RESUMEN
Inflammatory disorders of the peripheral nervous system (PNS) and central nervous system (CNS) are common, and contribute substantially to physical and emotional disability of affected individuals. Often, the afflicted are young and in their active years. In the past, physicians and scientists often had very little to offer in terms of diagnostic precision and therapeutic effectiveness. During the past two decades, both of these relative shortcomings have clearly improved. Some of the recent developments in clinical neuroimmunology are illustrated in this special edition of Clinical and Experimental Immunology.
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Enfermedades del Sistema Nervioso Central , Inflamación , Enfermedades del Sistema Nervioso Periférico , Enfermedades del Sistema Nervioso Central/diagnóstico , Enfermedades del Sistema Nervioso Central/tratamiento farmacológico , Enfermedades del Sistema Nervioso Central/etiología , Humanos , Inflamación/diagnóstico , Inflamación/tratamiento farmacológico , Inflamación/etiología , Enfermedades del Sistema Nervioso Periférico/diagnóstico , Enfermedades del Sistema Nervioso Periférico/tratamiento farmacológico , Enfermedades del Sistema Nervioso Periférico/etiologíaRESUMEN
Monoclonal antibodies (mAbs) are used as therapeutics in a number of disciplines in medicine, such as oncology, rheumatology, gastroenterology, dermatology and transplant rejection prevention. Since the introduction and reintroduction of the anti-alpha4-integrin mAb natalizumab in 2004 and 2006, mAbs have gained relevance in the treatment of multiple sclerosis (MS). At present, numerous mAbs have been tested in clinical trials in relapsing-remitting MS, and in progressive forms of MS. One of the agents that might soon be approved for very active forms of relapsing-remitting MS is alemtuzumab, a humanized mAb against CD52. This review provides insights into clinical studies with the mAbs natalizumab, alemtuzumab, daclizumab, rituximab, ocrelizumab and ofatumumab.
Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Factores Inmunológicos/uso terapéutico , Esclerosis Múltiple/tratamiento farmacológico , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/efectos adversos , Humanos , Factores Inmunológicos/administración & dosificación , Factores Inmunológicos/efectos adversosRESUMEN
During the last two decades, treatment options for patients with multiple sclerosis (MS) have broadened tremendously. All agents that are currently approved for clinical use have potential side effects, and a careful risk-benefit evaluation is part of a decision algorithm to identify the optimal treatment choice for an individual patient. Whereas glatiramer acetate and interferon beta preparations have been used in MS for decades and have a proven safety record, more recently approved drugs appear to be more effective, but potential risks might be more severe. The potential complications of some novel therapies might not even have been identified to their full extent. This review is aimed at the clinical neurologist in that it offers insights into potential adverse events of each of the approved MS therapeutics: interferon beta, glatiramer acetate, mitoxantrone, natalizumab, fingolimod and teriflunomide, as well as recently approved therapeutics such as dimethyl fumarate and alemtuzumab. It also provides recommendations for monitoring the different drugs during therapy in order to avoid common side effects.
Asunto(s)
Factores Inmunológicos/uso terapéutico , Esclerosis Múltiple/tratamiento farmacológico , Femenino , Humanos , Factores Inmunológicos/efectos adversos , Masculino , EmbarazoRESUMEN
BACKGROUND AND PURPOSE: Multiple sclerosis (MS) patients discontinuing natalizumab are at risk of rebound of disease activity. METHODS: In the present multi-center, open-label, non-randomized, prospective, pilot study, we tested whether treatment with glatiramer acetate (GA) is safe and effective after natalizumab in MS patients. The study was performed at academic tertiary medical centers. Forty active relapsing-remitting MS patients who never failed GA therapy and who discontinued natalizumab after 12-18 months of therapy were enrolled. GA was initiated 4 weeks after the last dose of natalizumab. RESULTS: 62.5% of patients were relapse-free 12 months after GA initiation. Annualized relapse rate and time to relapse were significantly lower than before natalizumab. Notably, the frequency of relapses was significantly lower amongst those patients who had experienced ≤2 relapses the year before initiation of natalizumab therapy, compared with patients who had had three or more relapses. No evidence of rebound was observed in magnetic resonance imaging scans. Furthermore, Expanded Disability Status Scale and Multiple Sclerosis Functional Composite were stable in our patients, again suggesting that 12 months of post-natalizumab-GA therapy is not associated with clinical deterioration. CONCLUSIONS: Following discontinuation of natalizumab, 12 months of therapy with GA is safe and well tolerated in MS patients. GA can reduce the risk of early reactivation/rebound of disease activity in this setting.
