RESUMO
BACKGROUND: B cells influence the pathogenesis of multiple sclerosis. Ocrelizumab is a humanized monoclonal antibody that selectively depletes CD20+ B cells. METHODS: In two identical phase 3 trials, we randomly assigned 821 and 835 patients with relapsing multiple sclerosis to receive intravenous ocrelizumab at a dose of 600 mg every 24 weeks or subcutaneous interferon beta-1a at a dose of 44 µg three times weekly for 96 weeks. The primary end point was the annualized relapse rate. RESULTS: The annualized relapse rate was lower with ocrelizumab than with interferon beta-1a in trial 1 (0.16 vs. 0.29; 46% lower rate with ocrelizumab; P<0.001) and in trial 2 (0.16 vs. 0.29; 47% lower rate; P<0.001). In prespecified pooled analyses, the percentage of patients with disability progression confirmed at 12 weeks was significantly lower with ocrelizumab than with interferon beta-1a (9.1% vs. 13.6%; hazard ratio, 0.60; 95% confidence interval [CI], 0.45 to 0.81; P<0.001), as was the percentage of patients with disability progression confirmed at 24 weeks (6.9% vs. 10.5%; hazard ratio, 0.60; 95% CI, 0.43 to 0.84; P=0.003). The mean number of gadolinium-enhancing lesions per T1-weighted magnetic resonance scan was 0.02 with ocrelizumab versus 0.29 with interferon beta-1a in trial 1 (94% lower number of lesions with ocrelizumab, P<0.001) and 0.02 versus 0.42 in trial 2 (95% lower number of lesions, P<0.001). The change in the Multiple Sclerosis Functional Composite score (a composite measure of walking speed, upper-limb movements, and cognition; for this z score, negative values indicate worsening and positive values indicate improvement) significantly favored ocrelizumab over interferon beta-1a in trial 2 (0.28 vs. 0.17, P=0.004) but not in trial 1 (0.21 vs. 0.17, P=0.33). Infusion-related reactions occurred in 34.3% of the patients treated with ocrelizumab. Serious infection occurred in 1.3% of the patients treated with ocrelizumab and in 2.9% of those treated with interferon beta-1a. Neoplasms occurred in 0.5% of the patients treated with ocrelizumab and in 0.2% of those treated with interferon beta-1a. CONCLUSIONS: Among patients with relapsing multiple sclerosis, ocrelizumab was associated with lower rates of disease activity and progression than interferon beta-1a over a period of 96 weeks. Larger and longer studies of the safety of ocrelizumab are required. (Funded by F. Hoffmann-La Roche; OPERA I and II ClinicalTrials.gov numbers, NCT01247324 and NCT01412333 , respectively.).
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Anticorpos Monoclonais Humanizados/uso terapêutico , Fatores Imunológicos/uso terapêutico , Interferon beta/uso terapêutico , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Adulto , Anticorpos Monoclonais Humanizados/efeitos adversos , Antígenos CD20 , Linfócitos B/imunologia , Encéfalo/diagnóstico por imagem , Progressão da Doença , Feminino , Humanos , Fatores Imunológicos/efeitos adversos , Infusões Intravenosas/efeitos adversos , Interferon beta/efeitos adversos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla Recidivante-Remitente/diagnóstico por imagem , RecidivaRESUMO
BACKGROUND: An evolving understanding of the immunopathogenesis of multiple sclerosis suggests that depleting B cells could be useful for treatment. We studied ocrelizumab, a humanized monoclonal antibody that selectively depletes CD20-expressing B cells, in the primary progressive form of the disease. METHODS: In this phase 3 trial, we randomly assigned 732 patients with primary progressive multiple sclerosis in a 2:1 ratio to receive intravenous ocrelizumab (600 mg) or placebo every 24 weeks for at least 120 weeks and until a prespecified number of confirmed disability progression events had occurred. The primary end point was the percentage of patients with disability progression confirmed at 12 weeks in a time-to-event analysis. RESULTS: The percentage of patients with 12-week confirmed disability progression was 32.9% with ocrelizumab versus 39.3% with placebo (hazard ratio, 0.76; 95% confidence interval [CI], 0.59 to 0.98; P=0.03). The percentage of patients with 24-week confirmed disability progression was 29.6% with ocrelizumab versus 35.7% with placebo (hazard ratio, 0.75; 95% CI, 0.58 to 0.98; P=0.04). By week 120, performance on the timed 25-foot walk worsened by 38.9% with ocrelizumab versus 55.1% with placebo (P=0.04); the total volume of brain lesions on T2-weighted magnetic resonance imaging (MRI) decreased by 3.4% with ocrelizumab and increased by 7.4% with placebo (P<0.001); and the percentage of brain-volume loss was 0.90% with ocrelizumab versus 1.09% with placebo (P=0.02). There was no significant difference in the change in the Physical Component Summary score of the 36-Item Short-Form Health Survey. Infusion-related reactions, upper respiratory tract infections, and oral herpes infections were more frequent with ocrelizumab than with placebo. Neoplasms occurred in 2.3% of patients who received ocrelizumab and in 0.8% of patients who received placebo; there was no clinically significant difference between groups in the rates of serious adverse events and serious infections. CONCLUSIONS: Among patients with primary progressive multiple sclerosis, ocrelizumab was associated with lower rates of clinical and MRI progression than placebo. Extended observation is required to determine the long-term safety and efficacy of ocrelizumab. (Funded by F. Hoffmann-La Roche; ORATORIO ClinicalTrials.gov number, NCT01194570 .).
Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Esclerose Múltipla Crônica Progressiva/tratamento farmacológico , Adolescente , Adulto , Anticorpos Monoclonais Humanizados/efeitos adversos , Antígenos CD20 , Linfócitos B/imunologia , Encéfalo/diagnóstico por imagem , Progressão da Doença , Método Duplo-Cego , Feminino , Humanos , Infusões Intravenosas/efeitos adversos , Análise de Intenção de Tratamento , Contagem de Linfócitos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla Crônica Progressiva/imunologia , Linfócitos T , Adulto JovemRESUMO
Quantitative magnetic resonance imaging (MRI) techniques have been developed as imaging biomarkers, aiming to improve the specificity of MRI to underlying pathology compared to conventional weighted MRI. For assessing the integrity of white matter (WM), myelin, in particular, several techniques have been proposed and investigated individually. However, comparisons between these methods are lacking. In this study, we compared four established myelin-sensitive MRI techniques in 56 patients with relapsing-remitting multiple sclerosis (MS) and 38 healthy controls. We used T2-relaxation with combined GRadient And Spin Echoes (GRASE) to measure myelin water fraction (MWF-G), multi-component driven equilibrium single pulse observation of T1 and T2 (mcDESPOT) to measure MWF-D, magnetization-transfer imaging to measure magnetization-transfer ratio (MTR), and T1 relaxation to measure quantitative T1 (qT1 ). Using voxelwise Spearman correlations, we tested the correspondence of methods throughout the brain. All four methods showed associations that varied across tissue types; the highest correlations were found between MWF-D and qT1 (median ρ across tissue classes 0.8) and MWF-G and MWF-D (median ρ = 0.59). In eight WM tracts, all measures showed differences (p < 0.05) between MS normal-appearing WM and healthy control WM, with qT1 showing the highest number of different regions (8), followed by MWF-D and MTR (6), and MWF-G (n = 4). Comparing the methods in terms of their statistical sensitivity to MS lesions in WM, MWF-D demonstrated the best accuracy (p < 0.05, after multiple comparison correction). To aid future power analysis, we provide the average and standard deviation volumes of the four techniques, estimated from the healthy control sample.
Assuntos
Encéfalo/diagnóstico por imagem , Imageamento por Ressonância Magnética/métodos , Esclerose Múltipla Recidivante-Remitente/diagnóstico por imagem , Bainha de Mielina/fisiologia , Neuroimagem/métodos , Adulto , Encéfalo/fisiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla Recidivante-Remitente/fisiopatologia , Adulto JovemRESUMO
OBJECTIVE: No evidence of progression or active disease (NEPAD) is a novel combined endpoint defined by the absence of both progression and inflammatory disease activity in primary progressive multiple sclerosis (PPMS). In the placebo-controlled phase III ORATORIO study (NCT01194570), we investigated the effect of ocrelizumab on this comprehensive outcome and its components in a post-hoc analysis. METHODS: The proportion of patients with NEPAD (no evidence of progression [NEP; no 12-week confirmed progression of ≥1/≥0.5 points on the Expanded Disability Status Scale if the baseline score was ≤5.5/>5.5 points, respectively; no 12-week confirmed progression of ≥20% on the Timed 25-Foot Walk test and 9-Hole Peg Test], no brain magnetic resonance imaging activity [no new/enlarging T2 lesions and no T1 gadolinium-enhancing lesions], and no protocol-defined relapse) from baseline to week 120 was determined in ocrelizumab- (600 mg; n = 465) and placebo-treated (n = 234) patients. RESULTS: The majority of ORATORIO study patients with PPMS experienced clinical progression or evidence of disease activity. From baseline to week 120, 29.9% and 42.7% ocrelizumab-treated compared to 9.4% and 29.1% placebo-treated patients maintained NEPAD (relative risk [95% confidence interval {CI}], 3.15 [2.07-4.79]; p < 0.001) and NEP (relative risk [95% CI], 1.47 [1.17-1.84]; p < 0.001), respectively. Effects on the individual components of both measures were consistent with the compound outcomes. INTERPRETATION: Compared to placebo, ocrelizumab enhanced 3-fold the proportion of PPMS patients with no evidence of either progression or inflammatory disease activity. NEPAD may represent a sensitive and meaningful comprehensive measure of disease control in patients with PPMS. Ann Neurol 2018;84:527-536.
