão , Resultado do Tratamento
6.
Rheumatology (Oxford) ; 57(4): 639-650, 2018 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-29340623

RESUMO

Objectives: To study the determinants of the pharmacokinetics (PK) of rituximab (RTX) in patients with ANCA-associated vasculitis (AAV) and its association with clinical outcomes. Methods: This study included data from 89 patients from the RTX in AAV trial who received the full dose of RTX (four weekly infusions of 375 mg/m2). RTX was quantified at weeks 2, 4, 8, 16 and 24, and summarized by computing the trapezoidal area under the curve. We explored potential determinants of the PK-RTX, and analysed its association with clinical outcomes: achievement of remission at 6 months, duration of B-cell depletion and time to relapse in patients who achieved complete remission. Results: RTX serum levels were significantly lower in males and in newly diagnosed patients, and negatively correlated with body surface area, baseline B-cell count and degree of disease activity. In multivariate analyses, the main determinants of PK-RTX were sex and new diagnosis. Patients reaching complete remission at month 6 had similar RTX levels compared with patients who did not reach complete remission. Patients with higher RTX levels generally experienced longer B-cell depletion than patients with lower levels, but RTX levels at the different time points and area under the curve were not associated with time to relapse. Conclusion: Despite the body-surface-area-based dosing protocol, PK-RTX is highly variable among patients with AAV, its main determinants being sex and newly diagnosed disease. We did not observe any relevant association between PK-RTX and clinical outcomes. The monitoring of serum RTX levels does not seem clinically useful in AAV.


Assuntos
Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/tratamento farmacológico , Rituximab/farmacocinética , Adulto , Idoso , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/sangue , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/imunologia , Linfócitos B/imunologia , Linfócitos B/patologia , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Humanos , Fatores Imunológicos/administração & dosagem , Fatores Imunológicos/farmacocinética , Infusões Intravenosas , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Indução de Remissão , Rituximab/administração & dosagem , Resultado do Tratamento
7.
Endocr Pract ; 19(3): e57-60, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23337142

RESUMO

OBJECTIVE: We describe a young woman with previously undiagnosed thyrotoxicosis who presented with acute liver failure (ALF). METHODS: We present a case report and review the relevant literature. RESULTS: An extensive evaluation excluded possible causes of ALF other than thyrotoxicosis. The management of thyrotoxicosis posed several unique challenges in the setting of ALF, particularly because we did not want to use potentially hepatotoxic thionamides. The patient was treated with prednisone and propranolol and was started on potassium iodide when she was listed for liver transplantation. She underwent an uncomplicated liver transplant and subsequent thyroidectomy and is doing well. CONCLUSION: This well-characterized case describes thyrotoxicosis as a possible cause of ALF after thoroughly excluding other possible causes and illustrates the challenges of simultaneously managing both disorders. To our knowledge, this is the first report of ALF possibly resulting from untreated thyrotoxicosis that was successfully treated with liver transplantation.


Assuntos
Falência Hepática Aguda/diagnóstico , Falência Hepática Aguda/cirurgia , Transplante de Fígado , Tireotoxicose/diagnóstico , Tireotoxicose/cirurgia , Adulto , Feminino , Humanos , Falência Hepática Aguda/tratamento farmacológico , Iodeto de Potássio/uso terapêutico , Prednisona/uso terapêutico , Propranolol/uso terapêutico , Tireotoxicose/tratamento farmacológico , Resultado do Tratamento
8.
Math Biosci ; 199(1): 55-78, 2006 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-16376950

RESUMO

Cancer virotherapy represents a dynamical system that requires mathematical modeling for complete understanding of the outcomes. The combination of virotherapy with radiation (radiovirotherapy) has been recently shown to successfully eliminate tumors when virotherapy alone failed. However, it introduces a new level of complexity. We have developed a mathematical model, based on population dynamics, that captures the essential elements of radiovirotherapy. The existence of corresponding equilibrium points related to complete cure, partial cure, and therapy failure is proved and discussed. The parameters of the model were estimated by fitting to experimental data. By using simulations we analyzed the influence of parameters that describe the interaction between virus and tumor cell on the outcome of the therapy. Furthermore, we evaluated relevant therapeutic scenarios for radiovirotherapy, and offered elements for optimization.


Assuntos
Modelos Biológicos , Neoplasias/terapia , Terapia Viral Oncolítica/métodos , Algoritmos , Animais , Terapia Combinada , Simulação por Computador , Humanos , Radioisótopos do Iodo/uso terapêutico , Análise dos Mínimos Quadrados , Vírus do Sarampo/genética , Camundongos , Mieloma Múltiplo/patologia , Mieloma Múltiplo/terapia , Neoplasias/patologia , Simportadores/genética , Ensaios Antitumorais Modelo de Xenoenxerto
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