Asunto(s)
Inmunosupresores/uso terapéutico , Esclerosis Múltiple/tratamiento farmacológico , Péptidos/uso terapéutico , Adolescente , Adulto , Anticuerpos Monoclonales Humanizados/uso terapéutico , Corteza Cerebral/patología , Evaluación de la Discapacidad , Progresión de la Enfermedad , Femenino , Acetato de Glatiramer , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Natalizumab , Evaluación de Resultado en la Atención de Salud , Proyectos Piloto , Estudios Prospectivos , Recurrencia , Médula Espinal/patología , Estadísticas no Paramétricas , Factores de Tiempo , Adulto JovenRESUMEN
Interferon beta and glatiramer acetate are still considered to be the first-line therapeutics for treatment of relapsing forms of multiple sclerosis (MS). The use of new compounds, such as natalizumab or fingolimod, is restricted to severe forms of relapsing MS or cases refractory to first-line treatment owing to substance-specific risk-benefit considerations. Teriflunomide is a new compound which has recently been approved as a first-line treatment of relapsing forms of MS in the USA and Australia. It is characterized by a once daily oral administration and a comparably well-established long-term safety profile. The main therapeutic effect is considered to be mediated via the inhibition of the de novo synthesis of pyrimidine in proliferating immune cells. The pro-drug of teriflunomide, leflunomide, has a label for treating rheumatoid arthritis (RA) for many years. Two recently published phase III clinical trials (TEMSO, TOWER) tested teriflunomide in patients with relapsing forms of MS and efficacy was demonstrated, with positive effects on relapse rates and disease progression using 14 mg/day. Overall, the safety profile in these studies was favorable as expected from experiences with leflunomide in RA. In patients treated with teriflunomide regular monitoring of blood cell counts and liver enzymes is required. Teriflunomide must not be used during pregnancy. In this article the recent phase II and phase III clinical trial data are reviewed and the potential of teriflunomide for the treatment of relapsing forms of MS is discussed.
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Crotonatos/administración & dosificación , Crotonatos/efectos adversos , Medicina Basada en la Evidencia , Esclerosis Múltiple/diagnóstico , Esclerosis Múltiple/tratamiento farmacológico , Toluidinas/administración & dosificación , Toluidinas/efectos adversos , Fármacos del Sistema Nervioso Central/administración & dosificación , Fármacos del Sistema Nervioso Central/efectos adversos , Relación Dosis-Respuesta a Droga , Humanos , Hidroxibutiratos , Nitrilos , Resultado del TratamientoAsunto(s)
Encéfalo/patología , Enfermedades Desmielinizantes/inducido químicamente , Enfermedades Desmielinizantes/diagnóstico por imagen , Preparaciones de Plantas/efectos adversos , Adulto , Enfermedades Desmielinizantes/terapia , Disartria/etiología , Parálisis Facial/etiología , Humanos , Imagen por Resonancia Magnética , Espectroscopía de Resonancia Magnética , Masculino , Fitoterapia , Preparaciones de Plantas/administración & dosificación , PlasmaféresisRESUMEN
BACKGROUND: Memantine, an NMDA antagonist, is effective for moderate to severe Alzheimer's disease. OBJECTIVE: Determine whether memantine improves cognitive performance (CP) among subjects with multiple sclerosis (MS) and cognitive impairment (CI). METHODS: This double-blind, randomized, placebo-controlled trial (Clinicaltrials.gov NCT00300716) compared memantine 10 mg twice a day (4 week titration followed by 12 weeks on the highest tolerated dose) with placebo. The primary outcome was the change from baseline to exit on the Paced Auditory Serial Addition Test (PASAT) and the California Verbal Learning Test-II (CVLT-II) Long Delay Free Recall (LDFR). Secondary outcomes included additional neuropsychological tests; self-report measures of quality of life, fatigue, and depression; and family/caregiver reports of subjects' CI and neuropsychiatric symptoms. RESULTS: The differences between the groups on the change on the PASAT (placebo-memantine = 0.0 correct responses, 95% CI 3.4, 3.4; p = 0.9) and on CVLT-II LDFR (placebo-memantine =-0.6 words, 95% CI -2.1, 0.8; p = 0.4) as well as on the other cognitive tests were not significant. Subjects on memantine had no serious adverse events (AEs) but had more fatigue and neurological AEs as well as, per family members' reports, less cognitive improvement and greater neuropsychiatric symptoms than subjects on placebo. CONCLUSION: Memantine 10 mg twice a day does not improve CP in subjects with MS, ages 18-65, without major depression, who have subjective cognitive complaints and perform worse than one SD below the mean on the PASAT or on the California Verbal Learning Test-II (total recall or delayed free recall).