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Anticorpos Monoclonais Humanizados/uso terapêutico , Progressão da Doença , Medicina Baseada em Evidências/métodos , Fatores Imunológicos/uso terapêutico , Esclerose Múltipla Crônica Progressiva/diagnóstico por imagem , Esclerose Múltipla Crônica Progressiva/tratamento farmacológico , Adolescente , Adulto , Método Duplo-Cego , Feminino , Humanos , Imageamento por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
BACKGROUND: Myelin water imaging is a magnetic resonance imaging (MRI) technique that quantifies myelin damage and repair in multiple sclerosis (MS) via the myelin water fraction (MWF). OBJECTIVE: In this substudy of a phase 3 therapeutic trial, OPERA II, MWF was assessed in relapsing MS participants assigned to interferon beta-1a (IFNb-1a) or ocrelizumab (OCR) during a two-year double-blind period (DBP) followed by a two-year open label extension (OLE) with ocrelizumab treatment. METHODS: MWF in normal appearing white matter (NAWM), including both whole brain NAWM and 5 white matter structures, and chronic lesions, was assessed in 29 OCR and 26 IFNb-1a treated participants at weeks 0, 24, 48 and 96 (DBP), and weeks 144 and 192 (OLE), and in white matter for 23 healthy control participants at weeks 0, 48 and 96. RESULTS: Linear mixed-effects models of data from baseline to week 96 showed a difference in the change in MWF over time favouring ocrelizumab in all NAWM regions. At week 192, lesion MWF was lower for participants originally randomised to IFNb-1a compared to those originally randomised to OCR. Controls showed no change in MWF over 96 weeks in any region. CONCLUSION: Ocrelizumab appears to protect against demyelination in MS NAWM and chronic lesions and may allow for a more permissive micro environment for remyelination to occur in focal and diffusely damaged tissue.
Assuntos
Esclerose Múltipla Recidivante-Remitente , Esclerose Múltipla , Anticorpos Monoclonais Humanizados , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Método Duplo-Cego , Humanos , Interferon beta-1a/análise , Interferon beta-1a/uso terapêutico , Imageamento por Ressonância Magnética/métodos , Esclerose Múltipla/patologia , Esclerose Múltipla Recidivante-Remitente/diagnóstico por imagem , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Esclerose Múltipla Recidivante-Remitente/patologia , Bainha de Mielina/patologia , Recidiva , Água/análiseRESUMO
Microarray analysis of multiple sclerosis (MS) lesions obtained at autopsy revealed increased transcripts of genes encoding inflammatory cytokines, particularly interleukin-6 and -17, interferon-gamma and associated downstream pathways. Comparison of two poles of MS pathology--acute lesions with inflammation versus 'silent' lesions without inflammation--revealed differentially transcribed genes. Some products of these genes were chosen as targets for therapy of experimental autoimmune encephalomyelitis (EAE) in mice. Granulocyte colony-stimulating factor is upregulated in acute, but not in chronic, MS lesions, and the effect on ameliorating EAE is more pronounced in the acute phase, in contrast to knocking out the immunoglobulin Fc receptor common gamma chain where the effect is greatest on chronic disease. These results in EAE corroborate the microarray studies on MS lesions. Large-scale analysis of transcripts in MS lesions elucidates new aspects of pathology and opens possibilities for therapy.
Assuntos
Encefalomielite Autoimune Experimental/genética , Interferon gama/genética , Interleucina-17/genética , Interleucina-6/genética , Esclerose Múltipla/genética , Análise de Sequência com Séries de Oligonucleotídeos , Doença Aguda , Animais , Autopsia , Doença Crônica , Encefalomielite Autoimune Experimental/patologia , Feminino , Fator Estimulador de Colônias de Granulócitos/fisiologia , Humanos , Inflamação/genética , Inflamação/patologia , Camundongos , Camundongos Endogâmicos C57BL , Esclerose Múltipla/patologia , Receptores Fc/fisiologia , Reprodutibilidade dos Testes , Transcrição GênicaRESUMO
Insulin is a major target for the autoimmune-mediated destruction of pancreatic beta cells during the pathogenesis of type I diabetes. A plasmid DNA vaccine encoding mouse proinsulin II reduced the incidence of diabetes in a mouse model of type I diabetes when administered to hyperglycemic (therapeutic mode) or normoglycemic (prophylactic mode) NOD mice. Therapeutic administration of proinsulin DNA was accompanied by a rapid decrease in the number of insulin-specific IFN-gamma-producing T cells, whereas prophylactic treatment was accompanied by enhanced IFN-gamma-secreting cells and a decrease in insulin autoantibodies. Adoptive transfer experiments demonstrated that the protection was not mediated by induction of CD25(+)/CD4(+) T regulatory cells. The efficacy of the DNA vaccine was enhanced by increasing the level of expression of the encoded Ag, more frequent dosing, increasing dose level, and localization of the protein product to the intracellular compartment. The efficacy data presented in this study demonstrate that Ag-specific plasmid DNA therapy is a viable strategy for preventing progression of type I diabetes and defines critical parameters of the dosing regime that influences tolerance induction.
