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1.
J Neuroimmunol ; 332: 187-197, 2019 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-31077854

RESUMO

Multiple sclerosis (MS) is a demyelinating disease of the central nervous system, thought to be mediated by myelin-specific CD4+ T cells. However, B cell depletion has proven to be an effective therapy for MS, but the mechanism is not well understood. This study was designed to determine how B cell depletion changes lymphocyte profiles. During a phase IIa clinical trial with ublituximab, a novel CD20 antibody, blood was collected from 48 MS patients at 11 time points over 24 weeks and the lymphocyte profiles were analyzed by flow cytometry. The percentage of naïve CD4+ and CD8+ T cells increased, while the percentage of both effector and central memory T cells declined. CD4+ Th1 effector cells decreased, while there was a significant increase in CD4+ regulatory T cells. The depletion of B cells had a favorable shift in the lymphocyte landscape, reducing the number of naïve T cells becoming activated and transitioning to memory T cells. The ratio of Th1 cells to CD4+ regulatory T cells declined, suggesting that immune regulation was being restored. These data suggest that loss of B cells as antigen presenting cells is a major mechanism of action for the beneficial effects of CD20 antibody therapy in MS.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Depleção Linfocítica , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Subpopulações de Linfócitos T/imunologia , Adolescente , Adulto , Anticorpos Monoclonais/farmacologia , Antígenos CD20/imunologia , Feminino , Humanos , Memória Imunológica , Células Matadoras Naturais/imunologia , Ativação Linfocitária , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla Recidivante-Remitente/imunologia , Células Mieloides/imunologia , Linfócitos T Reguladores/imunologia , Adulto Jovem
2.
Lancet ; 380(9856): 1829-39, 2012 Nov 24.
Artigo em Inglês | MEDLINE | ID: mdl-23122650

RESUMO

BACKGROUND: The anti-CD52 monoclonal antibody alemtuzumab reduces disease activity in previously untreated patients with relapsing-remitting multiple sclerosis. We aimed to assess efficacy and safety of alemtuzumab compared with interferon beta 1a in patients who have relapsed despite first-line treatment. METHODS: In our 2 year, rater-masked, randomised controlled phase 3 trial, we enrolled adults aged 18-55 years with relapsing-remitting multiple sclerosis and at least one relapse on interferon beta or glatiramer. Eligible participants were randomly allocated in a 1:2:2 ratio by an interactive voice response system, stratified by site, to receive subcutaneous interferon beta 1a 44 µg, intravenous alemtuzumab 12 mg per day, or intravenous alemtuzumab 24 mg per day. Interferon beta 1a was given three-times per week and alemtuzumab was given once per day for 5 days at baseline and for 3 days at 12 months. The 24 mg per day group was discontinued to aid recruitment, but data are included for safety assessments. Coprimary endpoints were relapse rate and time to 6 month sustained accumulation of disability, comparing alemtuzumab 12 mg and interferon beta 1a in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT00548405. FINDINGS: 202 (87%) of 231 patients randomly allocated interferon beta 1a and 426 (98%) of 436 patients randomly allocated alemtuzumab 12 mg were included in the primary analyses. 104 (51%) patients in the interferon beta 1a group relapsed (201 events) compared with 147 (35%) patients in the alemtuzumab group (236 events; rate ratio 0·51 [95% CI 0·39-0·65]; p<0·0001), corresponding to a 49·4% improvement with alemtuzumab. 94 (47%) patients in the interferon beta 1a group were relapse-free at 2 years compared with 278 (65%) patients in the alemtuzumab group (p<0·0001). 40 (20%) patients in the interferon beta 1a group had sustained accumulation of disability compared with 54 (13%) in the alemtuzumab group (hazard ratio 0·58 [95% CI 0·38-0·87]; p=0·008), corresponding to a 42% improvement in the alemtuzumab group. For 435 patients allocated alemtuzumab 12 mg, 393 (90%) had infusion-associated reactions, 334 (77%) had infections (compared with 134 [66%] of 202 patients in the interferon beta 1a group) that were mostly mild-moderate with none fatal, 69 (16%) had thyroid disorders, and three (1%) had immune thrombocytopenia. INTERPRETATION: For patients with first-line treatment-refractory relapsing-remitting multiple sclerosis, alemtuzumab could be used to reduce relapse rates and sustained accumulation of disability. Suitable risk management strategies allow for early identification of alemtuzumab's main adverse effect of secondary autoimmunity. FUNDING: Genzyme (Sanofi) and Bayer Schering Pharma.


Assuntos
Adjuvantes Imunológicos/administração & dosagem , Anticorpos Monoclonais Humanizados/administração & dosagem , Imunossupressores/administração & dosagem , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Peptídeos/administração & dosagem , Adjuvantes Imunológicos/efeitos adversos , Administração Cutânea , Adolescente , Adulto , Alemtuzumab , Anticorpos Monoclonais Humanizados/efeitos adversos , Feminino , Acetato de Glatiramer , Humanos , Imunossupressores/efeitos adversos , Infusões Intravenosas , Masculino , Pessoa de Meia-Idade , Peptídeos/efeitos adversos , Recidiva , Resultado do Tratamento , Adulto Jovem
3.
J Neurol Sci ; 291(1-2): 110-3, 2010 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-20144466

RESUMO

We describe a patient with a giant MS plaque developing during natalizumab administration whose clinical presentations mimicked PML. This 27year-old man developed new onset confusion, altered behavior, left hemianesthesia and worsening dysarthria, gait and balance with a new, large, rim-enhancing, temporoparietal subcortical lesion after four infusions of natalizumab. Cerebrospinal JC virus polymerase chain reaction was negative. No neutralizing antibody to natalizumab was detected. Following discontinuation of natalizumab, plasma exchange, and a single dose of 1000mg of methylprednisolone, he demonstrated clinical and radiographic improvement. Distinguishing PML from MS may be very difficult in some instances. The frequency with which an aggressive demyelinating disorder due to MS occurs during treatment with natalizumab remains to be determined.


Assuntos
Anticorpos Monoclonais/efeitos adversos , Encéfalo/patologia , Fatores Imunológicos/efeitos adversos , Leucoencefalopatia Multifocal Progressiva/patologia , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/patologia , Adulto , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados , Encéfalo/efeitos dos fármacos , Diagnóstico Diferencial , Humanos , Fatores Imunológicos/uso terapêutico , Leucoencefalopatia Multifocal Progressiva/diagnóstico , Imageamento por Ressonância Magnética , Masculino , Esclerose Múltipla/diagnóstico , Natalizumab
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