Asunto(s)
Trastornos del Conocimiento/tratamiento farmacológico , Memantina/uso terapéutico , Esclerosis Múltiple/complicaciones , Adolescente , Adulto , Anciano , Trastornos del Conocimiento/complicaciones , Trastornos del Conocimiento/psicología , Depresión/psicología , Método Doble Ciego , Fatiga/psicología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Esclerosis Múltiple/psicología , Pruebas Neuropsicológicas , Selección de Paciente , Calidad de Vida/psicología , Encuestas y Cuestionarios , Resultado del TratamientoRESUMEN
With the generation of monoclonal antibodies (mAbs), a new therapeutical concept has gained importance. MAbs aim against selective antigens and so have changed our treatment strategies from non-specific to specific. Four therapeuticals have gained importance in the therapy of multiple sclerosis (MS): One has already been approved for therapy (natalizumab), whereas the other three are either in clinical trials or are about to enter phase III studies. Currently, two phase III studies that evaluate the efficacy of alemtuzumab have begun with recruitment (MS CARE I and II). Another mAb (daclizumab) under study is directed to the interleukin-2alpha chain (CD25). Results of clinical trials are promising by reporting reduction of relapses and progression in relapsing remitting and secondary progressive MS accompanied by reduction of new lesions in magnetic resonance imaging. A multicenter randomized controlled trial of daclizumab in MS is going to be initiated. Trials with a humanised antibody directed against the cell surface molecule CD20 are under development. Although the future will emphasise this trend to mAbs, the risks should not be ignored as has been shown in recent news. Still, mAbs have the possibility to revolutionise therapeutical concepts in the treatment of immune-mediated diseases, and will therefore be a useful addition to current therapeutic concepts.
Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Factores Inmunológicos/uso terapéutico , Esclerosis Múltiple/terapia , Animales , Anticuerpos Monoclonales/química , Anticuerpos Monoclonales/farmacología , Ensayos Clínicos como Asunto , Humanos , Factores Inmunológicos/química , Factores Inmunológicos/clasificación , Factores Inmunológicos/farmacología , Esclerosis Múltiple/inmunologíaRESUMEN
The role of processing in antigen (Ag) presentation and T cell activation in experimental allergic encephalomyelitis (EAE) was evaluated in wild-type mice, mice that selectively express either Ii p31 or p41, and mice completely deficient in Ii or H-2M. We demonstrate that processing of myelin oligodendrocyte glycoprotein (MOG) is required for presentation of the dominant encephalitogenic MOG epitope, p35-55. Ii p31- and p41-expressing mice developed EAE with similar incidence to wild-type mice, although p41 mice had a more severe course. Ag-presenting cells (APCs) from Ii- or H-2M-deficient mice could present p35-55, but not MOG, demonstrating that these APCs could not process native MOG. Ii- and H-2M-deficient mice were not susceptible to EAE by immunization with p35-55 or MOG or by adoptive transfer of encephalitogenic T cells. However, CD4+ T cells from p35-55-immunized H-2M-deficient mice proliferated, secreted IFN-gamma, and transferred EAE to wild-type, but not H-2M-deficient, mice. Thus, EAE resistance in H-2M-deficient mice is not due to an inability of APCs to present p35-55, or an intrinsic defect in the encephalitogenic T cell repertoire, but reflects a defect in APC function. Our results indicate that processing is required for initial Ag presentation and CNS T cell activation and suggest that autopathogenic peptides of CNS autoantigen may not be readily available for presentation without processing.