Assuntos
Regulação da Expressão Gênica/imunologia , Hiperglicemia/prevenção & controle , Tolerância Imunológica , Líquido Intracelular/imunologia , Vacinas de DNA/administração & dosagem , Vacinas de DNA/imunologia , Sequência de Aminoácidos , Animais , Autoantígenos/administração & dosagem , Autoantígenos/biossíntese , Autoantígenos/genética , Autoantígenos/imunologia , Linhagem Celular , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/patologia , Diabetes Mellitus Tipo 1/prevenção & controle , Relação Dose-Resposta Imunológica , Feminino , Humanos , Hiperglicemia/genética , Hiperglicemia/imunologia , Hiperglicemia/patologia , Tolerância Imunológica/genética , Líquido Intracelular/metabolismo , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Dados de Sequência Molecular , Plasmídeos/administração & dosagem , Plasmídeos/genética , Plasmídeos/imunologia , Estado Pré-Diabético/genética , Estado Pré-Diabético/imunologia , Estado Pré-Diabético/patologia , Estado Pré-Diabético/terapia , Proinsulina/administração & dosagem , Proinsulina/biossíntese , Proinsulina/genética , Proinsulina/imunologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Vacinas de DNA/genéticaRESUMO
BACKGROUND: Satralizumab, a humanised monoclonal antibody targeting the interleukin-6 receptor, reduced the risk of relapse in patients with neuromyelitis optica spectrum disorder (NMOSD) when added to immunosuppressant therapy. This study assessed the safety and efficacy of satralizumab monotherapy in patients with the disorder. METHODS: In this phase 3, double-blind, placebo-controlled, parallel-group trial, we enrolled adults aged 18-74 years with aquaporin-4 antibody seropositive or seronegative NMOSD at 44 investigational sites in 13 countries. Eligible participants had experienced at least one documented NMOSD attack or relapse in the past 12 months and had a score of 6·5 or less on the Expanded Disability Status Scale. Exclusion criteria included clinical relapse 30 days or fewer before baseline. Participants were randomly assigned (2:1) to receive satralizumab 120 mg or visually matched placebo subcutaneously at weeks 0, 2, 4, and every 4 weeks thereafter. Taking immunosuppressants concomitantly was prohibited. The primary endpoint was time to the first protocol-defined relapse, based on the intention-to-treat population and analysed with stratification for two randomisation factors (previous therapy for prevention of attacks and nature of the most recent attack). Safety was assessed in all participants who received at least one dose of satralizumab or placebo. The double-blind phase was due to last until 44 protocol-defined relapses occurred or 1·5 years after random assignment of the last patient enrolled, whichever occurred first; participants could enter an open-label phase after the occurrence of a protocol-defined relapse or at the end of the double-blind phase. The study is registered with ClinicalTrials.gov, NCT02073279. FINDINGS: 95 (57%) of 168 screened participants were randomly assigned to treatment (63 to satralizumab; 32 to placebo) between Aug 5, 2014, and April 2, 2017. Protocol-defined relapses occurred in 19 (30%) patients receiving satralizumab and 16 (50%) receiving placebo (hazard ratio 0·45, 95% CI 0·23-0·89; p=0·018). 473·9 adverse events per 100 patient-years occurred in the satralizumab group, as did 495·2 per 100 patient-years in the placebo group; the incidence of serious adverse events and adverse events leading to withdrawal was similar between groups. INTERPRETATION: Satralizumab monotherapy reduced the rate of NMOSD relapse compared with placebo in the overall trial population, with a favourable safety profile. The patient population included a ratio of aquaporin-4 antibody seropositive and seronegative patients that was reflective of clinical practice. Satralizumab has the potential to become a valuable treatment option for patients with NMOSD. FUNDING: Chugai Pharmaceutical (Roche).
Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Imunossupressores/uso terapêutico , Neuromielite Óptica/tratamento farmacológico , Adolescente , Adulto , Idoso , Anticorpos Monoclonais Humanizados/efeitos adversos , Método Duplo-Cego , Feminino , Humanos , Imunossupressores/efeitos adversos , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento , Adulto JovemRESUMO
OBJECTIVE: To evaluate the efficacy and safety of BHT-3009 in relapsing-remitting multiple sclerosis (MS) and to confirm that BHT-3009 causes immune tolerance. METHODS: BHT-3009 is a tolerizing DNA vaccine for MS, encoding full-length human myelin basic protein. Relapsing-remitting MS patients were randomized 1:1:1 into three groups: placebo, 0.5 mg BHT-3009, or 1.5 mg BHT-3009, given intramuscularly at weeks 0, 2, 4, and every 4 weeks thereafter until week 44. The primary end point was the 4-week rate of occurrence of new gadolinium-enhancing lesions on brain magnetic resonance images from weeks 28 to 48. Protein microarrays were used to measure levels of anti-myelin autoantibodies. RESULTS: Compared with placebo, in the 267 patient analysis population the median 4-week rate of new enhancing lesions during weeks 28 to 48 was 50% lower with 0.5 mg BHT-3009 (p = 0.07) and during weeks 8 to 48 was 61% lower with 0.5 mg BHT-3009 (p = 0.05). The mean volume of enhancing lesions at week 48 was 51% lower on 0.5 mg BHT-3009 compared with placebo (p = 0.02). No significant improvement in magnetic resonance imaging lesion parameters was observed with 1.5 mg BHT-3009. Dramatic reductions in 23 myelin-specific autoantibodies in the 0.5 mg BHT-3009 arm were observed, but not with placebo or 1.5 mg BHT-3009. CONCLUSIONS: In relapsing-remitting MS patients, treatment with the lower dose (0.5 mg) of BHT-3009 for 44 weeks nearly attained the primary end point for reduction of the rate of new enhancing magnetic resonance imaging lesions (p = 0.07) and achieved several secondary end points including a reduction of the rate of enhancing magnetic resonance imaging lesions from weeks 8 to 48 (p = 0.05). Immunological data in a preselected subgroup of patients also indicated that treatment with 0.5 mg induced antigen-specific immune tolerance. The greater dose was ineffective.