Asunto(s)
Presentación de Antígeno , Encefalomielitis Autoinmune Experimental/inmunología , Animales , Antígenos de Diferenciación de Linfocitos B/genética , Antígenos de Diferenciación de Linfocitos B/metabolismo , Autoantígenos/metabolismo , Secuencia de Bases , ADN Complementario/genética , Encefalomielitis Autoinmune Experimental/genética , Encefalomielitis Autoinmune Experimental/metabolismo , Encefalomielitis Autoinmune Experimental/patología , Endocitosis/inmunología , Antígenos H-2/genética , Antígenos H-2/metabolismo , Antígenos de Histocompatibilidad Clase II/genética , Antígenos de Histocompatibilidad Clase II/metabolismo , Activación de Linfocitos , Ratones , Ratones Endogámicos C57BL , Ratones Mutantes , Proteínas de la Mielina , Glicoproteína Asociada a Mielina/inmunología , Glicoproteína Asociada a Mielina/metabolismo , Glicoproteína Mielina-Oligodendrócito , ARN Mensajero/genética , ARN Mensajero/metabolismo , Linfocitos T/inmunologíaRESUMEN
Major advancements have been achieved in our ability to diagnose multiple sclerosis (MS) and to commence treatment intervention with agents that can favorably affect the disease course. Although MS exacerbations and the emergence of disability constitute the more conspicuous aspects of the disease process, evidence has confirmed that most of the disease occurs on a constitutive and occult basis. Disease-modifying therapies appear to be modest in the magnitude of their treatment effects, particularly in the progressive stage of the disease. Therapeutic strategies currently used for MS primarily target the inflammatory cascade. Several potential mechanisms appear to be involved in the progression of MS. Characterizing these mechanisms will result in a better understanding of the various forms of the disorder and how to effectively treat its clinical manifestations. It is our objective within this 2-part series on progression in MS to offer both evidence-based observations and hypothesis-driven expert perspectives on what constitutes the cause of progression in MS. We have chosen areas of inquiry that appear to have been most productive in helping us to better conceptualize the landscape of what MS looks like pathologically, immunologically, neuroscientifically, radiographically, and genetically. We have attempted to advance hypotheses focused on a deeper understanding of what contributes to the progression of this illness and to illustrate new technical capabilities that are catalyzing novel research initiatives targeted at achieving a more complete understanding of progression in MS.
Asunto(s)
Esclerosis Múltiple/inmunología , Esclerosis Múltiple/patología , Esclerosis Múltiple/fisiopatología , Progresión de la Enfermedad , Genética , Humanos , Sistema Inmunológico/fisiopatología , Modelos Biológicos , Esclerosis Múltiple/genética , NeurocienciasRESUMEN
3-Hydroxy-3-methyglutaryl coenzyme A (HMG-CoA) reductase inhibitors, "statins," are widely used oral cholesterol-lowering drugs. Statins competitively inhibit HMG-CoA reductase, the enzyme that catalyzes conversion of HMG-CoA to L-mevalonate, a key intermediate in cholesterol synthesis. Certain metabolites of L-mevalonate are also involved in posttranslational modifications of specific proteins with cell proliferation and differentiation properties. Thus, statins have important biologic effects beyond their cholesterol-reducing properties. Here we discuss recent experimental and clinical data that may support a potential role for statins in the treatment of three central nervous system (CNS) neurological diseases: Multiple sclerosis (MS), Alzheimer's disease (AD), and ischemic stroke. Despite their considerable pathogenic differences, in animal models of these disorders statins have shown beneficial effects. In both stroke and AD cohort studies suggest a beneficial treatment effect in humans; in MS, results from small open-label studies look encouraging. Multicenter, randomized, placebo-controlled clinical trials are in the planning or recruiting stage to evaluate the therapeutic effects of statins in all three disorders.
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Investigación Biomédica/tendencias , Encefalopatías/tratamiento farmacológico , Ensayos Clínicos como Asunto/tendencias , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Pautas de la Práctica en Medicina/tendencias , HumanosRESUMEN
Interferon beta (IFN-beta) has been shown in several clinical trials to have efficacy in MS. Its mechanism of action, however, remains unclear. In this review, several biological activities of IFN-beta are highlighted, including its inhibitory effects on proliferation of leukocytes and antigen presentation. Furthermore, IFN-beta may modulate the profile of cytokine production toward that of the anti-inflammatory phenotype, and this appears to occur in the systemic circulation and within the CNS. Finally, IFN-beta can reduce T-cell migration by inhibiting the activity of T-cell matrix metalloproteinases. These activities are likely to act in concert to account for the mechanism of IFN-beta in MS.
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Interferón beta/farmacología , Esclerosis Múltiple/terapia , Adyuvantes Inmunológicos/fisiología , Animales , Moléculas de Adhesión Celular/metabolismo , Sistema Nervioso Central/efectos de los fármacos , Sistema Nervioso Central/inmunología , Citocinas/efectos de los fármacos , Citocinas/fisiología , Humanos , Interferón beta/uso terapéutico , Leucocitos/efectos de los fármacos , Metaloendopeptidasas/efectos de los fármacos , Ratones , Esclerosis Múltiple/inmunología , Células TH1/efectos de los fármacos , Células Th2/efectos de los fármacosRESUMEN
Four of 10 patients who were enrolled on protocols of high-dose immunosuppression with peripheral blood stem cell rescue for MS experienced neurologic worsening while receiving recombinant human granulocyte colony-stimulating factor. There was improvement when methylprednisolone was given to three of the patients, but one patient died of respiratory failure. The mechanism of the neurologic worsening is uncertain.
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Factor Estimulante de Colonias de Granulocitos/efectos adversos , Esclerosis Múltiple/tratamiento farmacológico , Adulto , Antiinflamatorios/uso terapéutico , Femenino , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Humanos , Masculino , Metilprednisolona/uso terapéutico , Persona de Mediana Edad , Parálisis/inducido químicamente , Parálisis/tratamiento farmacológico , Proteínas RecombinantesRESUMEN
The increased migration of peripheral blood mononuclear cells (PBMNCs) across a fibronectin (FN) matrix in response to the chemokines RANTES, MIP-1 alpha and MCP-1 is antagonized by interferon-beta-1b (IFN beta-1b). MCP-1 treatment of PBMNCs elevates their mRNA level and secretion of a matrix degrading enzyme, matrix metalloproteinase (MMP)-9, which is abrogated by IFN beta-1b. The clinical benefits of IFN beta-1b treatment in multiple sclerosis patients may in part be a result of this drug's ability to decrease the migration of PBMNCs in spite of a chemotactic gradient. Furthermore, the elevation of MMP-9 production by PBMNCs may be an important mechanism of action of chemokines.