Assuntos
Esclerose Múltipla/diagnóstico , Esclerose Múltipla/tratamento farmacológico , Proteína Básica da Mielina/genética , Vacinas de DNA/administração & dosagem , Vacinas de DNA/efeitos adversos , Adolescente , Adulto , Feminino , Humanos , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Resultado do TratamentoRESUMO
OBJECTIVE: The efficacy and safety of ocrelizumab, versus interferon (IFN) ß-1a, for the treatment of relapsing multiple sclerosis (RMS) from the identically designed OPERA I (NCT01247324) and OPERA II (NCT01412333) phase III studies has been reported; here we present subgroup analyses of efficacy endpoints from the pooled OPERA I and OPERA II populations. METHODS: Patients with RMS were randomized to either ocrelizumab 600 mg administered by intravenous infusion every 24 weeks or subcutaneous IFN ß-1a 44 µg three times per week throughout the 96-week treatment period. Relapse, disability, and MRI outcomes were analyzed for predefined and post hoc subgroups based on demographic and disease characteristics along with prior treatment using appropriate statistical tests to determine the treatment effect in subgroups and treatment-by-subgroup interactions. RESULTS: The significant treatment benefit of ocrelizumab, versus IFN ß-1a, observed in the overall OPERA I and OPERA II pooled populations was maintained across most subgroup strata for all endpoints, including annualized relapse rate, disability progression, and MRI outputs. CONCLUSIONS: The treatment effect of ocrelizumab versus IFN ß-1a, measured by clinical and MRI outcomes, was maintained across most of the subgroups and strata of interest, and the pattern of treatment benefit across all subgroups was consistent with that from the pooled OPERA studies.
Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Fatores Imunológicos/uso terapêutico , Esclerose Múltipla Recidivante-Remitente/classificação , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Adolescente , Adulto , Avaliação da Deficiência , Método Duplo-Cego , Vias de Administração de Medicamentos , Feminino , Gadolínio/efeitos adversos , Humanos , Processamento de Imagem Assistida por Computador , Interferon beta/uso terapêutico , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla Recidivante-Remitente/diagnóstico por imagem , Fatores Sexuais , Adulto JovemRESUMO
BACKGROUND: Magnetic resonance spectroscopy quantitatively monitors biomarkers of neuron-myelin coupling (N-acetylaspartate (NAA)), and inflammation (total creatine (tCr), total choline (tCho), myo-inositol (mI)) in the brain. OBJECTIVE: This study aims to investigate how ocrelizumab and interferon beta-1a differentially affects imaging biomarkers of neuronal-myelin coupling and inflammation in patients with relapsing multiple sclerosis (MS). METHODS: Forty patients with relapsing MS randomized to either treatment were scanned at 3T at baseline and weeks 24, 48, and 96 follow-up. Twenty-four healthy controls were scanned at weeks 0, 48, and 96. NAA, tCr, tCho, mI, and NAA/tCr were measured in a single large supra-ventricular voxel. RESULTS: There was a time × treatment interaction in NAA/tCr (p = 0.04), primarily driven by opposing tCr trends between treatment groups after 48 weeks of treatment. Patients treated with ocrelizumab showed a possible decline in mI after week 48 week, and stable tCr and tCho levels. Conversely, the interferon beta-1a treated group showed possible increases in mI, tCr, and tCho over 96 weeks. CONCLUSIONS: Results from this exploratory study suggest that over 2 years, ocrelizumab reduces gliosis compared with interferon beta-1a, demonstrated by declining ml, and stable tCr and tCho. Ocrelizumab may improve the physiologic milieu by decreasing neurotoxic factors that are generated by inflammatory processes.
RESUMO
BACKGROUND: Progressive solitary sclerosis is a unifocal demyelinating disease recently proposed as a possible multiple sclerosis variant. OBJECTIVE: To compare myelin content and brain metabolite ratio qualitatively in the normal-appearing white matter of progressive solitary sclerosis cases compared to multiple sclerosis and healthy control participants. METHODS: Case report. RESULTS: Progressive solitary sclerosis cases showed abnormal myelin in normal-appearing white matter tracts and global normal-appearing white matter as well as lower N-acetyl-aspartate to total creatine ratio compared to multiple sclerosis and healthy control groups. CONCLUSION: Despite a single demyelinating lesion along the corticospinal tract in progressive solitary sclerosis, we showed evidence of more extensive abnormality within the normal-appearing white matter.
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BACKGROUND: No evidence of disease activity (NEDA; defined as no 12-week confirmed disability progression, no protocol-defined relapses, no new/enlarging T2 lesions and no T1 gadolinium-enhancing lesions) using a fixed-study entry baseline is commonly used as a treatment outcome in multiple sclerosis (MS). OBJECTIVE: The objective of this paper is to assess the effect of ocrelizumab on NEDA using re-baselining analysis, and the predictive value of NEDA status. METHODS: NEDA was assessed in a modified intent-to-treat population (n = 1520) from the pooled OPERA I and OPERA II studies over various epochs in patients with relapsing MS receiving ocrelizumab (600 mg) or interferon beta-1a (IFN ß-1a; 44 µg). RESULTS: NEDA was increased with ocrelizumab vs IFN ß-1a over 96 weeks by 75% (p < 0.001), from Week 0â24 by 33% (p < 0.001) and from Week 24â96 by 72% (p < 0.001). Among patients with disease activity during Weeks 0â24, 66.4% vs 24.3% achieved NEDA during Weeks 24â96 in the ocrelizumab and IFN ß-1a groups (relative increase: 177%; p < 0.001). CONCLUSION: Superior efficacy with ocrelizumab compared with IFN ß-1a was consistently seen in maintaining NEDA status in all epochs evaluated. By contrast with IFN ß-1a, the majority of patients with disease activity early in the study subsequently attained NEDA status with ocrelizumab.
RESUMO
OBJECTIVE: To assess safety and immune modulation by BHT-3009, a tolerizing DNA vaccine encoding full-length human myelin basic protein, in patients with multiple sclerosis (MS). DESIGN: The study was a randomized, double-blind, placebo-controlled trial. Subjects receiving placebo were crossed over into an active arm after treatment unblinding. SETTING: The trial was conducted at 4 academic institutions within North America. Patients Thirty patients with relapsing-remitting or secondary progressive MS who were not taking any other disease-modifying drugs were enrolled in the trial. Further, the patients were required to have either 1 to 5 gadolinium-enhancing lesions on screening brain magnetic resonance imaging (MRI), a relapse in the previous 2 years, or disease worsening in the previous 2 years. INTERVENTIONS: BHT-3009 was administered as intramuscular injections at weeks 1, 3, 5, and 9 after randomization into the trial, with or without 80 mg of daily oral atorvastatin calcium in combination. Three dose levels of BHT-3009 were tested (0.5 mg, 1.5 mg, and 3 mg). MAIN OUTCOME MEASURES: The primary outcome measures were safety and tolerability of BHT-3009. Secondary outcome measures included the number and volume of gadolinium-enhanced lesions on MRI, relapses, and analysis of antigen-specific immune responses. RESULTS: BHT-3009 was safe and well tolerated, provided favorable trends on brain MRI, and produced beneficial antigen-specific immune changes. These immune changes consisted of a marked decrease in proliferation of interferon-gamma-producing, myelin-reactive CD4+ T cells from peripheral blood and a reduction in titers of myelin-specific autoantibodies from cerebral spinal fluid as assessed by protein microarrays. We did not observe a substantial benefit of the atorvastatin combination compared with BHT-3009 alone. CONCLUSION: In patients with MS, BHT-3009 is safe and induces antigen-specific immune tolerance with concordant reduction of inflammatory lesions on brain MRI.
Assuntos
Tolerância Imunológica/imunologia , Esclerose Múltipla/imunologia , Esclerose Múltipla/prevenção & controle , Proteína Básica da Mielina/imunologia , Vacinas de DNA/uso terapêutico , Adulto , Atorvastatina , Avaliação da Deficiência , Método Duplo-Cego , Determinação de Ponto Final , Feminino , Ácidos Heptanoicos/uso terapêutico , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Imunização , Injeções Intramusculares , Contagem de Linfócitos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla Recidivante-Remitente/imunologia , Esclerose Múltipla Recidivante-Remitente/prevenção & controle , Análise de Sequência com Séries de Oligonucleotídeos , Plasmídeos/genética , Plasmídeos/imunologia , Pirróis/uso terapêutico , Recidiva , Linfócitos T/imunologia , Vacinas de DNA/efeitos adversosRESUMO
The diversity of autoimmune responses poses a formidable challenge to the development of antigen-specific tolerizing therapy. We developed 'myelin proteome' microarrays to profile the evolution of autoantibody responses in experimental autoimmune encephalomyelitis (EAE), a model for multiple sclerosis (MS). Increased diversity of autoantibody responses in acute EAE predicted a more severe clinical course. Chronic EAE was associated with previously undescribed extensive intra- and intermolecular epitope spreading of autoreactive B-cell responses. Array analysis of autoantigens targeted in acute EAE was used to guide the choice of autoantigen cDNAs to be incorporated into expression plasmids so as to generate tolerizing vaccines. Tolerizing DNA vaccines encoding a greater number of array-determined myelin targets proved superior in treating established EAE and reduced epitope spreading of autoreactive B-cell responses. Proteomic monitoring of autoantibody responses provides a useful approach to monitor autoimmune disease and to develop and tailor disease- and patient-specific tolerizing DNA vaccines.