Asunto(s)
Inhibición de Migración Celular , Quimiocinas/farmacología , Interferón beta/farmacología , Leucocitos Mononucleares/inmunología , Inhibidores de la Metaloproteinasa de la Matriz , Movimiento Celular/efectos de los fármacos , Movimiento Celular/inmunología , Separación Celular , Quimiocina CCL2/antagonistas & inhibidores , Quimiocina CCL2/farmacología , Quimiocina CCL4 , Quimiocina CCL5/antagonistas & inhibidores , Quimiocina CCL5/farmacología , Quimiocinas/antagonistas & inhibidores , Colagenasas/genética , Colagenasas/metabolismo , Humanos , Interferón beta-1a , Interferon beta-1b , Leucocitos Mononucleares/enzimología , Leucocitos Mononucleares/metabolismo , Proteínas Inflamatorias de Macrófagos/antagonistas & inhibidores , Proteínas Inflamatorias de Macrófagos/farmacología , Metaloproteinasa 9 de la Matriz , ARN Mensajero/antagonistas & inhibidores , ARN Mensajero/biosíntesisRESUMEN
OBJECTIVE: To test efficacy and safety of atorvastatin in subjects with clinically isolated syndrome (CIS). METHODS: Subjects with CIS were enrolled in a phase II, double-blind, placebo-controlled, 14-center randomized trial testing 80 mg atorvastatin on clinical and brain MRI activity. Brain MRIs were performed quarterly. The primary endpoint (PEP) was development of ≥ 3 new T2 lesions, or one clinical relapse within 12 months. Subjects meeting the PEP were offered additional weekly interferon ß-1a (IFNß-1a). RESULTS: Due to slow recruitment, enrollment was discontinued after 81 of 152 planned subjects with CIS were randomized and initiated study drug. Median (interquartile range) numbers of T2 and gadolinium-enhancing (Gd) lesions were 15.0 (22.0) and 0.0 (0.0) at baseline. A total of 53.1% of atorvastatin recipients (n = 26/49) met PEP compared to 56.3% of placebo recipients (n = 18/32) (p = 0.82). Eleven atorvastatin subjects (22.4%) and 7 placebo subjects (21.9%) met the PEP by clinical criteria. Proportion of subjects who did not develop new T2 lesions up to month 12 or to starting IFNß-1a was 55.3% in the atorvastatin and 27.6% in the placebo group (p = 0.03). Likelihood of remaining free of new T2 lesions was significantly greater in the atorvastatin group compared with placebo (odds ratio [OR] = 4.34, p = 0.01). Likelihood of remaining free of Gd lesions tended to be higher in the atorvastatin group (OR = 2.72, p = 0.11). Overall, atorvastatin was well tolerated. No clear antagonistic effect of atorvastatin plus IFNß-1a was observed on MRI measures. CONCLUSION: Atorvastatin treatment significantly decreased development of new brain MRI T2 lesion activity, although it did not achieve the composite clinical and imaging PEP. CLASSIFICATION OF EVIDENCE: This study provided Class II evidence that atorvastatin did not reduce the proportion of patients with CIS meeting imaging and clinical criteria for starting immunomodulating therapy after 12 months, compared to placebo. In an analysis of a secondary endpoint (Class III), atorvastatin was associated with a reduced risk for developing new T2 lesions.
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Anticolesterolemiantes/uso terapéutico , Encéfalo/efectos de los fármacos , Encéfalo/patología , Ácidos Heptanoicos/uso terapéutico , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Imagen por Resonancia Magnética , Pirroles/uso terapéutico , Adulto , Anticolesterolemiantes/administración & dosificación , Anticolesterolemiantes/efectos adversos , Atorvastatina , Canadá , Factores de Confusión Epidemiológicos , Medios de Contraste , Método Doble Ciego , Femenino , Gadolinio , Ácidos Heptanoicos/administración & dosificación , Ácidos Heptanoicos/efectos adversos , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/administración & dosificación , Inhibidores de Hidroximetilglutaril-CoA Reductasas/efectos adversos , Interferón beta-1a , Interferón beta/uso terapéutico , Imagen por Resonancia Magnética/métodos , Masculino , Persona de Mediana Edad , Oportunidad Relativa , Pirroles/administración & dosificación , Pirroles/efectos adversos , Proyectos de Investigación , Síndrome , Resultado del Tratamiento , Estados UnidosAsunto(s)
Enfermedades Desmielinizantes/diagnóstico , Enfermedades Desmielinizantes/tratamiento farmacológico , Inmunosupresores/uso terapéutico , Esclerosis Múltiple/diagnóstico , Esclerosis Múltiple/tratamiento farmacológico , Selección de Paciente , Protocolos Clínicos , Diagnóstico Precoz , Humanos , Inmunosupresores/efectos adversos , Imagen por Resonancia Magnética/normas , Valor Predictivo de las Pruebas , Pronóstico , Ensayos Clínicos Controlados Aleatorios como Asunto/normas , Factores de Tiempo , Resultado del TratamientoRESUMEN
OBJECTIVE: Natalizumab is a humanized recombinant monoclonal antibody against very late activation antigen-4 approved for the treatment of patients with multiple sclerosis (MS). A phase II study failed to demonstrate a difference between natalizumab treatment groups and the placebo group with regard to gadolinium enhancing lesions on MRI 3 months after discontinuation of therapy. The objective of this study was to assess clinical MS disease activity, surrogate disease markers on MRI, immunologic parameters in peripheral blood and CSF, as well as safety in patients with MS after discontinuation of natalizumab therapy. METHODS: This study is a longitudinal and serial cross-sectional assessment, in which 23 patients who were treated with natalizumab in the context of two phase III clinical trials were originally enrolled. A subgroup of patients was followed over 14 months. The annual relapse rate, neurologic disease progression assessed by the Expanded Disability Status Scale, disease surrogate markers on MRI, cellular and humoral immune markers in peripheral blood and CSF, and adverse events of the drug were monitored. RESULTS: With regard to clinical disease activity, neuroimaging, and immune responses, the majority of patients in our cohort were stable. Decreased lymphocyte cell numbers and altered cell ratios returned to normal 14 months after cessation of natalizumab. No infectious complications were observed. CONCLUSION: This is the first long-term follow-up of patients who discontinued natalizumab. We did not observe a clinical, radiographic, or immunologic rebound phenomenon after discontinuation of natalizumab therapy.
Asunto(s)
Anticuerpos Monoclonales/efectos adversos , Sistema Nervioso Central/efectos de los fármacos , Esclerosis Múltiple/tratamiento farmacológico , Adulto , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales Humanizados , Biomarcadores/sangre , Biomarcadores/líquido cefalorraquídeo , Sistema Nervioso Central/inmunología , Sistema Nervioso Central/patología , Estudios Transversales , Evaluación de la Discapacidad , Progresión de la Enfermedad , Femenino , Humanos , Inmunosupresores/administración & dosificación , Inmunosupresores/efectos adversos , Estudios Longitudinales , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Esclerosis Múltiple/inmunología , Esclerosis Múltiple/patología , Natalizumab , Evaluación de Resultado en la Atención de Salud/métodos , Recurrencia , Índice de Severidad de la Enfermedad , Resultado del TratamientoRESUMEN
OBJECTIVE: The goal of this investigation was to demonstrate that internuclear ophthalmoparesis (INO) can be utilized to model the effects of body temperature-induced changes on the fidelity of axonal conduction in multiple sclerosis (Uhthoff's phenomenon). METHODS: Ocular motor function was measured using infrared oculography at 10-minute intervals in patients with multiple sclerosis (MS) with INO (MS-INO; n = 8), patients with MS without INO (MS-CON; n = 8), and matched healthy controls (CON; n = 8) at normothermic baseline, during whole-body heating (increase in core temperature 0.8 degrees C as measured by an ingestible temperature probe and transabdominal telemetry), and after whole-body cooling. The versional disconjugacy index (velocity-VDI), the ratio of abducting/adducting eye movements for velocity, was calculated to assess changes in interocular disconjugacy. The first pass amplitude (FPA), the position of the adducting eye when the abducting eye achieves a centrifugal fixation target, was also computed. RESULTS: Velocity-VDI and FPA in MS-INO patients was elevated (p < 0.001) following whole body heating with respect to baseline measures, confirming a compromise in axonal electrical impulse transmission properties. Velocity-VDI and FPA in MS-INO patients was then restored to baseline values following whole-body cooling, confirming the reversible and stereotyped nature of this characteristic feature of demyelination. CONCLUSIONS: We have developed a neurophysiologic model for objectively understanding temperature-related reversible changes in axonal conduction in multiple sclerosis. Our observations corroborate the hypothesis that changes in core body temperature (heating and cooling) are associated with stereotypic decay and restoration in axonal conduction mechanisms.