Assuntos
Encefalomielite Autoimune Experimental/tratamento farmacológico , Encefalomielite Autoimune Experimental/imunologia , Imunoensaio/métodos , Bainha de Mielina/imunologia , Análise Serial de Proteínas/métodos , Vacinas de DNA/imunologia , Vacinas de DNA/uso terapêutico , Animais , Tolerância a Medicamentos , Encefalomielite Autoimune Experimental/diagnóstico , Camundongos , Esclerose Múltipla/diagnóstico , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/imunologia , Mapeamento de Interação de Proteínas/métodos , Resultado do TratamentoRESUMO
The objective of this study was to assess the effect of secukinumab, a monoclonal antibody that inhibits interleukin (IL)-17A, on number of new active brain magnetic resonance imaging (MRI) lesions in subjects with relapsing-remitting multiple sclerosis (MS). Subjects (N = 73) were randomized 1:1 to secukinumab 10 mg/kg or placebo by intravenous infusion at weeks 0, 2, 4, 8, 12, 16, and 20. MRI scans were obtained within 30 days prior to randomization, on a monthly basis during the treatment period, and at study completion. The primary endpoint was the cumulative number of combined unique active lesions (CUAL) observed on brain MRI scans from week 4 to week 24. Compared with placebo, secukinumab non-significantly reduced the number of CUAL observed on 4-weekly MRI from week 4 to 24 (primary endpoint) by 49 % (95 % CI -10 to 77 %; P = 0.087) and significantly reduced the number of cumulative new gadolinium-enhancing T1 lesions by 67 % (31-84 %, P = 0.003). CUAL reductions were progressively greater from week 4 (1 %) to week 16 (49 %) and persisted until end-study (50 %). There were no serious adverse events; the adverse event rate was comparable to placebo (53 versus 49 %), although mild-to-moderate infection was somewhat more frequent (37 versus 23 %). This proof-of-concept study provides the first evidence that blocking IL-17A with an antibody may reduce MRI lesion activity in MS. Further studies are needed to confirm this finding and determine the magnitude of effect.
Assuntos
Anticorpos Monoclonais/efeitos adversos , Encéfalo/efeitos dos fármacos , Fatores Imunológicos/efeitos adversos , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Administração Intravenosa , Adolescente , Adulto , Anticorpos Monoclonais Humanizados , Encéfalo/diagnóstico por imagem , Avaliação da Deficiência , Método Duplo-Cego , Feminino , Seguimentos , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Resultado do Tratamento , Adulto JovemRESUMO
Multiple sclerosis (MS) is a complex immune-mediated disease resulting largely from an autoimmune attack against components of central nervous system myelin, including several proteins and lipids. Knowledge about the details of this anomalous immune response has come mostly from studies in the animal model experimental autoimmune encephalomyelitis (EAE). In this model, it has been possible to prevent and effectively treat established disease through several antigen-specific therapeutic strategies, which have included administration of whole myelin or myelin proteins by various routes, random copolymers consisting of the main major histocompatability complex (MHC) and T-cell receptor (TCR) contact amino acid residues, altered peptide ligands of dominant myelin epitopes in which one or more residues are selectively substituted, and lately DNA vaccination encoding self-myelin antigens. However, there have been difficulties in making successful transitions from animal models to human clinical trials, due either to lack of efficacy or unforeseen complications. Despite these problems, antigen-specific therapies have retained their attraction for clinicians and scientists alike, and hopefully the upcoming generation of agents--including altered peptide ligands and DNA vaccines--will benefit from the increasing knowledge about this disease and surmount existing difficulties to make an impact in the treatment of multiple sclerosis.
Assuntos
Autoantígenos/imunologia , Imunoterapia/métodos , Esclerose Múltipla/terapia , Animais , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/prevenção & controle , Encefalomielite Autoimune Experimental/terapia , Acetato de Glatiramer , Humanos , Terapia de Imunossupressão/métodos , Imunossupressores/imunologia , Imunossupressores/uso terapêutico , Modelos Imunológicos , Esclerose Múltipla/imunologia , Proteína Básica da Mielina/administração & dosagem , Proteína Básica da Mielina/imunologia , Proteína Básica da Mielina/uso terapêutico , Fragmentos de Peptídeos/administração & dosagem , Fragmentos de Peptídeos/imunologia , Fragmentos de Peptídeos/uso terapêutico , Peptídeos/imunologia , Peptídeos/uso terapêutico , Vacinas de DNA/imunologia , Vacinas de DNA/uso terapêuticoRESUMO
A recent type 1 diabetes (T1D) clinical trial of rituximab (a B cell-depleting anti-CD20 antibody) achieved some therapeutic benefit in preserving C-peptide for a period of approximately nine months in patients with recently diagnosed diabetes. Our previous data in the NOD mouse demonstrated that co-administration of antigen (insulin) with anti-CD3 antibody (a T cell-directed immunomodulator) offers better protection than either entity alone, indicating that novel combination therapies that include a T1D-related autoantigen are possible. To accelerate the identification and development of novel combination therapies that can be advanced into the clinic, we have evaluated the combination of a mouse anti-CD20 antibody with either oral insulin or a proinsulin-expressing DNA vaccine. Anti-CD20 alone, given once or on 4 consecutive days, produced transient B cell depletion but did not prevent or reverse T1D in the NOD mouse. Oral insulin alone (twice weekly for 6 weeks) was also ineffective, while proinsulin DNA (weekly for up to 12 weeks) showed a trend toward modest efficacy. Combination of anti-CD20 with oral insulin was ineffective in reversing diabetes in NOD mice whose glycemia was controlled with SC insulin pellets; these experiments were performed in three independent labs. Combination of anti-CD20 with proinsulin DNA was also ineffective in diabetes reversal, but did show modest efficacy in diabetes prevention (p = 0.04). In the prevention studies, anti-CD20 plus proinsulin resulted in modest increases in Tregs in pancreatic lymph nodes and elevated levels of proinsulin-specific CD4+ T-cells that produced IL-4. Thus, combination therapy with anti-CD20 and either oral insulin or proinsulin does not protect hyperglycemic NOD mice, but the combination with proinsulin offers limited efficacy in T1D prevention, potentially by augmentation of proinsulin-specific IL-4 production.