Asunto(s)
Temperatura Corporal/fisiología , Tronco Encefálico/fisiopatología , Modelos Neurológicos , Esclerosis Múltiple/fisiopatología , Conducción Nerviosa/fisiología , Trastornos de la Motilidad Ocular/fisiopatología , Potenciales de Acción/fisiología , Axones/patología , Tronco Encefálico/patología , Fiebre/complicaciones , Fiebre/fisiopatología , Humanos , Hipertermia Inducida , Hipotermia Inducida , Esclerosis Múltiple/complicaciones , Fibras Nerviosas Mielínicas/patología , Vías Nerviosas/patología , Vías Nerviosas/fisiopatología , Trastornos de la Motilidad Ocular/etiología , Músculos Oculomotores/inervación , Músculos Oculomotores/fisiopatología , Puente/patología , Puente/fisiopatología , Valores de Referencia , Movimientos Sacádicos/fisiologíaRESUMEN
Disease-modifying agents (DMAs), including interferon beta (IFNbeta) and glatiramer acetate (GA), are the mainstays of long-term treatment of multiple sclerosis (MS). Other potent anti-inflammatory agents like natalizumab and different types of chemotherapeutics are increasingly being used for treatment of MS, particularly in patients with breakthrough disease activity. Brain volume (BV) loss occurs early in the disease process, accelerates over time, and may be only partially affected by DMA therapy. Low-dose, low frequency IFNbeta administered once weekly and GA appear to partially reduce BV decline over the second and third years of treatment. High dose, high frequency IFNbeta demonstrated no clear effect on BV loss during this time period. Current evidence suggests that changes in BV after immunoablation may not be due entirely to the resolution of edema but may be related to potential chemotoxicity of high dose cyclophosphamide. Natalizumab reduces the development of BV decline in the second and third years of treatment. IV immunoglobulin showed a positive effect on decelerating BV reduction in relapsing and advanced stages of MS. These differences between DMAs may be explained by the extent of their therapeutic effects on inflammation and on the balance between inhibition or promotion of remyelination and neuronal repair in the CNS. We described the mechanisms of action by which DMAs induce accelerated, non-tissue-related BV loss (pseudoatrophy) in the short term but, in the long run, may still potentially lead to permanent BV decline. The effects of corticosteroid therapy on changes in BV in patients with MS help clarify the mechanisms through which potent anti-inflammatory treatments may prevent, stabilize, or induce BV loss.
Asunto(s)
Antiinflamatorios/efectos adversos , Encéfalo/patología , Esclerosis Múltiple/tratamiento farmacológico , Esclerosis Múltiple/patología , Corticoesteroides/efectos adversos , Alemtuzumab , Antiinflamatorios/farmacología , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales Humanizados , Anticuerpos Antineoplásicos/efectos adversos , Atrofia/inducido químicamente , Encéfalo/efectos de los fármacos , Cladribina/efectos adversos , Acetato de Glatiramer , Humanos , Inmunoglobulinas Intravenosas/efectos adversos , Interferón beta/efectos adversos , Natalizumab , Tamaño de los Órganos/efectos de los fármacos , Péptidos/efectos adversosRESUMEN
The biological role of the scrapie isoform of prion protein (PrP(Sc)) as an infectious agent in numerous human and non-human disorders of the central nervous system is well established. In contrast, and despite decades of intensive research, the physiological function of the endogenous cellular form of the prion protein (PrP(C)) remains elusive. In mammals, the ubiquitous expression of PrP(C) suggests biological functions other than its pathological role in propagating the accumulation of its misfolded isotype. Other functions that have been attributed to PrP(C) include signal transduction, synaptic transmission and protection against cell death through the apoptotic pathway. More recently, immunoregulatory properties of PrP(C) have been reported. We review accumulating in vitro and in vivo evidence regarding physiological functions of PrP(C).