Assuntos
Anticorpos Monoclonais/farmacologia , Antígenos CD20/imunologia , Linfócitos B/efeitos dos fármacos , Insulina/administração & dosagem , Proinsulina/administração & dosagem , Proinsulina/genética , Vacinas de DNA/administração & dosagem , Administração Oral , Animais , Anticorpos Monoclonais/imunologia , Linfócitos B/citologia , Linfócitos B/imunologia , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/imunologia , Diabetes Mellitus Tipo 1/tratamento farmacológico , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/imunologia , Quimioterapia Combinada/métodos , Feminino , Hiperglicemia/tratamento farmacológico , Hiperglicemia/imunologia , Insulina/genética , Insulina/imunologia , Interleucina-4/imunologia , Linfonodos/efeitos dos fármacos , Linfonodos/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Pâncreas/efeitos dos fármacos , Pâncreas/imunologia , Proinsulina/imunologia , Baço/efeitos dos fármacos , Baço/imunologia , Vacinas de DNA/genética , Vacinas de DNA/imunologiaRESUMO
In type 1 diabetes (T1D), there is an intense inflammatory response that destroys the ß cells in the pancreatic islets of Langerhans, the site where insulin is produced and released. A therapy for T1D that targets the specific autoimmune response in this disease while leaving the remainder of the immune system intact, has long been sought. Proinsulin is a major target of the adaptive immune response in T1D. We hypothesized that an engineered DNA plasmid encoding proinsulin (BHT-3021) would preserve ß cell function in T1D patients through reduction of insulin-specific CD8⺠T cells. We studied 80 subjects over 18 years of age who were diagnosed with T1D within the past 5 years. Subjects were randomized 2:1 to receive intramuscular injections of BHT-3021 or BHT-placebo, weekly for 12 weeks, and then monitored for safety and immune responses in a blinded fashion. Four dose levels of BHT-3021 were evaluated: 0.3, 1.0, 3.0, and 6.0 mg. C-peptide was used both as an exploratory efficacy measure and as a safety measure. Islet-specific CD8⺠T cell frequencies were assessed with multimers of monomeric human leukocyte antigen class I molecules loaded with peptides from pancreatic and unrelated antigens. No serious adverse events related to BHT-3021 were observed. C-peptide levels improved relative to placebo at all doses, at 1 mg at the 15-week time point (+19.5% BHT-3021 versus -8.8% BHT-placebo, P < 0.026). Proinsulin-reactive CD8⺠T cells, but not T cells against unrelated islet or foreign molecules, declined in the BHT-3021 arm (P < 0.006). No significant changes were noted in interferon-γ, interleukin-4 (IL-4), or IL-10 production in CD4 T cells. Thus, we demonstrate that a plasmid encoding proinsulin reduces the frequency of CD8⺠T cells reactive to proinsulin while preserving C-peptide over the course of dosing.
Assuntos
Peptídeo C/metabolismo , Linfócitos T CD8-Positivos/microbiologia , Diabetes Mellitus Tipo 1/imunologia , Diabetes Mellitus Tipo 1/terapia , Plasmídeos/genética , Proinsulina/metabolismo , Adulto , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Masculino , Proinsulina/genéticaRESUMO
Persistent black holes (PBH) are associated with axonal loss and disability progression in multiple sclerosis (MS). The objective of this work was to determine if BHT-3009, a DNA plasmid-encoding myelin basic protein (MBP), reduces the risk of new lesions becoming PBH, compared to placebo, and to test if pre-treatment serum anti-MBP antibody levels impact on the effect of BHT-3009 treatment. In this retrospective, blinded MRI study, we reviewed MRI scans of 155 MS patients from a double-blind, randomized, phase II trial with three treatment arms (placebo, 0.5 and 1.5 mg BHT-3009). New lesions at weeks 8 and 16 were tracked at week 48 and those appearing as T1-hypointense were classified as PBH. A subset of 46 patients with available pre-treatment serum anti-MBP IgM levels were analyzed separately. Overall, there was no impact of treatment on the risk for PBH. However, there was a significant interaction between anti-MBP antibodies and treatment effect: patients receiving 0.5 mg BHT-3009 showed a reduced risk of PBH with higher antibody levels compared to placebo (p < 0.01). Although we found no overall reduction of the risk for PBH in treated patients, there may be an effect of low-dose BHT-3009, depending on the patients' pre-treatment immune responses.